synthesisofsomepyrimidine,pyrazole,andpyridine

Research ArticleSynthesis of Some Pyrimidine Pyrazole and PyridineDerivatives and Their Reactivity Descriptors

Nour E A Abd El-Sattar 1 Eman H K Badawy1 and M S A Abdel-Mottaleb 2

1Department of Chemistry Organic Labs Faculty of Science Ain Shams University Abbasiya Cairo 11566 Egypt2Department of Chemistry Computational Chemistry Lab Faculty of Science Ain Shams University AbbasiyaCairo 11566 Egypt

Correspondence should be addressed to M S A Abdel-Mottaleb phochem08photoenergyorg

Received 2 September 2018 Revised 9 October 2018 Accepted 22 October 2018 Published 13 November 2018

Academic Editor Pedro M Mancini

Copyright copy 2018 Nour E A Abd El-Sattar et al (is 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 properly cited

A series of novel pyrimidine (2 3) pyrazole (4 5) and pyridine (6) derivatives were synthesized using a chalcone-bearingthiophene nucleus (1) (e target compounds were synthesized by reaction of compound (1) with urea thiourea malononitrilehydrazine hydrate and 24-dinitrophenyl hydrazine respectively Molecular electronic structures have been modeled withindensity functional theory framework (DFT) Reactivity indices and electrostatic surface potential maps (ESP maps) allow us toestablish trends that enable making predictions about chemical characteristics of the newly synthesized molecules and theirproton transfer tautomers Proton transfer is generally more favored in solution than in the gas phase In acetonitrile keto-formtautomers and thione-form tautomers become more energetically stable than the corresponding enol or thiol tautomers due tosolvent-induced enhancement in the molecular polarity identified by computed dipole moment

1 Introduction

Chalcone derivatives from natural sources or synthetic or-igin exhibit diverse pharmacological activities such as an-timicrobial [1] anticancer [2] antioxidant [3] antitumor[4] anti-inflammatory [5] and antitubercular [6]

Heterocyclic compounds particularly five- or six-membered ring compounds have occupied the first placeamong various classes of organic compounds for theirdiverse biological activities(ese compounds possess diversechemotherapeutic and pharmacological activities Pyrim-idine and their derivatives have been found to possessa broad spectrum of biological activities such as antimi-crobial anti-inflammatory analgesic antiviral and anti-cancer activities [7]

Pyrazolines are well-known important nitrogen-containing five-membered heterocyclic compounds It isalso worthy to mention that pyrazoline derivatives have beenknown to possess widespread pharmacological activitiessuch as anti-inflammatory [8] anticonvulsant [9 10] an-timicrobial [11 12] anticancer [13] antiviral [14] andhypotensive [15] activities

In the present work a chalcone-bearing thiophene nu-cleus (1) was prepared and used as a key starting material forobtaining the desired pyrimidine pyrazoline and pyridinederivatives (2ndash6) (Figure 1) Experimentally obtained physicaland spectroscopic properties will be presented and validatedby theoretical parameters related to the molecular reactivities(such as electrophilicity nucleophilicity chemical potentialand hardness) which are obtained by quantum chemicalcomputations using DFT approximations ESP maps of theenergetically optimized new molecules will also be reported(e ESP map surfaces that enable exploration of molecularreactive sites will be discussed Moreover the reliably iden-tified lowest energy tautomers will be explored in the gasphase as well as in acetonitrile (aprotic solvent)

2 Experimental Section

21 Synthesis

211 General Procedure for the Preparation of Compounds(2 and 3) A mixture of chalcone (1) (25 g 10 mmol) anddifferent nucleophilic reagents namely urea and thiourea

HindawiJournal of ChemistryVolume 2018 Article ID 8795061 11 pageshttpsdoiorg10115520188795061

(10 mmol) was dissolved in ethanolic sodium hydroxide (4 gNaOH and 10mL ethanol) and was stirred for about 2-3hours with a magnetic stirrer (is was then poured into400ml of cold water with continuous stirring for an hourand after that we kept the mixture in a refrigerator for 24

hours (e precipitate obtained was filtered washed andrecrystallized (mostly in ethanol)

4-(4-Nitrophenyl)-6-(thiophen-2-yl) pyrimidin-2-ol (2)Yields 80 mp 252ndash255oC yellow powder IR (KBr]cmminus1) 3434 (3877) cmminus1 (]OH) 3096 (3242) cmminus1

1

1-(4-Nitrophenyl)-3-(thiophen-2-yl)prop-2-en-1-

one

2

4-(4-Nitrophenyl)-6-(thiophen-2-yl)pyrimidin-2-ol

3

4-(4-Nitrophenyl)-6-(thiophen-2-yl)pyrimidine-2-

iol

4

3-(4-Nitrophenyl)-5-(thiophen-2-yl)-45-dihydro-

1H-pyrazole

5

1-(24-Dinitrophenyl)-3-(4-nitrophenyl)-5-(thiophen-2-yl)-45-dihydro-1H-pyrazole

6

2-Amino-6-(4-nitrophenyl)-4-(thiophen-2-yl)nicotinonitrile

S

N N

NO2

OH

NO2

NO2

NO2

NO2

NO2

NN

O2N

S

NH2

NCN

S

S

N N

SH

S

HN N

S CH=CH-C

O

NO2

Figure 1 Optimized geometries (best view) of chalcone (1) and newly synthesized molecules (left side) as well as nomenclature (right side)Hydrogen atoms are removed from some molecules for clarity

