Research ArticleA Thermochemical Parameters and TheoreticalStudy of the Chlorinated Compounds of Thiophene

Ibrahim A M Saraireh 1 Mohammednoor Altarawneh 23

Jibril Alhawarin1 and Mansour H Almatarneh45

1Department of Chemistry Al-Hussein Bin Talal University Marsquoan Jordan2Department of Chemical Engineering Al-Hussein Bin Talal University Marsquoan Jordan3School of Engineering and Information Technology Murdoch University 6150 WA Australia4Department of Chemistry University of Jordan Amman 11942 Jordan5Department of Chemistry Memorial University St Johnrsquos Newfoundland and Labrador Canada A1B 3X7

Correspondence should be addressed to Ibrahim A M Saraireh dribrahim9997gmailcom

Received 17 October 2018 Accepted 18 December 2018 Published 9 January 2019

Academic Editor Mariateresa Giustiniano

Copyright copy 2019 Ibrahim A M Saraireh et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

This contribution sets out to compute thermochemical and geometrical parameters of the complete series of chlorinated isomersof thiophene based on the accurate chemistry model of CBS-QB3 Herein we compute standard entropies standard enthalpiesof formation standard Gibbs free energies of formation and heat capacities Our calculated enthalpy values agree with availablelimited experimental values The DFT-based reactivity descriptors were used to elucidate the site selectivity for the chlorinationsequence of thiopheneThe relative preference for chlorination was found to be in accord with the thermodynamic stability trendsinferredbasedon theHscale CalculatedFukui indices predict a chlorination sequence to ensue as follows 2-chloro997888rarr 25-dichloro997888rarr 235-trichloro 997888rarr 2345-tetrachlorothiophene

1 Introduction

Thiophene (C4H4S) is a heterocyclic organic compoundwith a five-membered ring similar to cyclopentadiene withreplacement of a -CH2- group by sulfur atom [1] Thiopheneand its derivatives can be found in some natural resourcessuch as petroleum and coal and in several pharmacologicallyactive compounds [2] Thiophene has high potential forbioactivation which in some cases has been linked to toxicity[3] Medicinal chemistry approaches to minimize the bioac-tivation potential of thiophenes often include substitutionat the 120572-carbon position to provide a potential site formetabolism Such thiophene derivative that is often used inmedicinal chemistry is the 120572-chlorothiophene and there areseveral examples of marketed drugs containing this moietysuch as tioconazole lornoxicam and rivaroxaban [4]

Halothiophenes and their secondary products are inter-mediate compounds in the synthesis of drugs and plant

protection agents [5] Chlorothiophene isomers may beused in the synthesis of many important organic com-pounds [6ndash8] Experimentally nine isomers of chloroth-iophene could be produced by chlorination of thiophenein several methods [9] and all isomers were isolableMonochlorothiophene was formed in high percent duringsubstitution reaction of chlorine with thiophene Similarly[10] chlorination of 2-chlorothiophene yielded a dichloroth-iophene fraction composed of high percent of 25-dichlorothiophene and 23-dichlorothiophene 23- 24- and 34-dichlorothiophenes were formed largely by dehydrohalo-genation of 2345-tetrachlorothiolane and not by substi-tution 25-Dichlorothiophene was formed by substitutionOn the other hand 234-trichlorothiophene was preparedby low temperature chlorination and was formed largelyafter the chlorination by the action of alkali on 22345-pentachlorothiolane 235-Trichlorothiophene was preparedby high temperature chlonation and was formed both

HindawiHeteroatom ChemistryVolume 2019 Article ID 7680264 6 pageshttpsdoiorg10115520197680264

2 Heteroatom Chemistry

by the substitution of 25-dichlorothiophene and by thepyrolysis of pentachlorothiolane Tetrachlorothiophene wasformed both by substitution of 235-trichlorothiophene andby pyrolytic or alkaline dehydrohalogenation of 223455-hexachlorothiolane [11 12] 25-dichlorothiophene was usedin the preparation of chalcones compounds which havebeen evaluated for antimicrobial activity [13] The effects ofthe number and the position of the chlorine atoms on theproperties of the thiophene ring for the chlorothiopheneshave been studied theoretically by the CBS-QB3 compositemethod [14] It is well-established that this method per-forms very well in predicting thermochemistry in generalapplications pertinent to halogenated systems In previousstudies we have demonstrated the accuracy of the CBS-QB3 methodology against analogous experimental valuesand calculated parameters by CBS-QB3 in these studies spankinetics reaction rate constants [15] pka values [16] andbond dissociation enthalpies [17] The focus in this study ison acquiring standard entropies heat capacities enthalpyand the free energy barrier for the addition of Cl to thering-carbon sites at selected temperature for the optimizedstructures of chlorinated thiophene compounds which arecalculated

2 Computational Details

The Gaussian 09 [18] suite of programs carries out all struc-tural optimization and energy estimations for the completeseries of chlorinated congeners of thiophene at the compos-ite chemistry model of CBS-QB3 [19] CBS-QB3 performsstructural optimization and frequency calculations at theB3LYP6-311+G(dp) theoretical level This is followed byseveral subsequent single point energies at higher theoreticallevels including MP2 and CCSD(T) methodologies We haveshown in our previous studies that the CBS-QB3 methodperforms very well in estimating thermos-kinetics param-eters for general applications of halogenated hydrocarbons[17 20 21]The DMol3 software [22] was deployed to acquireFukui (1198911) [23] indices of electrophilic attack The values arethen used to underpin the preferred chlorination sequence ofthiophene

We compute standard Δ119891119866119900298(119892) via utilizing our calcu-lated standard entropies (Table 3) and the standard entropiesof elements (CHN andCl) in their standard state accordingto

Δ119891119866119900298 (119892) = Δ119891119867

119900298 (119892) minus 119879119878

119900298

minus 119879sum119878119900298 (elements)(1)

Calculating Gibbs free energies of formation in the aqueousphase Δ119891119866119900298(119886119902) requires estimation of the energy ofsolvation Δ119866119900119904119900119897V

Δ119891119866119900298 (119886119902) = Δ119891119866

119900298 (119892) + Δ119866

119900119904119900119897V (2)

Standard entropies and heat capacities are computed basedon vibrational frequencies and moments of inertia via theChemRate code [24]

3 Result and Discussion

31 The Optimized Geometries Optimized structures for allchlorinated isomers are presented in Figure 1 Change in theposition and the extent of chlorination exerts rather minimalchanges in the structural parameters when contrasted withanalogous values in the unsubstituted thiophene moleculeFor instance all C-C distances in the chlorinated isomers ofthiophene are within 0007 A Likewise all C-C-C and C-S-C angles in the chlorinated isomers of thiophene reside with002o of the corresponding angles of the thiophene molecule

32 Sequence of Chlorination Chlorination of thiopheneoccurs via electrophilic aromatic substitution (Scheme 1)These substitutions ensue by an initial electrophile additionfollowed by a hydrogen atom loss from the intermediateforming the aromatic ring

We have previously utilized Fukui 119891-1 indices forelectrophilic substitution to reproduce the experimentallyobserved halogenation patterns for chlorinated several aro-matic compounds [25] Herein we adapt the same approachto calculate the chlorination pattern of chlorinated com-pounds of thiophene

