Research Article Structural and Vibrational Study on ...

Hindawi Publishing CorporationJournal of SpectroscopyVolume 2013, Article ID 538917, 13 pageshttp://dx.doi.org/10.1155/2013/538917

Research ArticleStructural and Vibrational Study on Monomer andDimer Forms and Water Clusters of Acetazolamide

Aysen E. Ozel,1 Serda Kecel Gunduz,1 Sefa Celik,2 and Sevim Akyuz3

1 Physics Department, Science Faculty, Istanbul University, Vezneciler, 34134 Istanbul, Turkey2 Electrical-Electronics Eng. Department, Engineering Faculty, Istanbul University, Avcilar, 34320 Istanbul, Turkey3 Physics Department, Science and Letters Faculty, Istanbul Kultur University, Atakoy Campus, Bakirkoy, 34156 Istanbul, Turkey

Correspondence should be addressed to Aysen E. Ozel; [email protected]

Received 24 June 2013; Revised 6 September 2013; Accepted 7 October 2013

Academic Editor: Shin ichi Morita

Copyright © 2013 Aysen E. Ozel et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Experimental IR and Raman spectra of solid acetazolamide have been analysed by computing the molecular structures andvibrational spectra of monomer and dimer forms and water clusters of acetazolamide. The possible stable conformers of freeacetazolamidemolecule in the ground state were obtained by scanning the potential energy surface through the dihedral angles, D

1

(1S-2C-6S-9N), D2(4N-5C-12N-14C), andD

3(5C-12N-14C-16C).The final geometry parameters for the obtained stable conformers

were determined bymeans of geometry optimization, carried out atDFT/B3LYP/6-31G++(d,p) theory level. Afterwards the possibledimer forms of the molecule and acetazolamide-H

2O clusters were formed and their energetically preferred conformations were

investigated using the same method and the same level of theory. The effect of BSSE on the structure and energy of acetazolamidedimer has been investigated.The assignment of the vibrational modes was performed based on the potential energy distribution ofthe vibrational modes, calculated by using GAR2PED program.The experimental vibrational wavenumbers of solid acetazolamideare found to be in better agreement with the calculated wavenumbers of dimer form of acetazolamide than those of its monomericform. NBO analysis has been performed on both monomer and dimer geometries.

1. Introduction

Acetazolamide, C4H6N4O3S2

(1,3,4-thiadiazole-2-sulfona-mide,5-acetamido), is a sulfonamide derivative and carbonicanhydrase inhibitor used clinically to lower intraocular pres-sure in glaucomatous patients. It is also used as a diureticagent for treating acute high-altitude sickness and used forthe treatment of epilepsy, and most frequently it is usedas a drug for the prophylaxis of high-altitude disorders[1–3]. Recently, it has played a major role as a remedyagainst respiratory diseases and it has been used to preventadverse effects of drugs in the treatment of influenza [4] andepilepsy and as diuretic [5]. Traditionally, carbonic anhydraseinhibitors derived from acetazolamide were shown to inhibitthe growth of several tumor cell lines in vitro and in vivo[6, 7].

Acetazolamide is known to exist in two crystal forms(modifications I and II), which was first reported by Pala in1956 [8]. Mathew and Palenik solved the crystal structure of

triclinic acetazolamide (polymorphic form A, modificationII) [9]. Griesser et al. [10] reported the crystal structureof acetazolamide polymorphic form B (modification I) andnotified that crystal polymorphism of acetazolamide wasbased on changes in the spatialmolecular arrangement and inthe connectivities of hydrogen bonds. The experimental andcalculated vibrational spectra [11] and crystal structure [12]of an acetazolamide derivative (5-amino-1,3,4-thiadiazole-2-sulfonamide; Hats) have been reported. The experimen-tal vibrational spectra of the two polymorphic forms (A,B) of acetazolamide were reported by Baraldi et al. [13].The structure and spectroscopic behaviours of some 1,3,4-thiadiazole ligands containing –SO