2 Journal of Chemistry

(]Aromatic) 157459 (1629) cmminus1 (]CC) 16527 cmminus1 (]CN)1H-NMR (300MHz DMSO-d6) δ ppm 83 (88) (doublet2H ArH J 68Hz) 82 (86) (doublet 2H ArH J 68Hz)79 (77) (singlet 1H pyrimidine) 78 (58) (singlet 1H OHD2O exchangeable) 71ndash77 (73ndash8) (multiplet 3H thiophen)anal calculated for C14H9N3O3S (29930) C 5618 H 303 N1404 S 1071 found C 5600 H 301 N 1420 S 1067 [16]

4-(4-Nitrophenyl)-6-(thiophen-2-yl) pyrimidine-2-thiol(3) Yields 85 mp 250degC yellow powder IR (KBr ]cmminus1)309808 (3237) cmminus1 (]Aromatic) 236237 (2797) cmminus1 (]SH)157556 (1516) cmminus1 (]CC) 16527 (1627) cmminus1 (]CN) 1H-NMR (300MHz DMSO-d6) δ ppm 83 (87) (doublet 2HArH J 79Hz) 82 (85) (doublet 2H ArH J 79Hz) 80(77) (singlet 1H pyrimidine) 79ndash72 (79ndash73) (multiplet3H thiophen) 72 (48) (singlet 1H SH) anal calculated forC14H9N3O2S2 (31537) C 5332 H 288 N 1332 S 2033found C 5329 H 281 N 1330 S 1998 [17]

212 General Procedure for the Preparation of Compounds (4and 5) We dissolved a mixture of chalcone (1) (25 g 10mmol) and different nucleophilic reagents namely hydra-zine hydrate and 24-dinitrophenyl hydrazine (10 mmol)50ml ethanol and furthermore we added a few drops ofconc HCl (en the reaction mixture was refluxed for 4 hrand after that we poured the mixture on crushed ice (eprecipitate was filtered dried and recrystallized from eth-anol to give compounds 4 and 5

3-(4-Nitrophenyl)-5-(thiophen-2-yl)-4 5-dihydro-1H-pyrazole (4) Yields 70 mp 91ndash92degC yellow powder IR(KBr ]cmminus1) 342785 cmminus1 (]NH) 310001 cmminus1 (]Aromatic)157652 cmminus1 (]CC) 16566 cmminus1 (]CN) 1H-NMR(300MHz DMSO-d6) δ ppm 83 (86) (doublet 2H ArHJ 76Hz) 79 (74) (doublet 2H ArH J 76Hz) 72ndash69(72ndash69) (multiplet 3H thiophene) 71 (singlet 1H NHD2O exchangeable) 40 (32) (triplet 1H pyrazole) 34(doublet 2H pyrazole) anal calculated for C13H11N3O2S(27331) C 5713 H 406 N 1537 S 1173 found C 5701H 396 N 1517 S 1151

1-(24-Dinitrophenyl)-3-(4-nitrophenyl)-5-(thiophen-2-yl)-4 5-dihydro-1H-pyrazole (5) Yields 87 mp 145ndash147oCbrown crystal IR (KBr ]cmminus1) 314051 cmminus1 (3253)(]Aromatic) 157749 cmminus1 (]CC) 162763 cmminus1 (]CN)123904 cmminus1 (] CndashSndashC group) 1H-NMR (300MHz DMSO-d6)δ ppm 83 (86) (doublet 2H ArH J 68Hz) 75 (74)(doublet 2H ArH J 68Hz) δ ppm 71 (72ndash75) (multiplet3H thiophene) 40 (36) (triplet 1H pyrazole) 31 (doublet2H pyrazole) anal calculated for C19H13N5O6S (43940) C5194 H 298 N 1594 S 730 found C 5154 H 268 N1579 S 721

213 Synthesis of 2-Amino-6-(4-nitrophenyl)-4-(thiophen-2-yl) Nicotinonitrile (6) A mixture of compound 1 (25 g10mmol) ammonium acetate (05 g) and malononitrile(066 g 10mmol) in 30mL ethanol was refluxed for 4 hr(esolvent was evaporated under reduced pressure and theremaining residue was poured into cold water (e obtainedprecipitate was filtered off and recrystallized from ethanol toproduce compound 6 (6) yields 90 mp 110ndash112degCyellowish brown powder IR (KBr ]cmminus1) 336325

30162 cmminus1 (]NH2) 310676 cmminus1 (]Aromatic) 219749 cmminus1(]CN) 157459 cmminus1 (]CC) 163727 cmminus1 (]CN) 134607 cmminus1(]C-S-C group)1H-NMR (300MHz DMSO-d6) δ ppm 101(singlet 1H NH D2O exchangeable) δ ppm 83 (doublet 2HArH J 82Hz) 81 (doublet 2H ArH J 82Hz) 80 (singlet1H pyridine) δ ppm 70ndash78 (multiplet 3H thiophene) analcalculated for C16H10N4O2S (32234) C 5962 H 313 N1738 S 995 found C 5932 H 299 N 1707 S 955

22 Instrumentation (e infrared spectra were recordedusing potassium bromide disks on a Pye Unicam SP-3-300infrared spectrophotometer 1H-NMR spectra were run at300MHz on a Varian Mercury VX-300 NMR spectrometerusing TMS as an internal standard in deuterated dime-thylsulphoxide (e microanalytical data were measured inthe Central Lab of Cairo University Egypt the Ministry ofDefense Chemical Laboratories Egypt and the Microana-lytical Center of Ain Shams University Egypt All thechemical reactions were monitored by TLC Melting pointsmeasured were uncorrected