Calculated 119891-1 values in Figure 2 predict the chlorinationsequence as follows 2-chloro 997888rarr 25-dichloro 997888rarr 235-trichloro 997888rarr 2345-tetrachlorothiophene This sequenceof chlorination allows less repulsion between the chlorineatoms Experimentally chlorination of thiophene is preferredat the C-2 (120572-position) of the ring An explanation for the 120572-selectivity of this substitution reaction is apparent from themechanism in Scheme 1 The intermediate that is formed byelectrophile attack atC-2 is stabilized by charge delocalizationto a greater degree than the intermediate from C-3 attack

33 Standard Enthalpies of Formation The standard en-tropies heat capacities enthalpy and the free energy barrierfor the addition of Cl to the ring-carbon sites at selectedtemperature for these reactions were calculated The resultsare given in Tables 1 2 and 3 We calculated standardenthalpies of formation (119891119867

o298) based on two isodesmic

reactions shown in Scheme 2Based on the 119891119867o

298 of chlorobenzene (1301 plusmn 050kcalmol) [26] benzene (198 plusmn 02 kcalmol) [27] thiophene(5220 kcalmol) [28] and the 119891119867

o298 for the selected

chlorothiophene compounds were estimated using CBS-QB3 along with the selected isodesmic reaction Scheme 2(Table 2)

Similarly the 119891119867o298 for the 2-chlorothiophene calcu-

lated at 46507 kcalmol is less than 3-chlorothiophene isomer(47330 kcalmol) This indicates that the 2-chlorothiopheneisomer is more stable than the 3-chlorothiophene isomerAlong the same line of discussion the 119891119867

o298 of 25-

dichlorothiophene (44403 kcalmol) is less than the otherdichloro isomers This infers that the 25-dichloro isomer ismore stable than the other dichloro isomers Such findingis attributed the S-atom that separates between the twochlorine atoms in thiophene These positions are denoted as120572-positions with respect to sulfur atom Obviously higherthermodynamic stability for this isomer stems from a smaller

Heteroatom Chemistry 3

iophene 2-Chlorothiophene 3-chlorothiophene

25-dichlorothiophene24-dichlorothiophene23-dichlorothiophene

34-dichlorothiophene 234-trichloroyhiophene 235-trichlorothiophene

2345-tetrachlorothiophene

Figure 1 Optimized structures at the B3LYP6-311+G(dp) level of theory for chlorinated isomers of thiophene

S

3

2 + E+

S SE

H

E

H

SE

H

S

EH

S

EH

Scheme 1 Resonance stabilization of 2-substitution intermediate is greater than that of the 3-substitution intermediate

enthalpic penalty associated with the repulsion between thechlorine atoms

It is noticed that the heat of formation 119891119867o298 of the

chlorothiophene compounds decreases with the additionof the number of chlorine atoms To the contrary and asexpected entropies (So) and the heat capacities at constantpressure (119862op) for chlorothiophene compounds increase withthe addition of chlorine atoms Table 1 lists calculated stan-dard entropies and heat capacities at selected temperatures

34 Gaseous and Aqueous Gibbs Free Energies of FormationThe polarizable continuum model (PCM) [29] is used toestimate values of Δ119866119900119904119900119897V This approach utilizes a continuumsurface charge formalism that incorporates a robust and asmooth perturbing reaction field Values of Δ119866119900119904119900119897V are mod-estly negative indicating an exothermic nature for dissolvingof pyridine and its chlorinated compounds in water Valuesof Δ119866119900119904119900119897V randomly vary among isomers but reside in thenarrow range of -15 and sim 225 kcalmol Nevertheless no

4 Heteroatom Chemistry

iophene 2-Chlorothiophene 23-Dichlorothiophene

2345-Trichlorothiophene 235-Trichlorothiophene

0055

0075008700940144

0106 0106017017

0075

Figure 2 Chlorination sequence of thiophene predicted based on Fukui indices of electrophilic attack fminus1(r)

Table 1 Values of standard entropy (119878o) and heat capacity at constant pressure (119862op) at selected temperatures for chlorinated thiopheneisomers 119878o298 in cal(mol K) and Co

p (T) in cal(mol K)

119878o298 119862op29815K 300K 500K 800K 1000K 1500K

Thiophene 70566 17895 18006 27771 35679 38827 434532-Chlorothiophene 77534 21624 21730 26875 37967 40709 446123-Chlorothiophene 78109 21685 21792 30929 38022 40738 4461423-Dichlorothiophene 85559 25327 25429 33915 40280 42608 4577624-Dichlorothiophene 85716 25431 25533 33995 40320 42630 4578125-Dichlorothiophene 85860 25354 25455 33881 40257 42595 4577534-Dichlorothiophene 85377 25379 25483 34024 40344 42645 45784234-Trichlorothiophene 92799 29059 29158 37041 42625 44532 46956235-Trichlorothiophene 93197 29067 29163 36968 42573 44497 469422345-Tetrachlorothiophene 100252 32697 32789 40005 44875 46395 48114

Table 2 119891119867o298

(kcalmol) for chlorinated thiophene isomers

119891119867o298

Thiophene + 522002-Chlorothiophene + 465073-Chlorothiophene + 4733023-Dichlorothiophene + 4584624-Dichlorothiophene + 4507725-Dichlorothiophene + 4440334-Dichlorothiophene + 45395234-Trichlorothiophene + 41334235-Trichlorothiophene + 431192345-Tetrachlorothiophene + 40366

conclusive observation can be drawn regarding the effectof degree and pattern of chlorination on computed valuesof Δ119866119900119904119900119897V Values of Δ119891119866

119900298(119892) and Δ119891119866

119900298(119886119902) highlight a

highly spontaneous nature for the formation of chlorinatedcompounds of thiophene in the gas phase as well as in theaqueous medium Water is a polar solvent so the solva-tion effect depends on the dipole moments of chlorinated

Table 3 The calculated properties of chlorinated thiophene at 298K the Gibbs free energies in the gas phase Gf (g) the Gibbs freeenergies for solvation (GSolv) and the standard and relative Gibbsfree energies in aqueous phase Gf (aq) All are in kcalmol

Δ fG(g) ΔGSolv Δ fG(aq)Thiophene -40656 -2028 -426832-Chlorothiophene -48723 -1949 -506703-Chlorothiophene -51070 -2272 -5334223-Dichlorothiophene -56867 -2144 -5901124-Dichlorothiophene -57083 -1936 -5901925-Dichlorothiophene -54600 -1636 -5623634-Dichlorothiophene -60464 -2506 -62970234-Trichlorothiophene -68030 -2128 -70158235-Trichlorothiophene -66363 -1551 -679142345-Tetrachlorothiophene -74512 -1511 -76023

thiophenes 34-dichlorothiophene should have the greatestdipole moment and thus the greatest interaction withpolar solvent This explains why this isomer acquires lowerΔ119891G(aq) among other dechlorinated congeners Calculatingpolarizability effects on the selected chlorinated thiophene

Heteroatom Chemistry 5

S

Cl

S

(C l)n+ +n n

Scheme 2 Hypothetical reaction between thiophene and chlorobenzene

using various other solvents will be investigated in a duecourse

4 Conclusion

The thermochemical and the optimized geometrical param-eters are presented for the selected chlorothiophene iso-mers Isodesmic reactions were used to estimate standardenthalpies of formationThe standard enthalpies of formationdecrease as the degree of chlorination increases in both thegaseous and aqueous media No trend can be deduced withrespect to the effect of degree and pattern of chlorinationon the computed solvation energies Similarly geometries ofchlorinated isomers of thiophene exhibit to a large extent theanalogous structural parameters in the thiophene moleculeThe degree and pattern of chlorination indices a minor in

Data Availability

The data used to support the findings of this study areincluded within the article