2NH2groups and their

metal clusters were examined [14–23]. Recently, Brandanet al. [24] calculated the harmonic vibrational wavenum-bers for the optimized geometry of acetazolamide, usingDFT/B3LYP method with the 6-31G∗ and 6-311++G∗∗ basissets. Chaturvedi et al. [25] reported calculated vibrationalspectra of monomer and dimer forms of acetazolamide,

2 Journal of Spectroscopy

but the calculations were performed on the most stableconformer, obtained by geometry optimization, and on threepossible dimers. The basis set superposition error (BSSE)correction was not taken into account on the dimer forms.In the present work, we have extended the investigation ofthe possible stable conformers of title molecule by means oftorsion potential energy surface scan studies through dihe-dral angles, D

1(1S-2C-6S-9N), D

2(4N-5C-12N-14C), and D

3

(5C-12N-14C-16C), and calculated the vibrational modes andwavenumbers of the most stable conformer. Moreover, thestructures and vibrational wavenumbers of four energeticallyfavorable dimers and ten H

2O clusters of acetazolamide were

investigated and the effect of basis set superposition error(BSSE) on the structure and energy of acetazolamide dimershas been evaluated. Acetazolamide is very slightly soluble inwater. However, its solubility is significantly important and itsslight changes affect the bioavailability of acetazolamide [10].The aims of this study are to elucidate the conformationalpreferences of acetazolamide and the effect of hydrogenbonding in the formation of molecular dimers and uponinteraction with water molecules.

2. Experimental and Computational Methods

2.1. Experimental Part. Theacetazolamidemolecule was pur-chased fromSigma-Aldrich (≥%99)withCASnumber 59-66-5 and used as received. The FT-IR spectra of KBr disc (forsolid sample) and aqueous solution (between ZnSe plates)of the molecule were recorded on a Jasco FT/IR-6300 spec-trometer in the range 400–4000 cm−1 with a resolution of2 cm−1 based on averaging 200 samples and 100 backgroundscans. The Raman spectrum of the sample was taken with aJasco NRS-3100 micro-Raman spectrometer (1800 lines/mmor 1200 lines/mm grating and high sensitivity cooled CCD).Sample was excited with a 531.96 nm diode laser. The Ramansystem was calibrated with a silicon semiconductor usingthe Raman peak at 520 cm−1. A 20x microscope objective(Olympus) was used to focus the laser and collect Ramanscattering on the sample. Spectral resolution was 1.08 cm−1and 100 spectra were accumulated.

2.2. Computational Part. All of the calculations were carriedout by using theGaussian03© program suite [26]. Due to suc-cess in calculating the electronic structure and energy, the cal-culations were carried out by using the hybrid density func-tional theory (DFT/B3LYP) method. For the calculations ofmonomer, dimer forms of acetazolamide and acetazolamide-water clusters 6-31++G(d,p) basis set was used. The X-raycrystallographic results [9] of acetazolamide molecule wereused as initial input geometrical data. The minimum energyconformers of acetazolamide were identified by scanningthe potential energy surface by varying D

1(1S-2C-6S-9N),

D2(4N-5C-12N-14C), and D

3(5C-12N-14C-16C) dihedral

angles. The final geometry parameters for the obtainedstable conformers were determined by means of geometryoptimization carried out at DFT/B3LYP/6-31G++(d,p) levelof theory. Furthermore, acetazolamide dimers were con-structed by bringing two identical acetazolamide monomers

1S-2C-6S-9N

4N-5C-12N-14C

5C-12N-14C-16C

D1

D2 D3

Figure 1:Themost stable geometry, atom numbering, and searcheddihedral angles of acetazolamide.

together in possible configurations, and energetically pre-ferred conformations of dimers were investigated usingthe same method and the same level of theory. In orderto correct overestimation between unscaled and observedwavenumbers dual scaling factors were used. We scaledall the computed harmonic wavenumbers under 1800 cm−1with the scale factor 0.977 and wavenumbers greater than1800 cm−1 with the scale factor 0.955 [27]. The potentialenergy distribution (PED) of the vibrational modes of themolecules was calculated with GAR2PED program [28], andthe fundamental vibrational modes were characterized bytheir PED values.