23 Computations Computations were performed usingGaussian 16 revision A03 package [18] andor Spartanrsquo16parallel QC program (Wavefunction Inc USA) Optimizedstructures and spectroscopic data were obtained within DFTby employing the widely used wB97X-D6-31G (dp) modelLong-range corrected hybrid density functional the wB97X-Dfunctional [19] includes empirical damped atom-atom dis-persion corrections wB97X-D is significantly more accuratethan the commonly used functional B3LYP Harmonic vi-brational frequencies of the optimized geometries were cal-culated with the same model in order to verify that they aretrue minima (with zero imaginary frequencies) Tight SCFconvergence (energy change 10eminus08 au) and larger integrationgrids are used (e list of the convergence criteria followed is5eminus9 for RMS density change 1eminus7 for maximum densitychange 5eminus7 for direct inversion in the iterative subspace(DIIS) error convergence and 1eminus5 for orbital gradientconvergence Finally we used successfully a less-expensivecomputational model wB97X-D6-31G (d) without anychange in the trends obtained from the basis set 6-31G(dp)

3 Results and Discussion

31 Synthesis and Spectroscopic Properties New pyrimidinederivatives are prepared by reaction of the chalcone (1) withurea and thiourea in ethanolic sodium hydroxide to produce4-(4-nitrophenyl)-6-(thiophen-2-yl) pyrimidin-2-ol molecule(2) and 4-(4-nitrophenyl)-6-(thiophen-2-yl) pyrimidine-2-thiol (3) respectively (e structure of the products wasconfirmed by IR which showed OH group stretching at 3434(calculated 3675) cmminus1 (e 1H-NMR showed singlet ofpyrimidine protons at δ 796 (75 calculated) ppm in com-pound 2 (e IR of compound 3 confirms the presence ofthe SH group at 236237 (2689 calculated) cmminus1 while its1H-NMR showed the formation of pyrimidine by presence ofsinglet proton at δ 8002 (δ 74 calculated) ppm as shown inexperimental (Scheme 1)

Journal of Chemistry 3

(e IR of compound 4 showed stretching vibration of theNH group at 342785 cmminus1 and its 1H-NMR showed singlet ofthe pyrazole protons at δ 4061 (32) ppm (e 1H-NMR ofcompound 5 shows a singlet due to pyrazole protons at δ5105ppm Finally reaction of chalcone (1) with malononitrilein presence of ethanol and ammonium acetate produced thecorresponding pyridine derivatives 2-amino-6-(4-nitrophenyl)-4-(thiophen-2-yl) nicotinonitrile (6) (e IR spectrum ofcompound 6 exhibits stretching vibrations of the NH group at336325 cmminus1 and CN group at 219749 cmminus1 Unfortunatelythe computed IR spectra of these compounds in gaseous phasewere not in good agreement with the experimentallymeasuredIR spectra in the solid phase It seems that the difference in thephase has influence in these molecules whereas the computed(using the same model) 1H-NMR shifts (given between pa-rentheses in the Experimental Section 21) are in a fairagreement with experimentally measured values

32 Molecular Reactivities Chemical reactivity theoryquantifies the reactive propensity of isolated species throughthe introduction of a set of reactivity indices or descriptors Itsroots go deep into the history of chemistry as far back as theintroduction of such fundamental concepts as acid baseLewis acid and Lewis base It pervades almost all of chemistry

(eoretical reactivity indices based on the conceptualdensity functional theory (DFT) have become a powerful toolfor the semiquantitative study of organic reactivity and themost relevant indices defined within the conceptual DFT [20]are reviewed and discussed elsewhere [21ndash26] Molecularreactivity indices [20ndash26] such as chemical potential (μ)hardness (η) and electrophilicity (ω) were computed from theenergies of frontier orbitals (graphically represented in Fig-ure 2 and summarized in Table 1) and defined in terms ofionization energy (I) and electron affinity (A) as follows

(1) Chemical potential is defined as

μ asymp minus12

(I + A) asymp12isinL minusisinH( 1113857

or simply μ 05(LUMO + HOMO)

(1)

Chemical potential is the link between structure andreactivity (e greater a structurersquos chemical potential thegreater is its reactivity (e most important factors thatcontribute to the chemical potential are low-energy LUMOindicating strong acid behavior (reactive electrophile) andhigh-energy HOMO reflecting strong base behavior (re-active nucleophile) However the defined index of chemical

1

2

6

3

4

5

S

NC

NH2

N

SN

N N NS

OH

NO2 NO2C2H5OH

amm acetate

CH2(CN)2

NH2CONH2

40 NaOH

40 NaOH

S CH=CH-C

Chalcone

NO2

NO2

O

C2H5OHN

H2-

NH

2

C 2H

5OH

NH2CSNH2

NO2

O2N

N N

NO2

NO2SH

S

NHN

S

24-Dinitrophenylhydrazine

Scheme 1


Compound HOMO

HOMO-LOMO

LOMO

1

2

3

4

5

6

Figure 2 HOMO-LUMO frontier orbital of the newly synthesized molecules and the starting molecule (red color represents negative phasewhile the blue color points to the positive one) All molecules containing one or three nitro groups are of noticeable charge transfer charactershowing larger contribution of the orbitals localized on the nitro groups in the LUMOs