Conflicts of Interest

The authors declare that they have no conflicts of interest

Acknowledgments

This study has been supported by a grant of computingtime from the Australian Centre of Australian nationalComputational Infrastructure (NCI) in Canberra

References

[1] R S Hosmane and J F Liebman ldquoAromaticity of heterocy-cles experimental realization of dewar-breslow definition ofaromaticityrdquo Tetrahedron Letters vol 32 no 32 pp 3949ndash39521991

[2] C S Chidan Kumar C Parlak H-K Fun et al ldquoExperimentaland theoretical FT-IR Raman and XRD study of 2-acetyl-5-chlorothiophenerdquo Spectrochimica Acta Part A Molecular andBiomolecular Spectroscopy vol 127 pp 67ndash73 2014

[3] D K Dalvie A S Kalgutkar S C Khojasteh-Bakht R SObach and J P OrsquoDonnell ldquoBiotransformation reactions offive-membered aromatic heterocyclic ringsrdquo Chemical Researchin Toxicology vol 15 no 3 pp 269ndash299 2002

[4] W Chen J Caceres-Cortes H Zhang D Zhang W GHumphreys and J Gan ldquoBioactivation of substituted thio-phenes including 120572-chlorothiophene- containing compoundsin human liver microsomesrdquo Chemical Research in Toxicologyvol 24 no 5 pp 663ndash669 2011

[5] U Dettmeier K Eichler K Kuhlein E I Leupold and HLitterer ldquoPreparation of 120573-Halothiophenes by Isomerization of120572-Halothiophenes on Zeolite Catalystsrdquo Angewandte ChemieInternational Edition vol 26 no 5 pp 468-469 1987

[6] R E Conrow W D Dean P W Zinke et al ldquoEnantioselectivesynthesis of brinzolamide (AL-4862) a new topical carbonicanhydrase inhibitor The ldquoDCAT Routerdquo to thiophenesulfon-amidesrdquo Organic Process Research amp Development vol 3 no 2pp 114ndash120 1999

[7] J W Hull Jr D R Romer D E Podhorez M L Ash andC H Brady ldquoDevelopment of potential manufacturing routesfor substituted thiophenes - Preparation of halogenated 2-thiophenecarboxylic acid derivatives as building blocks for anew family of 26-dihaloaryl 124-triazole insecticidesrdquo Beil-stein Journal of Organic Chemistry vol 3 2007

[8] F E Nielsen S Ebdrup A F Jensen et al ldquoNew 3-alkylamino-4H-thieno-124-thiadiazine 11-dioxide derivativesactivate ATP-sensitive potassium channels of pancreatic betacellsrdquo Journal of Medicinal Chemistry vol 49 no 14 pp 4127ndash4139 2006

[9] H L Coonradt H D Hartough and G C Johnson ldquoTheChlorination of Thiophene II Substitution Products PhysicalProperties of the Chlorothiophenes the Mechanism of theReactionrdquo Journal of the American Chemical Society vol 70 no7 pp 2564ndash2568 1948

[10] H L Coonradt and H D Hartough ldquoThe Chlorination ofThiophene I Addition Productsrdquo Journal of the AmericanChemical Society vol 70 no 3 pp 1158ndash1161 1948

[11] E A Chernyshev N G Komalenkova G N Yakovleva V GBykovchenko M A Dubikhina and V G Lakhtin ldquoGas-phasereactions of tetrachlorogermane with chlorothiophenes in thepresence of hexachlorodisilane Synthesis of thienylchloroger-manesrdquo Russian Journal of General Chemistry vol 77 no 8 pp1332ndash1336 2007

[12] W R Harshbarger and S H Bauer ldquoAn electron diffractionstudy of the structure of thiophene 2-chlorothiophene and 2-bromothiophenerdquo Acta Crystallographica Section B StructuralScience Crystal Engineering and Materials vol 26 no 7 pp1010ndash1020 1970

[13] V Tomar G Bhattacharjee and A Kumar ldquoSynthesis andantimicrobial evaluation of new chalcones containing piper-azine or 2 5-dichlorothiophenemoietyrdquoBioorganicampMedicinalChemistry Letters vol 17 no 19 pp 5321ndash5324 2007

[14] H S L Beigi and S Jameh-Bozorghi ldquoTheoretical study onthe electronic structural properties and reactivity of a series

6 Heteroatom Chemistry

of mono- di- tri- and tetrachlorothiophenes as well as cor-responding radical cation forms as monomers for conductingpolymersrdquo Chemistry Central Journal vol 5 no 1 2011

[15] K SiddiqueMAltarawneh A Saeed Z Zeng J Gore andB ZDlugogorski ldquoInteraction of NH2 radical with alkylbenzenesrdquoCombustion and Flame vol 200 pp 85ndash96 2019

[16] M Altarawneh T Dar and B Z Dlugogorski ldquoThermochem-ical parameters and pK a values for chlorinated congeners ofthiophenolrdquo Journal of Chemicalamp EngineeringData vol 57 no6 pp 1834ndash1842 2012

[17] M Altarawneh and B Z Dlugogorski ldquoThermal decomposi-tion of 12-bis(246-tribromophenoxy)ethane (BTBPE) a novelbrominated flame retardantrdquo Environmental Science amp Technol-ogy vol 48 no 24 pp 14335ndash14343 2014

[18] M J Frisch G W Trucks H B Schlegel et al Gaussian 16Revision B01 Gaussian Inc Wallingford CT Oxfordshire uk2016

[19] J A Montgomery Jr M J Frisch J W Ochterski and G APetersson ldquoA complete basis set model chemistry VII Use ofthe minimum population localization methodrdquo The Journal ofChemical Physics vol 112 no 15 pp 6532ndash6542 2000

[20] N Ahubelem M Altarawneh and B Z Dlugogorski ldquoDehy-drohalogenation of ethyl halidesrdquo Tetrahedron Letters no 35pp 4860ndash4868 2014

[21] M Altarawneh ldquoA theoretical study on the pyrolysis of perfluo-robutanoic acid as a model compound for perfluoroalkyl acidsrdquoTetrahedron Letters vol 53 no 32 pp 4070ndash4073 2012

[22] B Delley ldquoFrommolecules to solids with the DMol3 approachrdquoThe Journal of Chemical Physics vol 113 no 18 pp 7756ndash77642000

[23] K Fukui ldquoRole of frontier orbitals in chemical reactionsrdquoScience vol 218 no 4574 pp 747ndash754 1982

[24] V BMokrushin V TsangW Zachariah andVKnyazev ldquo2002NIST Gaithersburg MDrdquo

[25] M Altarawneh and B Z Dlugogorski ldquoFormation and chlori-nation of carbazole phenoxazine and phenazinerdquoEnvironmen-tal Science amp Technology vol 49 no 4 pp 2215ndash2221 2015

[26] D Thompson ldquoEnthalpies of formation and entropies of chlo-rinated dibenzo-p-dioxins and dibenzofurans selected data forcomputer-based studiesrdquo Thermochimica Acta vol 261 no Cpp 7ndash20 1995

[27] H Y Afeefy J F Liebman and S E Stein ldquoNeutral Ther-mochemical Datardquo in NIST Chemistry WebBook NIST Stan-dard Reference Database Number W G Mallard and PJ Linstrom Eds vol 69 November 1998 httpwebbooknistgovchemistry

[28] M Zaheeruddin and Z Lodhi ldquoEnthalpies of formation ofsome cyclic compoundsrdquo The Journal of Physical Chemistry(Peshawar Pak) vol 10 pp 111ndash118 1991