3. Result and Discussion

3.1. Conformational Analysis and H-Bonding Interactions.The molecular model of acetazolamide with the atomnumbering scheme is given in Figure 1. Stable low energyconformers of free acetazolamide molecule were obtainedfirstly by potential energy surface scan studies by iterativelyvarying D

1(1S-2C-6S-9N), D

2(4N-5C-12N-14C), and D

3

(5C-12N-14C-16C) dihedral angles with step angle of 60∘.PES scan for acetazolamide calculated with D

1(1S-2C-

6S-9N), D2(4N-5C-12N-14C), and D

3(5C-12N-14C-16C)

dihedral angles at the B3LYP/6-31G++(d,p) method is shownin Figure S1 (see Figure S1 in Supplementary Materialsavailable online at http://dx.doi.org/10.1155/2013/538917).The45 conformers were identified between 0 and 10 kcal/molrelative energy intervals. Their dihedral angles and relativeenergies were given in Table S1. The geometry optimizationwas then performed on the lowest energy conformer. Theestimated four most stable conformers of acetazolamidedimers are illustrated in Figure 2. All possible conformationsof acetazolamide interacting with one water molecule wereinvestigated, and acetazolamide interacting with five watermolecules was determined as the final possible conformationof acetazolamide-water cluster. Figure 3 demonstrates thegeometries of the 10 stable acetazolamide-water clustersobtained using DFTmethod with B3LYP/6-31++G(d,p) basisset. The energies of the four most stable dimers (I–IV) andenergetically preferred H

2O-acetazolamide clusters are given

in Table 1. It is known that the basis set superposition error

Journal of Spectroscopy 3

1.88908

1.88901

(I)

1.97319

(II)

4.36302

4.14105

2.02168

(III)

1.97248

1.97144

(IV)

AA

A

A

AAA

A

Figure 2:The energyminimized structures of four low energy conformers (I–IV) of the dimer forms of the acetazolamide, (I–IV), respectively.

Table 1: (a)The calculated energies of monomeric, dimeric (I–IV), and H2O clusters (I–IX). (b)The counterpoise uncorrected and correctedinteratomic distance (A) and binding energy (kcal/mol) of dimer I.

(a)

Calculated energy (kcal/mol) Energy differences (kcal/mol)Monomer −876645.7 —

Dimer I −1753308.7 0Dimer II −1753299.4 9.3Dimer III −1753297.9 10.8Dimer IV −1753301.5 7.2

Cluster I −924613.6 6.1Cluster II −924617.1 2.6Cluster III −924613.6 6.0Cluster IV −924614.6 5.1Cluster V −924619.1 0.6Cluster VI −924619.7 0Cluster VII −924619.1 0.6Cluster VIII −924612.9 6.7Cluster IX −924614.6 5.1

(b)

BSSE uncorrected BSSE correctedR(5C–22C) (A) ΔE (kcal/mol) R(5C–22C) (A) Δ(E + BSSE) (kcal/mol)

Dimer I 4.23 17.4 4.25 16.1


2.00405

(I)

2.06788

(II)

1.98321

(III)

1.95379

(IV)

2.02345

1.906211.89256

2.00620

(V) (VI)

1.89194 2.00736

(VII)

1.97836

(VIII)

1.95396

(IX)

1.92619

1.70750

2.474222.19320

2.27260

2.03566

1.98489

1.83405

(X)

A AA

AA

AA

A

AA

A

A

A

A

A

A

A

A

A

A

Figure 3: The energy minimized structures of ten low energy conformers (I–X) of H2O clusters of the acetazolamide (I–X), respectively.