Table 1 (e structure-properties relationships in gas phase reflecting the effect of molecular structure on the associated energy andthermodynamic parameters which are important for molecular characterization (HOMO-LUMO values of geometry-optimized moleculesin acetonitrile (ACN) are also given)

Moleculelabel

Energy(kcalmol)

Gas ACN acetonitrile Dipole(debye)

Hdeg

(kcalmol)Gdeg

(kcalmol)Sdeg

(JmolmiddotK)EHOMO (eV) ELUMO (eV) EHOMO (eV) ELUMO (eV)1 minus739848 minus836 minus115 minus811 minus115 597 minus739716 minus739755 130732 minus832472 minus852 minus094 minus831 minus099 635 minus832327 minus832368 136443 minus1035131 minus852 minus101 minus833 minus102 596 minus1034990 minus1035031 140304 minus762106 minus791 minus061 minus780 minus084 710 minus761954 minus761993 131585 minus1163613 minus816 minus116 minus778 minus114 958 minus1163402 minus1163457 182466 minus867806 minus84 minus099 minus817 minus100 342 minus867646 minus867690 14588


potential takes into account the mean value of HOMO andLUMO

(2) Hardness is given by

η asymp12

(IminusA) asymp12isinL minus isinH( 1113857

or simply η 05(LUMOminusHOMO)

(2)

(e chemical hardness η can be thought as a resistance ofa molecule to exchange electron density with the environment

(3) Electrophilicity Parr (in 1999) defined the electro-philicity index [26] ω μ22η which measures thetotal ability to attract electrons (e electrophilicityindex gives a measure of the energy stabilization ofa molecule in case it acquires an additional amountof electron density from the environment (eelectrophilicity index shows the tendency of anelectrophile to acquire an extra amount of electrondensity given by μ and the resistance of a moleculeto exchange electron density with the environmentgiven by η (erefore a good electrophile exhibitsa high absolute μ value and a low η value (eelectrophilicity index is considered an importantfacility for the study of the reactivity of organicmolecules [21]

(4) Nucleophilicity (N) Domingo and his coworkers[21ndash25] suggested that a simple index chosen forthe nucleophilicity N based on the HOMO en-ergy within DFT could be employed to explainthe reactivity of the organic material towardselectrophiles

(e nucleophilicity index is defined as N EHOMO(ev) +

912(ev) where minus912 is the energy of the HOMO of tetra-cyanoethylene (TCE) (us this nucleophilicity scale is re-ferred to TCE and taken as a reference because TCE exhibitsthe lowest HOMO energy (minus912 eV) in a large series ofmolecules investigated [22]

Inspecting moleculersquos ESP surface is probably a goodstart for considerations of the moleculersquos reactivity since thisis where two approachingmolecules would first interact ESPmaps are depicted in Figure 3(e results should point to thebinding sites which are of potential influence in chemicalreactivities and medical applications

Table 1 shows a compilation of some thermodynamicparameters and dipole moment values reflecting molec-ular polarities All molecules are fairly polar and shouldbe soluble in polar solvents (e computed total energyand thermodynamic parameters reflect the stability of themolecules Solvent effect induced by acetonitrile (aproticsolvent) is reflected in destabilization of HOMO LUMOenergy levels are almost unaffected except in case ofmolecule 4 where its LUMO is stabilized by about 023 eV(is is reflected in the difference in reactivity indices givenin Table 2 Nucleophilicity is markedly enhanced whilechemical potential and hardness values are lowered inpresence of the solvent Electrophilicity shows irregularbehavior relative to the gas phase values It seems that

the more simple indices of chemical potential hardnessand nucleophilicity are more reliable than the electro-philicity parameter which is defined as the square ofchemical potential divided by double of the hardness(Section 32)

Inspection of Table 2 reveals the reactivities of the newmolecules molecule 4 is the most susceptible molecule toelectrophilic attack due to its large N value of 121 eV andsmaller ω value of 249 eV whereas molecule 3 is the mostlikely attacked by a nucleophile Molecule 3 is of highestchemical potential (minus477 eV) lowest nucleophilicity N(060 eV) and of considerable high electrophilicity (302)(us molecule 3 is the most chemically reactive among therelated molecules (2 4ndash6) and is seeking for electronsHowever in presence of a solvent such as acetonitrilemolecule 5 is of highest nucleophilic character Nucleo-philicity decreases in the order 5 gt 4 gt 1 gt 6 gt 2 gt 3 Morewill be discussed later

Spartan codes enabled identification of tautomers (dueto proton transfer) through tautomer search Each ofmolecules 2 and 3 has two tautomers whereas molecule 6has only one tautomer Geometry optimized (employingwB97X-D6-31G (dp) model) tautomerrsquos information issummarized in Table 3 and their optimized geometries aredepicted in Figure 4 It seems that the lowest energy (moststable) tautomers are the genuine 2 3 and 6 moleculesthemselves Proton transfer to form other tautomers (Fig-ure 4) results in energy destabilization Relative energy isreported for comparing relative energy of tautomers ofindividual compounds (Table 3) Largest destabilizationcould be seen in case of proton transfer in tautomer 6-1