[29] DMYork andMKarplus ldquoA smooth solvation potential basedon the conductor-like screening modelrdquoThe Journal of PhysicalChemistry A vol 103 no 50 pp 11060ndash11079 1999

Heteroatom Chemistry 3

iophene 2-Chlorothiophene 3-chlorothiophene

25-dichlorothiophene24-dichlorothiophene23-dichlorothiophene

34-dichlorothiophene 234-trichloroyhiophene 235-trichlorothiophene

2345-tetrachlorothiophene

Figure 1 Optimized structures at the B3LYP6-311+G(dp) level of theory for chlorinated isomers of thiophene

S

3

2 + E+

S SE

H

E

H

SE

H

S

EH

S

EH

Scheme 1 Resonance stabilization of 2-substitution intermediate is greater than that of the 3-substitution intermediate

enthalpic penalty associated with the repulsion between thechlorine atoms

It is noticed that the heat of formation 119891119867o298 of the

chlorothiophene compounds decreases with the additionof the number of chlorine atoms To the contrary and asexpected entropies (So) and the heat capacities at constantpressure (119862op) for chlorothiophene compounds increase withthe addition of chlorine atoms Table 1 lists calculated stan-dard entropies and heat capacities at selected temperatures

34 Gaseous and Aqueous Gibbs Free Energies of FormationThe polarizable continuum model (PCM) [29] is used toestimate values of Δ119866119900119904119900119897V This approach utilizes a continuumsurface charge formalism that incorporates a robust and asmooth perturbing reaction field Values of Δ119866119900119904119900119897V are mod-estly negative indicating an exothermic nature for dissolvingof pyridine and its chlorinated compounds in water Valuesof Δ119866119900119904119900119897V randomly vary among isomers but reside in thenarrow range of -15 and sim 225 kcalmol Nevertheless no

4 Heteroatom Chemistry

iophene 2-Chlorothiophene 23-Dichlorothiophene

2345-Trichlorothiophene 235-Trichlorothiophene

0055

0075008700940144

0106 0106017017

0075

Figure 2 Chlorination sequence of thiophene predicted based on Fukui indices of electrophilic attack fminus1(r)

Table 1 Values of standard entropy (119878o) and heat capacity at constant pressure (119862op) at selected temperatures for chlorinated thiopheneisomers 119878o298 in cal(mol K) and Co

p (T) in cal(mol K)

119878o298 119862op29815K 300K 500K 800K 1000K 1500K

Thiophene 70566 17895 18006 27771 35679 38827 434532-Chlorothiophene 77534 21624 21730 26875 37967 40709 446123-Chlorothiophene 78109 21685 21792 30929 38022 40738 4461423-Dichlorothiophene 85559 25327 25429 33915 40280 42608 4577624-Dichlorothiophene 85716 25431 25533 33995 40320 42630 4578125-Dichlorothiophene 85860 25354 25455 33881 40257 42595 4577534-Dichlorothiophene 85377 25379 25483 34024 40344 42645 45784234-Trichlorothiophene 92799 29059 29158 37041 42625 44532 46956235-Trichlorothiophene 93197 29067 29163 36968 42573 44497 469422345-Tetrachlorothiophene 100252 32697 32789 40005 44875 46395 48114

Table 2 119891119867o298

(kcalmol) for chlorinated thiophene isomers

119891119867o298

Thiophene + 522002-Chlorothiophene + 465073-Chlorothiophene + 4733023-Dichlorothiophene + 4584624-Dichlorothiophene + 4507725-Dichlorothiophene + 4440334-Dichlorothiophene + 45395234-Trichlorothiophene + 41334235-Trichlorothiophene + 431192345-Tetrachlorothiophene + 40366

conclusive observation can be drawn regarding the effectof degree and pattern of chlorination on computed valuesof Δ119866119900119904119900119897V Values of Δ119891119866

119900298(119892) and Δ119891119866

119900298(119886119902) highlight a

highly spontaneous nature for the formation of chlorinatedcompounds of thiophene in the gas phase as well as in theaqueous medium Water is a polar solvent so the solva-tion effect depends on the dipole moments of chlorinated

Table 3 The calculated properties of chlorinated thiophene at 298K the Gibbs free energies in the gas phase Gf (g) the Gibbs freeenergies for solvation (GSolv) and the standard and relative Gibbsfree energies in aqueous phase Gf (aq) All are in kcalmol

Δ fG(g) ΔGSolv Δ fG(aq)Thiophene -40656 -2028 -426832-Chlorothiophene -48723 -1949 -506703-Chlorothiophene -51070 -2272 -5334223-Dichlorothiophene -56867 -2144 -5901124-Dichlorothiophene -57083 -1936 -5901925-Dichlorothiophene -54600 -1636 -5623634-Dichlorothiophene -60464 -2506 -62970234-Trichlorothiophene -68030 -2128 -70158235-Trichlorothiophene -66363 -1551 -679142345-Tetrachlorothiophene -74512 -1511 -76023

thiophenes 34-dichlorothiophene should have the greatestdipole moment and thus the greatest interaction withpolar solvent This explains why this isomer acquires lowerΔ119891G(aq) among other dechlorinated congeners Calculatingpolarizability effects on the selected chlorinated thiophene

Heteroatom Chemistry 5

S

Cl

S

(C l)n+ +n n

Scheme 2 Hypothetical reaction between thiophene and chlorobenzene

using various other solvents will be investigated in a duecourse

4 Conclusion

The thermochemical and the optimized geometrical param-eters are presented for the selected chlorothiophene iso-mers Isodesmic reactions were used to estimate standardenthalpies of formationThe standard enthalpies of formationdecrease as the degree of chlorination increases in both thegaseous and aqueous media No trend can be deduced withrespect to the effect of degree and pattern of chlorinationon the computed solvation energies Similarly geometries ofchlorinated isomers of thiophene exhibit to a large extent theanalogous structural parameters in the thiophene moleculeThe degree and pattern of chlorination indices a minor in

Data Availability

The data used to support the findings of this study areincluded within the article

Conflicts of Interest

The authors declare that they have no conflicts of interest

Acknowledgments

This study has been supported by a grant of computingtime from the Australian Centre of Australian nationalComputational Infrastructure (NCI) in Canberra

References

[1] R S Hosmane and J F Liebman ldquoAromaticity of heterocy-cles experimental realization of dewar-breslow definition ofaromaticityrdquo Tetrahedron Letters vol 32 no 32 pp 3949ndash39521991

[2] C S Chidan Kumar C Parlak H-K Fun et al ldquoExperimentaland theoretical FT-IR Raman and XRD study of 2-acetyl-5-chlorothiophenerdquo Spectrochimica Acta Part A Molecular andBiomolecular Spectroscopy vol 127 pp 67ndash73 2014

[3] D K Dalvie A S Kalgutkar S C Khojasteh-Bakht R SObach and J P OrsquoDonnell ldquoBiotransformation reactions offive-membered aromatic heterocyclic ringsrdquo Chemical Researchin Toxicology vol 15 no 3 pp 269ndash299 2002

[4] W Chen J Caceres-Cortes H Zhang D Zhang W GHumphreys and J Gan ldquoBioactivation of substituted thio-phenes including 120572-chlorothiophene- containing compoundsin human liver microsomesrdquo Chemical Research in Toxicologyvol 24 no 5 pp 663ndash669 2011

[5] U Dettmeier K Eichler K Kuhlein E I Leupold and HLitterer ldquoPreparation of 120573-Halothiophenes by Isomerization of120572-Halothiophenes on Zeolite Catalystsrdquo Angewandte ChemieInternational Edition vol 26 no 5 pp 468-469 1987