(e reactivities of the tautomers in the gas phase aretabulated in Table 3 and could be easily seen by inspectionof Figure 5 However it should be mentioned that solventnature could be of influential effect on the stability ofa tautomer (us we tried geometry optimization in theacetonitrile solvent (aprotic solvent) using the wB97X-D6-31G(dp) model and CPCM solvation model [27] andfound a drastic effect on the relative stability of the tau-tomers as can be seen from the data summarized in Table 4Proton transfer is generally more favored in solutionthan in the gas phase Moreover keto-form tautomers andthione-form tautomers become more energetically stablethan the corresponding enol (2) or thiol (3) tautomersmost probably because of the increase in conjugationHowever although solvent induces tiny stability relative tothat of the gas phase proton transfer in 6 is still a less-favored process Understanding how reactivity descriptorsof these polar molecules and their tautomers are modifiedin going from the gas phase into solution can be un-derstood with the solvent-induced increase in the dipolemoment value (Table 4) as well as thermodynamic pa-rameters (e more polar the molecule is the more it isenergetically stabilized as could be seen from the dipolemoment data summarized in Table 4 for the gas andsolvent phases Furthermore from thermodynamics pointof view (Table 5) enhancements in the computed enthalpyand Gibbs free energy are noticed in acetonitrile (evalues verify the conclusions drawn from Table 4


1

2

3

4

5

6

Figure 3 Solid surface (8 bands) of ESP maps and color codes (e color code reflects electrostatic potential energy values in kJmol (eredder the area is the higher the electron density is susceptible to electrophilic attack and the bluer the area is the lower the electron densityis that could easily bind with a nucleophile

Table 2 Effect of the solvent on computed reactivity indices in eV sorted according to descending nucleophilicity in the gas phase

MoleculeGas Acetonitrile

μ η ω N μ η ω N4 minus426 365 249 121 minus432 348 268 1325 minus466 350 310 096 minus446 332 300 1341 minus476 361 314 076 minus463 348 308 1016 minus470 371 297 072 minus459 359 293 0952 minus473 379 295 060 minus465 366 295 0813 minus477 376 302 060 minus468 366 299 079


Reactivity indices also altered significantly Nucleo-philicity increases for 2 and its tautomers as well as for 3and 6 because the solvent has a noticeable effect onHOMO stabilization (e solvent has smaller effect on

stabilizing the HOMO of the thione tautomers of 3 andon 6-1 tautomer Chemical potential and hardnessmarkedly decrease except for thione tautomers of 3whereas it increases in acetonitrile due to influential

2 2-1 2-2

3 3-1

6 6-1

3-2

Figure 4 Optimized geometries of the tautomers of molecules 2 3 and 6

Table 3 Relative energies and frontier orbital energies of the tautomers of molecules 2 (denoted as 2-1 and 2-2) 3 (3-1 and 3-2) and 6 (6-1)in the gas phase

Tautomer Relative energy (kJmol) EHOMO (eV) ELUMO (eV) μ η ω N Dipole (debye)2 0 minus852 minus094 minus473 379 295 06 6352-1 151 minus864 minus128 minus496 368 334 048 4332-2 1807 minus852 minus108 minus480 372 31 06 9183 0 minus852 minus101 minus477 3755 302 06 5963-1 185 minus779 minus142 minus461 3185 333 133 6033-2 221 minus783 minus13 minus457 3265 319 129 9926 0 minus84 minus099 minus470 3705 297 072 3426-1 7469 minus747 minus153 minus450 297 341 165 381


destabilization of LUMO Electrophilicity dominantlydecreases in acetonitrile

More about the reactivities of other molecules could bepredicted by inspection of Figure 5 It is of interest to

visualize (Figure 5) the structure-properties relationship inthe gaseous phase Systematic increase in nucleophilicitywhile changing from moleculetautomer 2-1 (of lowestnucleophilicity index) to 6-1 (of highest nucleophilic

ndash42

ndash44

ndash46

ndash48

ndash51

3

2

2-1 2-

2

3-2

3-1

6-1

61

5

411

38

36

34

32

3

28

2

15

1

05

0

36

34

32

3

28

Molecule

26

24

NucleophilicityChemical potential Electrophilicity

Hardness

Elec

trop

hilic

ity ω

Har

dnes

s η

Nuc

leop

hilic

ity N

Chem

ical

pot

entia

l μ

Figure 5 Quantitative structure-reactivity descriptor relationships of the synthesized molecules and its tautomers Each of molecules 2 and3 has two other tautomers while molecule 6 can exist in two tautomeric shapes (Figure 4) Similar figure is obtained in the solution phase(ACN)

Table 4 Relative energies and frontier orbital energies of the tautomers of 2 (denoted as 2-1 and 2-2) 3 (denoted as 3-1 and 3-2) and 6(denoted as 6-1) in acetonitrile

Tautomer Relative energy (kJmol) EHOMO (eV) ELUMO (eV) μ η ω NDipole (debye)ACN lowastGas

2 0 minus831 minus099 minus465 366 295 081 802 6352-1 minus077 minus827 minus107 minus467 36 303 085 649 4332-2 minus1051 minus845 minus109 minus477 368 309 067 1244 9183 0 minus833 minus102 minus468 3655 299 079 779 5963-1 minus1422 minus801 minus126 minus464 3375 318 111 1032 6033-2 minus2461 minus808 minus122 minus465 343 315 104 1485 9926 0 minus817 minus101 minus459 358 294 095 373 3426-1 6096 minus777 minus113 minus445 332 298 135 542 381lowastDipole moment in the gas phase is given for quick comparison

Table 5 (ermodynamic parameters in (kJmol) of the tautomers calculated using less-expensive wB97X-D6-31G(d) computationalmodel

TautomerGas phase Acetonitrile

Relative energy H G Relative energy H G2 0 minus3482461966 minus3482630103 0 minus3482505024 minus34826775462-1 1667 minus3482444454 minus3482612486 minus643 minus3482511089 minus34826836632-2 1993 minus3482441645 minus3482609834 minus1619 minus348252041 minus34826928263 0 minus4330401034 minus4330574264 0 minus4330442438 minus43306202373-1 2645 minus4330365747 minus4330537638 minus1352 minus4330447715 minus4330624073-2 2222 minus4330369659 minus4330541209 minus2399 minus4330457876 minus43306338896 0 minus3630234663 minus3630415639 0 minus3630280845 minus36304669416-1 7494 minus3630157368 minus3630335692 6113 minus3630217623 minus3630400936


property) could be suggested as a measure of tuningmolecular properties One can quickly predict any re-activity descriptor of a molecule or a tautomer by a glimpseof Figure 5 One can easily correlate all reactivity indices ofa molecule to each other

4 Conclusion

We synthesized five new products of pyrimidine pyrazoleand pyridine derivatives using a chalcone substituted witha thiophene nucleus Spectroscopic data were introduced aswell as reactivity indices

(e wB97X-D6-31G (dp) model within the DFT is usedto optimize the structures and predict the structure-propertiesrelationships Reactivity parameters calculated from thefrontier orbitals help in prediction of nucleophilicity elec-trophilicity and hardness as well as chemical potential of themolecules synthesized Proton transfer from functionalgroups in some molecules results in presence of severaltautomers In the gas phase proton transfer destabilizes thetautomermolecules Proton transfer is generallymore favoredin solution than in the gas phase due to solvent-inducedenhancement of the molecular polarity identified by thecomputed dipole moment values In particular keto-formtautomers and thione-form tautomers become more ener-getically stable than the corresponding enol (2) or thiol (3)tautomers However proton transfer in 6 is still a less-favoredprocess since the solvent induced small increase in the dipolemoment value Additionally thermodynamic parametersverify the conclusions drawn from the molecular polarity

Computed and visualized ESP map surfaces enable ex-ploration of molecular reactive sites

Generally based on the relative nucleophilicity index Nnucleophilicity increases in the order 3 lt 2 lt 6 lt 1 lt 5 lt 4 inthe gas phase while the order in acetonitrile is slightlydifferent 3 lt 2 lt 6 lt 1 lt 4 lt 5 Generally all reactivity indicescomputed could be easily predicted for a compound bya glimpse of a reactivity indices-molecule graph

Data Availability

(e data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

(e authors declare that there are no conflicts of interest inpublishing this manuscript

References

[1] A S Rao L Simon K K Srinivasan et al ldquoSynthesis and invitro antimicrobial evaluation of 5rsquo-acetamido-2rsquo-hydroxychalcone derivativesrdquo Research Journal of Chemical Sciencesvol 4 no 2 pp 56ndash59 2014

[2] P Champelovier X Chauchet F H Puch et al ldquoCellular andmolecular mechanisms activating the cell death processes bychalcones critical structural effectsrdquo Toxicology In Vitrovol 27 no 8 pp 2305ndash2315 2013

[3] B-T Kim K-J O J-C Chun and K Hwang ldquoSynthesis ofdihydroxylated chalcone derivatives with diverse substitutionpatterns and their radical scavenging ability toward DPPHfree radicalsrdquo Bulletin of the Korean Chemical Society vol 29no 6 pp 1125ndash1130 2008

[4] D Kumar N M Kumar K Akamatsu E Kusaka H Haradaand T Ito ldquoSynthesis and biological evaluation of indolylchalcones as antitumor agentsrdquo Bioorganic and MedicinalChemistry Letters vol 20 pp 3916ndash3919 2010

[5] S B Jadhav R S Annapure D K B Rathi P PatilN P Adlinge and S D Rathod ldquoSynthesis and evaluation ofantimicrobial and invitro antindashinflammatory activity of somepyrimidine derivatives from chalconesrdquo International Journalof Applied Biology and Pharmaceutical Technology vol 7pp 221ndash227 2016

[6] M Kachroo R Panda and Y Yadav ldquoSynthesis and bi-ological activities of some new pyrimidine derivatives fromchalconesrdquo Der Pharma Chemica vol 6 no 2 pp 352ndash3592014

[7] S F Mohamed E M Flefel A E E Amr and D N Abd El-Shafy ldquoAnti-HSV-1 activity and mechanism of action of somenew synthesized substituted pyrimidine thiopyrimidine andthiazolopyrimidine derivativesrdquo European Journal of Medic-inal Chemistry vol 45 no 4 pp 1494ndash1501 2010

[8] F F Barsoum and A S Girgis ldquoFacile synthesis of bis 4 5-dihydro-1H-pyrazole-1-carboxamides and their thio-analogues of potential PGE2 inhibitory propertiesrdquo Euro-pean Journal of Medicinal Chemistry vol 44 no 5pp 2172ndash2177 2009

[9] M Yusuf and P Jain ldquoSynthetic and biological studies ofpyrazolines and related heterocyclic compoundsrdquo ArabianJournal of Chemistry vol 7 no 5 pp 553ndash596 2014

[10] A A Siddiqui M A Rahman M Shaharyar and R MishraldquoSynthesis and anticonvulsant activity of some substituted 35-diphenyl-2- pyrazoline-1-carboxamide derivativesrdquo ChemSci Jvol 8 pp 1ndash10 2010

[11] E M Sharshira and N M M Hamada ldquoSynthesis and in vitroantimicrobial activity of some pyrazolyl-1-carboxamide de-rivativesrdquo Molecules vol 16 no 9 pp 7736ndash7745 2011