[6] R E Conrow W D Dean P W Zinke et al ldquoEnantioselectivesynthesis of brinzolamide (AL-4862) a new topical carbonicanhydrase inhibitor The ldquoDCAT Routerdquo to thiophenesulfon-amidesrdquo Organic Process Research amp Development vol 3 no 2pp 114ndash120 1999

[7] J W Hull Jr D R Romer D E Podhorez M L Ash andC H Brady ldquoDevelopment of potential manufacturing routesfor substituted thiophenes - Preparation of halogenated 2-thiophenecarboxylic acid derivatives as building blocks for anew family of 26-dihaloaryl 124-triazole insecticidesrdquo Beil-stein Journal of Organic Chemistry vol 3 2007

[8] F E Nielsen S Ebdrup A F Jensen et al ldquoNew 3-alkylamino-4H-thieno-124-thiadiazine 11-dioxide derivativesactivate ATP-sensitive potassium channels of pancreatic betacellsrdquo Journal of Medicinal Chemistry vol 49 no 14 pp 4127ndash4139 2006

[9] H L Coonradt H D Hartough and G C Johnson ldquoTheChlorination of Thiophene II Substitution Products PhysicalProperties of the Chlorothiophenes the Mechanism of theReactionrdquo Journal of the American Chemical Society vol 70 no7 pp 2564ndash2568 1948

[10] H L Coonradt and H D Hartough ldquoThe Chlorination ofThiophene I Addition Productsrdquo Journal of the AmericanChemical Society vol 70 no 3 pp 1158ndash1161 1948

[11] E A Chernyshev N G Komalenkova G N Yakovleva V GBykovchenko M A Dubikhina and V G Lakhtin ldquoGas-phasereactions of tetrachlorogermane with chlorothiophenes in thepresence of hexachlorodisilane Synthesis of thienylchloroger-manesrdquo Russian Journal of General Chemistry vol 77 no 8 pp1332ndash1336 2007

[12] W R Harshbarger and S H Bauer ldquoAn electron diffractionstudy of the structure of thiophene 2-chlorothiophene and 2-bromothiophenerdquo Acta Crystallographica Section B StructuralScience Crystal Engineering and Materials vol 26 no 7 pp1010ndash1020 1970

[13] V Tomar G Bhattacharjee and A Kumar ldquoSynthesis andantimicrobial evaluation of new chalcones containing piper-azine or 2 5-dichlorothiophenemoietyrdquoBioorganicampMedicinalChemistry Letters vol 17 no 19 pp 5321ndash5324 2007

[14] H S L Beigi and S Jameh-Bozorghi ldquoTheoretical study onthe electronic structural properties and reactivity of a series

6 Heteroatom Chemistry

of mono- di- tri- and tetrachlorothiophenes as well as cor-responding radical cation forms as monomers for conductingpolymersrdquo Chemistry Central Journal vol 5 no 1 2011

[15] K SiddiqueMAltarawneh A Saeed Z Zeng J Gore andB ZDlugogorski ldquoInteraction of NH2 radical with alkylbenzenesrdquoCombustion and Flame vol 200 pp 85ndash96 2019

[16] M Altarawneh T Dar and B Z Dlugogorski ldquoThermochem-ical parameters and pK a values for chlorinated congeners ofthiophenolrdquo Journal of Chemicalamp EngineeringData vol 57 no6 pp 1834ndash1842 2012

[17] M Altarawneh and B Z Dlugogorski ldquoThermal decomposi-tion of 12-bis(246-tribromophenoxy)ethane (BTBPE) a novelbrominated flame retardantrdquo Environmental Science amp Technol-ogy vol 48 no 24 pp 14335ndash14343 2014

[18] M J Frisch G W Trucks H B Schlegel et al Gaussian 16Revision B01 Gaussian Inc Wallingford CT Oxfordshire uk2016

[19] J A Montgomery Jr M J Frisch J W Ochterski and G APetersson ldquoA complete basis set model chemistry VII Use ofthe minimum population localization methodrdquo The Journal ofChemical Physics vol 112 no 15 pp 6532ndash6542 2000

[20] N Ahubelem M Altarawneh and B Z Dlugogorski ldquoDehy-drohalogenation of ethyl halidesrdquo Tetrahedron Letters no 35pp 4860ndash4868 2014

[21] M Altarawneh ldquoA theoretical study on the pyrolysis of perfluo-robutanoic acid as a model compound for perfluoroalkyl acidsrdquoTetrahedron Letters vol 53 no 32 pp 4070ndash4073 2012

[22] B Delley ldquoFrommolecules to solids with the DMol3 approachrdquoThe Journal of Chemical Physics vol 113 no 18 pp 7756ndash77642000

[23] K Fukui ldquoRole of frontier orbitals in chemical reactionsrdquoScience vol 218 no 4574 pp 747ndash754 1982

[24] V BMokrushin V TsangW Zachariah andVKnyazev ldquo2002NIST Gaithersburg MDrdquo

[25] M Altarawneh and B Z Dlugogorski ldquoFormation and chlori-nation of carbazole phenoxazine and phenazinerdquoEnvironmen-tal Science amp Technology vol 49 no 4 pp 2215ndash2221 2015

[26] D Thompson ldquoEnthalpies of formation and entropies of chlo-rinated dibenzo-p-dioxins and dibenzofurans selected data forcomputer-based studiesrdquo Thermochimica Acta vol 261 no Cpp 7ndash20 1995

[27] H Y Afeefy J F Liebman and S E Stein ldquoNeutral Ther-mochemical Datardquo in NIST Chemistry WebBook NIST Stan-dard Reference Database Number W G Mallard and PJ Linstrom Eds vol 69 November 1998 httpwebbooknistgovchemistry

[28] M Zaheeruddin and Z Lodhi ldquoEnthalpies of formation ofsome cyclic compoundsrdquo The Journal of Physical Chemistry(Peshawar Pak) vol 10 pp 111ndash118 1991

[29] DMYork andMKarplus ldquoA smooth solvation potential basedon the conductor-like screening modelrdquoThe Journal of PhysicalChemistry A vol 103 no 50 pp 11060ndash11079 1999

4 Heteroatom Chemistry

iophene 2-Chlorothiophene 23-Dichlorothiophene

2345-Trichlorothiophene 235-Trichlorothiophene

0055

0075008700940144

0106 0106017017

0075

Figure 2 Chlorination sequence of thiophene predicted based on Fukui indices of electrophilic attack fminus1(r)

Table 1 Values of standard entropy (119878o) and heat capacity at constant pressure (119862op) at selected temperatures for chlorinated thiopheneisomers 119878o298 in cal(mol K) and Co

p (T) in cal(mol K)

119878o298 119862op29815K 300K 500K 800K 1000K 1500K

Thiophene 70566 17895 18006 27771 35679 38827 434532-Chlorothiophene 77534 21624 21730 26875 37967 40709 446123-Chlorothiophene 78109 21685 21792 30929 38022 40738 4461423-Dichlorothiophene 85559 25327 25429 33915 40280 42608 4577624-Dichlorothiophene 85716 25431 25533 33995 40320 42630 4578125-Dichlorothiophene 85860 25354 25455 33881 40257 42595 4577534-Dichlorothiophene 85377 25379 25483 34024 40344 42645 45784234-Trichlorothiophene 92799 29059 29158 37041 42625 44532 46956235-Trichlorothiophene 93197 29067 29163 36968 42573 44497 469422345-Tetrachlorothiophene 100252 32697 32789 40005 44875 46395 48114