[12] H Naoufel Ben H Amel M Mahbouba and M MoncefldquoSynthesis of new pyrazolines and their biological evaluationas antimicrobial agentsrdquo Journal of Chemical Research vol 36no 10 pp 563ndash565 2012

[13] H Dmytro Z Borys V Olexandr Z Lucjusz G Andrzej andL Roman ldquoSynthesis of novel thiazolone-based compoundscontaining pyrazoline moiety and evaluation of their anti-cancer activityrdquo European Journal of Medicinal Chemistryvol 44 no 4 pp 1396ndash1404 2009

[14] M S Mui B N Siew A D Buss S C Crasta L G Kah andK L Sue ldquoBenzylidene rhodanines as novel inhibitors ofUDP-N-acetylmuramatel-alanine ligaserdquo Bioorganic andMedicinal Chemistry Letters vol 12 no 4 pp 697ndash699 2012

[15] G Turan-zitouni P Chevallet F S Kilic and K ErolldquoSynthesis of some thiazolyl-pyrazoline derivatives and pre-liminary investigation of their hypotensive activityrdquo EuropeanJournal of Medicinal Chemistry vol 35 pp 635ndash641 2000

[16] V D Joshi M D Kshirsagar and S Singhal ldquoSynthesis andpharmacological study of some novel pyrimidinesrdquo DerPharmacia Sinica vol 3 no 3 pp 343ndash348 2012

[17] M M M Hussain k Ishwar Bhat B C Revanasiddappa andD R Bharathi ldquoSynthesis and biological evaluation ofsome novel 2-mercapto pyrimidinesrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 55 pp 471ndash4732013


[18] M J Frisch G W Trucks H B Schlegel et al Gaussian 16Gaussian Inc Wallingford CT USA 2016

[19] J D Chai and M Head-Gordon ldquoLong-range correctedhybrid density functionals with damped atom-atom disper-sion correctionsrdquo Physical Chemistry Chemical Physicsvol 10 no 44 pp 6615ndash6620 2008

[20] P Geerlings F de Proft and W Langenaeker ldquoConceptualdensity functional theoryrdquo Chemical Reviews vol 103 no 5pp 1793ndash1873 2003

[21] I Fleming Frontier Orbitals and Organic Chemical ReactionsJohn Wiley and Sons New York NY USA 1976

[22] L R Domingo E Chamorro and P Perez ldquoUnderstandingthe reactivity of captodative ethylenes in polar cycloadditionreactions A theoretical studyrdquo Journal of Organic Chemistryvol 73 pp 4615ndash4624 2008

[23] L R Domingo M Rıos-Gutierrez and P Perez ldquoApplica-tions of the conceptual density functional theory indices toorganic chemistry reactivityrdquo Molecules vol 21 no 6748 pages 2016

[24] L R Domingo ldquoA new CndashC bond formation model based onthe quantum chemical topology of electron densityrdquo RSCAdvances vol 4 no 61 pp 32415ndash32428 2014

[25] L R Domingo ldquoMolecular electron density theory a modernview of reactivity in organic chemistryrdquo Molecules vol 21no 10 p 1319 2016

[26] F Zielinski V Tognetti and L Joubert ldquoCondensed de-scriptors for reactivity a methodological studyrdquo ChemicalPhysics Letters vol 527 pp 67ndash72 2012

[27] M Cossi N Rega G Scalmani and V Barone ldquoEnergiesstructures and electronic properties of molecules in solutionwith the C-PCM solvation modelrdquo Journal of ComputationalChemistry vol 24 no 6 pp 669ndash681 2003


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nom

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ls


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Submit your manuscripts atwwwhindawicom

(10 mmol) was dissolved in ethanolic sodium hydroxide (4 gNaOH and 10mL ethanol) and was stirred for about 2-3hours with a magnetic stirrer (is was then poured into400ml of cold water with continuous stirring for an hourand after that we kept the mixture in a refrigerator for 24

hours (e precipitate obtained was filtered washed andrecrystallized (mostly in ethanol)

4-(4-Nitrophenyl)-6-(thiophen-2-yl) pyrimidin-2-ol (2)Yields 80 mp 252ndash255oC yellow powder IR (KBr]cmminus1) 3434 (3877) cmminus1 (]OH) 3096 (3242) cmminus1

1

1-(4-Nitrophenyl)-3-(thiophen-2-yl)prop-2-en-1-

one

2

4-(4-Nitrophenyl)-6-(thiophen-2-yl)pyrimidin-2-ol

3

4-(4-Nitrophenyl)-6-(thiophen-2-yl)pyrimidine-2-

iol

4

3-(4-Nitrophenyl)-5-(thiophen-2-yl)-45-dihydro-

1H-pyrazole

5

1-(24-Dinitrophenyl)-3-(4-nitrophenyl)-5-(thiophen-2-yl)-45-dihydro-1H-pyrazole

6

2-Amino-6-(4-nitrophenyl)-4-(thiophen-2-yl)nicotinonitrile

S

N N

NO2

OH

NO2

NO2

NO2

NO2

NO2

NN

O2N

S

NH2

NCN

S

S

N N

SH

S

HN N

S CH=CH-C

O

NO2

Figure 1 Optimized geometries (best view) of chalcone (1) and newly synthesized molecules (left side) as well as nomenclature (right side)Hydrogen atoms are removed from some molecules for clarity


















μ asymp minus12



(1)