Table 2 119891119867o298

(kcalmol) for chlorinated thiophene isomers

119891119867o298

Thiophene + 522002-Chlorothiophene + 465073-Chlorothiophene + 4733023-Dichlorothiophene + 4584624-Dichlorothiophene + 4507725-Dichlorothiophene + 4440334-Dichlorothiophene + 45395234-Trichlorothiophene + 41334235-Trichlorothiophene + 431192345-Tetrachlorothiophene + 40366

conclusive observation can be drawn regarding the effectof degree and pattern of chlorination on computed valuesof Δ119866119900119904119900119897V Values of Δ119891119866

119900298(119892) and Δ119891119866

119900298(119886119902) highlight a

highly spontaneous nature for the formation of chlorinatedcompounds of thiophene in the gas phase as well as in theaqueous medium Water is a polar solvent so the solva-tion effect depends on the dipole moments of chlorinated

Table 3 The calculated properties of chlorinated thiophene at 298K the Gibbs free energies in the gas phase Gf (g) the Gibbs freeenergies for solvation (GSolv) and the standard and relative Gibbsfree energies in aqueous phase Gf (aq) All are in kcalmol

Δ fG(g) ΔGSolv Δ fG(aq)Thiophene -40656 -2028 -426832-Chlorothiophene -48723 -1949 -506703-Chlorothiophene -51070 -2272 -5334223-Dichlorothiophene -56867 -2144 -5901124-Dichlorothiophene -57083 -1936 -5901925-Dichlorothiophene -54600 -1636 -5623634-Dichlorothiophene -60464 -2506 -62970234-Trichlorothiophene -68030 -2128 -70158235-Trichlorothiophene -66363 -1551 -679142345-Tetrachlorothiophene -74512 -1511 -76023

thiophenes 34-dichlorothiophene should have the greatestdipole moment and thus the greatest interaction withpolar solvent This explains why this isomer acquires lowerΔ119891G(aq) among other dechlorinated congeners Calculatingpolarizability effects on the selected chlorinated thiophene

Heteroatom Chemistry 5

S

Cl

S

(C l)n+ +n n

Scheme 2 Hypothetical reaction between thiophene and chlorobenzene

using various other solvents will be investigated in a duecourse

4 Conclusion

The thermochemical and the optimized geometrical param-eters are presented for the selected chlorothiophene iso-mers Isodesmic reactions were used to estimate standardenthalpies of formationThe standard enthalpies of formationdecrease as the degree of chlorination increases in both thegaseous and aqueous media No trend can be deduced withrespect to the effect of degree and pattern of chlorinationon the computed solvation energies Similarly geometries ofchlorinated isomers of thiophene exhibit to a large extent theanalogous structural parameters in the thiophene moleculeThe degree and pattern of chlorination indices a minor in

Data Availability

The data used to support the findings of this study areincluded within the article

Conflicts of Interest

The authors declare that they have no conflicts of interest

Acknowledgments

This study has been supported by a grant of computingtime from the Australian Centre of Australian nationalComputational Infrastructure (NCI) in Canberra

References

[1] R S Hosmane and J F Liebman ldquoAromaticity of heterocy-cles experimental realization of dewar-breslow definition ofaromaticityrdquo Tetrahedron Letters vol 32 no 32 pp 3949ndash39521991

[2] C S Chidan Kumar C Parlak H-K Fun et al ldquoExperimentaland theoretical FT-IR Raman and XRD study of 2-acetyl-5-chlorothiophenerdquo Spectrochimica Acta Part A Molecular andBiomolecular Spectroscopy vol 127 pp 67ndash73 2014

[3] D K Dalvie A S Kalgutkar S C Khojasteh-Bakht R SObach and J P OrsquoDonnell ldquoBiotransformation reactions offive-membered aromatic heterocyclic ringsrdquo Chemical Researchin Toxicology vol 15 no 3 pp 269ndash299 2002

[4] W Chen J Caceres-Cortes H Zhang D Zhang W GHumphreys and J Gan ldquoBioactivation of substituted thio-phenes including 120572-chlorothiophene- containing compoundsin human liver microsomesrdquo Chemical Research in Toxicologyvol 24 no 5 pp 663ndash669 2011

[5] U Dettmeier K Eichler K Kuhlein E I Leupold and HLitterer ldquoPreparation of 120573-Halothiophenes by Isomerization of120572-Halothiophenes on Zeolite Catalystsrdquo Angewandte ChemieInternational Edition vol 26 no 5 pp 468-469 1987

[6] R E Conrow W D Dean P W Zinke et al ldquoEnantioselectivesynthesis of brinzolamide (AL-4862) a new topical carbonicanhydrase inhibitor The ldquoDCAT Routerdquo to thiophenesulfon-amidesrdquo Organic Process Research amp Development vol 3 no 2pp 114ndash120 1999

[7] J W Hull Jr D R Romer D E Podhorez M L Ash andC H Brady ldquoDevelopment of potential manufacturing routesfor substituted thiophenes - Preparation of halogenated 2-thiophenecarboxylic acid derivatives as building blocks for anew family of 26-dihaloaryl 124-triazole insecticidesrdquo Beil-stein Journal of Organic Chemistry vol 3 2007

[8] F E Nielsen S Ebdrup A F Jensen et al ldquoNew 3-alkylamino-4H-thieno-124-thiadiazine 11-dioxide derivativesactivate ATP-sensitive potassium channels of pancreatic betacellsrdquo Journal of Medicinal Chemistry vol 49 no 14 pp 4127ndash4139 2006

[9] H L Coonradt H D Hartough and G C Johnson ldquoTheChlorination of Thiophene II Substitution Products PhysicalProperties of the Chlorothiophenes the Mechanism of theReactionrdquo Journal of the American Chemical Society vol 70 no7 pp 2564ndash2568 1948

[10] H L Coonradt and H D Hartough ldquoThe Chlorination ofThiophene I Addition Productsrdquo Journal of the AmericanChemical Society vol 70 no 3 pp 1158ndash1161 1948

[11] E A Chernyshev N G Komalenkova G N Yakovleva V GBykovchenko M A Dubikhina and V G Lakhtin ldquoGas-phasereactions of tetrachlorogermane with chlorothiophenes in thepresence of hexachlorodisilane Synthesis of thienylchloroger-manesrdquo Russian Journal of General Chemistry vol 77 no 8 pp1332ndash1336 2007

[12] W R Harshbarger and S H Bauer ldquoAn electron diffractionstudy of the structure of thiophene 2-chlorothiophene and 2-bromothiophenerdquo Acta Crystallographica Section B StructuralScience Crystal Engineering and Materials vol 26 no 7 pp1010ndash1020 1970

[13] V Tomar G Bhattacharjee and A Kumar ldquoSynthesis andantimicrobial evaluation of new chalcones containing piper-azine or 2 5-dichlorothiophenemoietyrdquoBioorganicampMedicinalChemistry Letters vol 17 no 19 pp 5321ndash5324 2007

[14] H S L Beigi and S Jameh-Bozorghi ldquoTheoretical study onthe electronic structural properties and reactivity of a series

6 Heteroatom Chemistry

of mono- di- tri- and tetrachlorothiophenes as well as cor-responding radical cation forms as monomers for conductingpolymersrdquo Chemistry Central Journal vol 5 no 1 2011

[15] K SiddiqueMAltarawneh A Saeed Z Zeng J Gore andB ZDlugogorski ldquoInteraction of NH2 radical with alkylbenzenesrdquoCombustion and Flame vol 200 pp 85ndash96 2019

[16] M Altarawneh T Dar and B Z Dlugogorski ldquoThermochem-ical parameters and pK a values for chlorinated congeners ofthiophenolrdquo Journal of Chemicalamp EngineeringData vol 57 no6 pp 1834ndash1842 2012

[17] M Altarawneh and B Z Dlugogorski ldquoThermal decomposi-tion of 12-bis(246-tribromophenoxy)ethane (BTBPE) a novelbrominated flame retardantrdquo Environmental Science amp Technol-ogy vol 48 no 24 pp 14335ndash14343 2014

[18] M J Frisch G W Trucks H B Schlegel et al Gaussian 16Revision B01 Gaussian Inc Wallingford CT Oxfordshire uk2016

[19] J A Montgomery Jr M J Frisch J W Ochterski and G APetersson ldquoA complete basis set model chemistry VII Use ofthe minimum population localization methodrdquo The Journal ofChemical Physics vol 112 no 15 pp 6532ndash6542 2000

[20] N Ahubelem M Altarawneh and B Z Dlugogorski ldquoDehy-drohalogenation of ethyl halidesrdquo Tetrahedron Letters no 35pp 4860ndash4868 2014

[21] M Altarawneh ldquoA theoretical study on the pyrolysis of perfluo-robutanoic acid as a model compound for perfluoroalkyl acidsrdquoTetrahedron Letters vol 53 no 32 pp 4070ndash4073 2012

[22] B Delley ldquoFrommolecules to solids with the DMol3 approachrdquoThe Journal of Chemical Physics vol 113 no 18 pp 7756ndash77642000

[23] K Fukui ldquoRole of frontier orbitals in chemical reactionsrdquoScience vol 218 no 4574 pp 747ndash754 1982

[24] V BMokrushin V TsangW Zachariah andVKnyazev ldquo2002NIST Gaithersburg MDrdquo

[25] M Altarawneh and B Z Dlugogorski ldquoFormation and chlori-nation of carbazole phenoxazine and phenazinerdquoEnvironmen-tal Science amp Technology vol 49 no 4 pp 2215ndash2221 2015

[26] D Thompson ldquoEnthalpies of formation and entropies of chlo-rinated dibenzo-p-dioxins and dibenzofurans selected data forcomputer-based studiesrdquo Thermochimica Acta vol 261 no Cpp 7ndash20 1995

[27] H Y Afeefy J F Liebman and S E Stein ldquoNeutral Ther-mochemical Datardquo in NIST Chemistry WebBook NIST Stan-dard Reference Database Number W G Mallard and PJ Linstrom Eds vol 69 November 1998 httpwebbooknistgovchemistry

[28] M Zaheeruddin and Z Lodhi ldquoEnthalpies of formation ofsome cyclic compoundsrdquo The Journal of Physical Chemistry(Peshawar Pak) vol 10 pp 111ndash118 1991

[29] DMYork andMKarplus ldquoA smooth solvation potential basedon the conductor-like screening modelrdquoThe Journal of PhysicalChemistry A vol 103 no 50 pp 11060ndash11079 1999

Heteroatom Chemistry 5

S

Cl

S

(C l)n+ +n n

Scheme 2 Hypothetical reaction between thiophene and chlorobenzene

using various other solvents will be investigated in a duecourse

4 Conclusion

The thermochemical and the optimized geometrical param-eters are presented for the selected chlorothiophene iso-mers Isodesmic reactions were used to estimate standardenthalpies of formationThe standard enthalpies of formationdecrease as the degree of chlorination increases in both thegaseous and aqueous media No trend can be deduced withrespect to the effect of degree and pattern of chlorinationon the computed solvation energies Similarly geometries ofchlorinated isomers of thiophene exhibit to a large extent theanalogous structural parameters in the thiophene moleculeThe degree and pattern of chlorination indices a minor in

Data Availability

The data used to support the findings of this study areincluded within the article

Conflicts of Interest

The authors declare that they have no conflicts of interest

Acknowledgments

This study has been supported by a grant of computingtime from the Australian Centre of Australian nationalComputational Infrastructure (NCI) in Canberra

References

[1] R S Hosmane and J F Liebman ldquoAromaticity of heterocy-cles experimental realization of dewar-breslow definition ofaromaticityrdquo Tetrahedron Letters vol 32 no 32 pp 3949ndash39521991

[2] C S Chidan Kumar C Parlak H-K Fun et al ldquoExperimentaland theoretical FT-IR Raman and XRD study of 2-acetyl-5-chlorothiophenerdquo Spectrochimica Acta Part A Molecular andBiomolecular Spectroscopy vol 127 pp 67ndash73 2014

[3] D K Dalvie A S Kalgutkar S C Khojasteh-Bakht R SObach and J P OrsquoDonnell ldquoBiotransformation reactions offive-membered aromatic heterocyclic ringsrdquo Chemical Researchin Toxicology vol 15 no 3 pp 269ndash299 2002

[4] W Chen J Caceres-Cortes H Zhang D Zhang W GHumphreys and J Gan ldquoBioactivation of substituted thio-phenes including 120572-chlorothiophene- containing compoundsin human liver microsomesrdquo Chemical Research in Toxicologyvol 24 no 5 pp 663ndash669 2011

[5] U Dettmeier K Eichler K Kuhlein E I Leupold and HLitterer ldquoPreparation of 120573-Halothiophenes by Isomerization of120572-Halothiophenes on Zeolite Catalystsrdquo Angewandte ChemieInternational Edition vol 26 no 5 pp 468-469 1987

[6] R E Conrow W D Dean P W Zinke et al ldquoEnantioselectivesynthesis of brinzolamide (AL-4862) a new topical carbonicanhydrase inhibitor The ldquoDCAT Routerdquo to thiophenesulfon-amidesrdquo Organic Process Research amp Development vol 3 no 2pp 114ndash120 1999

[7] J W Hull Jr D R Romer D E Podhorez M L Ash andC H Brady ldquoDevelopment of potential manufacturing routesfor substituted thiophenes - Preparation of halogenated 2-thiophenecarboxylic acid derivatives as building blocks for anew family of 26-dihaloaryl 124-triazole insecticidesrdquo Beil-stein Journal of Organic Chemistry vol 3 2007

[8] F E Nielsen S Ebdrup A F Jensen et al ldquoNew 3-alkylamino-4H-thieno-124-thiadiazine 11-dioxide derivativesactivate ATP-sensitive potassium channels of pancreatic betacellsrdquo Journal of Medicinal Chemistry vol 49 no 14 pp 4127ndash4139 2006

[9] H L Coonradt H D Hartough and G C Johnson ldquoTheChlorination of Thiophene II Substitution Products PhysicalProperties of the Chlorothiophenes the Mechanism of theReactionrdquo Journal of the American Chemical Society vol 70 no7 pp 2564ndash2568 1948

[10] H L Coonradt and H D Hartough ldquoThe Chlorination ofThiophene I Addition Productsrdquo Journal of the AmericanChemical Society vol 70 no 3 pp 1158ndash1161 1948

[11] E A Chernyshev N G Komalenkova G N Yakovleva V GBykovchenko M A Dubikhina and V G Lakhtin ldquoGas-phasereactions of tetrachlorogermane with chlorothiophenes in thepresence of hexachlorodisilane Synthesis of thienylchloroger-manesrdquo Russian Journal of General Chemistry vol 77 no 8 pp1332ndash1336 2007