1

2

6

3

4

5

S

NC

NH2

N

SN

N N NS

OH

NO2 NO2C2H5OH

amm acetate

CH2(CN)2

NH2CONH2

40 NaOH

40 NaOH

S CH=CH-C

Chalcone

NO2

NO2

O

C2H5OHN

H2-

NH

2

C 2H

5OH

NH2CSNH2

NO2

O2N

N N

NO2

NO2SH

S

NHN

S


Scheme 1


Compound HOMO

HOMO-LOMO

LOMO

1

2

3

4

5

6



Moleculelabel

Energy(kcalmol)


Hdeg

(kcalmol)Gdeg

(kcalmol)Sdeg





η asymp12



(2)













1

2

3

4

5

6








2 2-1 2-2

3 3-1

6 6-1

3-2








ndash42

ndash44

ndash46

ndash48

ndash51

3

2

2-1 2-

2

3-2

3-1

6-1

61

5

411

38

36

34

32

3

28

2

15

1

05

0

36

34

32

3

28

Molecule

26

24


Hardness

Elec

trop

hilic

ity ω

Har

dnes

s η

Nuc

leop

hilic

ity N

Chem

ical

pot

entia

l μ










4 Conclusion





Data Availability




References



































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls




















μ asymp minus12



(1)


1

2

6

3

4

5

S

NC

NH2

N

SN

N N NS

OH

NO2 NO2C2H5OH

amm acetate

CH2(CN)2

NH2CONH2

40 NaOH

40 NaOH

S CH=CH-C

Chalcone

NO2

NO2

O

C2H5OHN

H2-

NH

2

C 2H

5OH

NH2CSNH2

NO2

O2N

N N

NO2

NO2SH

S

NHN

S


Scheme 1


Compound HOMO

HOMO-LOMO

LOMO

1

2

3

4

5

6



Moleculelabel

Energy(kcalmol)


Hdeg

(kcalmol)Gdeg

(kcalmol)Sdeg





η asymp12



(2)













1

2

3

4

5

6








2 2-1 2-2

3 3-1

6 6-1

3-2








ndash42

ndash44

ndash46

ndash48

ndash51

3

2

2-1 2-

2

3-2

3-1

6-1

61

5

411

38

36

34

32

3

28

2

15

1

05

0

36

34

32

3

28

Molecule

26

24


Hardness

Elec

trop

hilic

ity ω

Har

dnes

s η

Nuc

leop

hilic

ity N

Chem

ical

pot

entia

l μ










4 Conclusion





Data Availability




References



































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls




Compound HOMO

HOMO-LOMO

LOMO

1

2

3

4

5

6



Moleculelabel

Energy(kcalmol)


Hdeg

(kcalmol)Gdeg

(kcalmol)Sdeg





η asymp12



(2)













1

2

3

4

5

6








2 2-1 2-2

3 3-1

6 6-1

3-2








ndash42

ndash44

ndash46

ndash48

ndash51

3

2

2-1 2-

2

3-2

3-1

6-1

61

5

411

38

36

34

32

3

28

2

15

1

05

0

36

34

32

3

28

Molecule

26

24


Hardness

Elec

trop

hilic

ity ω

Har

dnes

s η

Nuc

leop

hilic

ity N

Chem

ical

pot

entia

l μ










4 Conclusion





Data Availability




References



































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls






η asymp12



(2)













1

2

3

4

5

6








2 2-1 2-2

3 3-1

6 6-1

3-2








ndash42

ndash44

ndash46

ndash48

ndash51

3

2

2-1 2-

2

3-2

3-1

6-1

61

5

411

38

36

34

32

3

28

2

15

1

05

0

36

34

32

3

28

Molecule

26

24


Hardness

Elec

trop

hilic

ity ω

Har

dnes

s η

Nuc

leop

hilic

ity N

Chem

ical

pot

entia

l μ










4 Conclusion





Data Availability




References



































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls




1

2

3

4

5

6








2 2-1 2-2

3 3-1

6 6-1

3-2








ndash42

ndash44

ndash46

ndash48

ndash51

3

2

2-1 2-

2

3-2

3-1

6-1

61

5

411

38

36

34

32

3

28

2

15

1

05

0

36

34

32

3

28

Molecule

26

24


Hardness

Elec

trop

hilic

ity ω

Har

dnes

s η

Nuc

leop

hilic

ity N

Chem

ical

pot

entia

l μ










4 Conclusion





Data Availability




References



































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls






2 2-1 2-2

3 3-1

6 6-1

3-2








ndash42

ndash44

ndash46

ndash48

ndash51

3

2

2-1 2-

2

3-2

3-1

6-1

61

5

411

38

36

34

32

3

28

2

15

1

05

0

36

34

32

3

28

Molecule

26

24


Hardness

Elec

trop

hilic

ity ω

Har

dnes

s η

Nuc

leop

hilic

ity N

Chem

ical

pot

entia

l μ










4 Conclusion





Data Availability




References



































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls







ndash42

ndash44

ndash46

ndash48

ndash51

3

2

2-1 2-

2

3-2

3-1

6-1

61

5

411

38

36

34

32

3

28

2

15

1

05

0

36

34

32

3

28

Molecule

26

24


Hardness

Elec

trop

hilic

ity ω

Har

dnes

s η

Nuc

leop

hilic

ity N

Chem

ical

pot

entia

l μ










4 Conclusion





Data Availability




References



































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls





4 Conclusion





Data Availability




References



































Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls




















Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls




synthesisofsomepyrimidine,pyrazole,andpyridine

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