[12] W R Harshbarger and S H Bauer ldquoAn electron diffractionstudy of the structure of thiophene 2-chlorothiophene and 2-bromothiophenerdquo Acta Crystallographica Section B StructuralScience Crystal Engineering and Materials vol 26 no 7 pp1010ndash1020 1970

[13] V Tomar G Bhattacharjee and A Kumar ldquoSynthesis andantimicrobial evaluation of new chalcones containing piper-azine or 2 5-dichlorothiophenemoietyrdquoBioorganicampMedicinalChemistry Letters vol 17 no 19 pp 5321ndash5324 2007

[14] H S L Beigi and S Jameh-Bozorghi ldquoTheoretical study onthe electronic structural properties and reactivity of a series

6 Heteroatom Chemistry

of mono- di- tri- and tetrachlorothiophenes as well as cor-responding radical cation forms as monomers for conductingpolymersrdquo Chemistry Central Journal vol 5 no 1 2011

[15] K SiddiqueMAltarawneh A Saeed Z Zeng J Gore andB ZDlugogorski ldquoInteraction of NH2 radical with alkylbenzenesrdquoCombustion and Flame vol 200 pp 85ndash96 2019

[16] M Altarawneh T Dar and B Z Dlugogorski ldquoThermochem-ical parameters and pK a values for chlorinated congeners ofthiophenolrdquo Journal of Chemicalamp EngineeringData vol 57 no6 pp 1834ndash1842 2012

[17] M Altarawneh and B Z Dlugogorski ldquoThermal decomposi-tion of 12-bis(246-tribromophenoxy)ethane (BTBPE) a novelbrominated flame retardantrdquo Environmental Science amp Technol-ogy vol 48 no 24 pp 14335ndash14343 2014

[18] M J Frisch G W Trucks H B Schlegel et al Gaussian 16Revision B01 Gaussian Inc Wallingford CT Oxfordshire uk2016

[19] J A Montgomery Jr M J Frisch J W Ochterski and G APetersson ldquoA complete basis set model chemistry VII Use ofthe minimum population localization methodrdquo The Journal ofChemical Physics vol 112 no 15 pp 6532ndash6542 2000

[20] N Ahubelem M Altarawneh and B Z Dlugogorski ldquoDehy-drohalogenation of ethyl halidesrdquo Tetrahedron Letters no 35pp 4860ndash4868 2014

[21] M Altarawneh ldquoA theoretical study on the pyrolysis of perfluo-robutanoic acid as a model compound for perfluoroalkyl acidsrdquoTetrahedron Letters vol 53 no 32 pp 4070ndash4073 2012

[22] B Delley ldquoFrommolecules to solids with the DMol3 approachrdquoThe Journal of Chemical Physics vol 113 no 18 pp 7756ndash77642000

[23] K Fukui ldquoRole of frontier orbitals in chemical reactionsrdquoScience vol 218 no 4574 pp 747ndash754 1982

[24] V BMokrushin V TsangW Zachariah andVKnyazev ldquo2002NIST Gaithersburg MDrdquo

[25] M Altarawneh and B Z Dlugogorski ldquoFormation and chlori-nation of carbazole phenoxazine and phenazinerdquoEnvironmen-tal Science amp Technology vol 49 no 4 pp 2215ndash2221 2015

[26] D Thompson ldquoEnthalpies of formation and entropies of chlo-rinated dibenzo-p-dioxins and dibenzofurans selected data forcomputer-based studiesrdquo Thermochimica Acta vol 261 no Cpp 7ndash20 1995

[27] H Y Afeefy J F Liebman and S E Stein ldquoNeutral Ther-mochemical Datardquo in NIST Chemistry WebBook NIST Stan-dard Reference Database Number W G Mallard and PJ Linstrom Eds vol 69 November 1998 httpwebbooknistgovchemistry

[28] M Zaheeruddin and Z Lodhi ldquoEnthalpies of formation ofsome cyclic compoundsrdquo The Journal of Physical Chemistry(Peshawar Pak) vol 10 pp 111ndash118 1991

[29] DMYork andMKarplus ldquoA smooth solvation potential basedon the conductor-like screening modelrdquoThe Journal of PhysicalChemistry A vol 103 no 50 pp 11060ndash11079 1999

6 Heteroatom Chemistry

of mono- di- tri- and tetrachlorothiophenes as well as cor-responding radical cation forms as monomers for conductingpolymersrdquo Chemistry Central Journal vol 5 no 1 2011

[15] K SiddiqueMAltarawneh A Saeed Z Zeng J Gore andB ZDlugogorski ldquoInteraction of NH2 radical with alkylbenzenesrdquoCombustion and Flame vol 200 pp 85ndash96 2019

[16] M Altarawneh T Dar and B Z Dlugogorski ldquoThermochem-ical parameters and pK a values for chlorinated congeners ofthiophenolrdquo Journal of Chemicalamp EngineeringData vol 57 no6 pp 1834ndash1842 2012

[17] M Altarawneh and B Z Dlugogorski ldquoThermal decomposi-tion of 12-bis(246-tribromophenoxy)ethane (BTBPE) a novelbrominated flame retardantrdquo Environmental Science amp Technol-ogy vol 48 no 24 pp 14335ndash14343 2014

[18] M J Frisch G W Trucks H B Schlegel et al Gaussian 16Revision B01 Gaussian Inc Wallingford CT Oxfordshire uk2016

[19] J A Montgomery Jr M J Frisch J W Ochterski and G APetersson ldquoA complete basis set model chemistry VII Use ofthe minimum population localization methodrdquo The Journal ofChemical Physics vol 112 no 15 pp 6532ndash6542 2000

[20] N Ahubelem M Altarawneh and B Z Dlugogorski ldquoDehy-drohalogenation of ethyl halidesrdquo Tetrahedron Letters no 35pp 4860ndash4868 2014

[21] M Altarawneh ldquoA theoretical study on the pyrolysis of perfluo-robutanoic acid as a model compound for perfluoroalkyl acidsrdquoTetrahedron Letters vol 53 no 32 pp 4070ndash4073 2012

[22] B Delley ldquoFrommolecules to solids with the DMol3 approachrdquoThe Journal of Chemical Physics vol 113 no 18 pp 7756ndash77642000

[23] K Fukui ldquoRole of frontier orbitals in chemical reactionsrdquoScience vol 218 no 4574 pp 747ndash754 1982

[24] V BMokrushin V TsangW Zachariah andVKnyazev ldquo2002NIST Gaithersburg MDrdquo

[25] M Altarawneh and B Z Dlugogorski ldquoFormation and chlori-nation of carbazole phenoxazine and phenazinerdquoEnvironmen-tal Science amp Technology vol 49 no 4 pp 2215ndash2221 2015

[26] D Thompson ldquoEnthalpies of formation and entropies of chlo-rinated dibenzo-p-dioxins and dibenzofurans selected data forcomputer-based studiesrdquo Thermochimica Acta vol 261 no Cpp 7ndash20 1995

[27] H Y Afeefy J F Liebman and S E Stein ldquoNeutral Ther-mochemical Datardquo in NIST Chemistry WebBook NIST Stan-dard Reference Database Number W G Mallard and PJ Linstrom Eds vol 69 November 1998 httpwebbooknistgovchemistry

[28] M Zaheeruddin and Z Lodhi ldquoEnthalpies of formation ofsome cyclic compoundsrdquo The Journal of Physical Chemistry(Peshawar Pak) vol 10 pp 111ndash118 1991

[29] DMYork andMKarplus ldquoA smooth solvation potential basedon the conductor-like screening modelrdquoThe Journal of PhysicalChemistry A vol 103 no 50 pp 11060ndash11079 1999

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