(BSSE) effect is rather significant on the structure and energyof dimer forms, so removing this effect is very important.Therefore, optimization of the dimer I was also carried outalong with the counterpoise correction scheme proposed byBoys and Bernardi [29].The BSSE uncorrected and correcteddistances between two acetazolamide units {𝑅(5C−22C) (A)}and binding energy (Δ𝐸) of acetazolamide dimer {Δ𝐸 =2∗𝐸monomer − 𝐸dimer} are given in Table 1(b). As seen in

Table 1(b), the energy of dimer I is found to be 17.39 kcal/mol

lower then total energy of the two monomer (2∗𝐸monomer)

units, indicating that intermolecular hydrogen bonding playsan important role in stabilization of the molecule.

The predicted geometrical parameters such as bondlengths and bond angles of the stable conformation ofacetazolamide monomer, dimer (dimer I), and water cluster(VI and X) of acetazolamide, calculated at B3LYP methodwith 6–31G++(d,p), are presented in Table S2 in accordancewith the atom numbering scheme as given in Figure 1. By


Abso

rptio

n in

tens

ityRa

man

inte

nsity

(a)

(b)

Infrared

Raman

Wavenumber (cm−1)Wavenumber (cm−1)3600 3500 3400 3300 3200 30003100 2900 2800 1800 1600 1400 1200 1000 800 600 400 200

Figure 4: Experimental FT-IR (a) and micro-Raman spectra (b) of acetazolamide in the regions 3600–2800 cm−1 and 1800–200 cm−1,respectively.

Abso

rptio

n in

tens

ity

Wavenumber (cm−1)3600 3400 3200 3000 2800 2600

Monomer

Dimer I

Exp.

(a)

Abso

rptio

n in

tens

ity

Wavenumber (cm−1)1800 1600 1400 1200 1000 800 600 400

Monomer

Dimer I

Exp.

(b)

Figure 5: Experimental FT-IR (solid) and calculated (scaled) absorption intensity spectra of acetazolamide in the regions 3600–2600 cm−1(a) and 1800–400 cm−1 (b), respectively.

comparing theoretical and experimental bond lengths [9], itis easily seen that the computed bond lengths at B3LYP/6-31++G(d,p) method were slightly longer since the theoreticalcalculations were performed on isolated molecule in thegaseous state, whereas the experimental results are for thesolid phase of the molecule [9, 10, 12]. Main differencesbetween crystal structure [9] and monomer acetazolamideoccur in H containing bond lengths and angles, and this isprobably due to insufficient predictions for light atoms in thecrystal structure study done in 1974 [9].The theoretical resultsare mainly consistent with reports of other studies [11, 24].Comparison of the geometry parameters of monomer formwith those of dimer andwater cluster of acetazolamide clearlyshows the effects of intermolecular hydrogen bonding.

The intra- and intermolecular hydrogen bonds of thedimer forms (I–IV) of the four low energy conformationstogether with those of ten energetically preferred water clus-ters are tabulated in Table 2. The lowest energy conformer ofdimer form (dimer I) makes stronger interhydrogen bondinginteractions.

3.2. Vibrational Analysis. The experimental FT-IR (a) andmicro-Raman spectra (b) of acetazolamide are given inFigure 4. The experimental FT-IR and Raman spectra of thesolid acetazolamide are also given in comparison with thoseof calculated gas phase spectra in Figures 5 and 6, respectively.

The calculated wavenumbers, the calculated Ramanintensities, and the potential energy distributions of the


Ram

an in

tens

ity

−1)Raman shift (cm3600 3400 3200 3000 2800

Monomer

Dimer I

Exp.

(a)

Ram

an in

tens

ity−1)Raman shift (cm

Monomer

Dimer I

Exp.

1800 1600 1400 1200 1000 800 600 400 200

(b)

Figure 6: Experimental (solid) and calculated (scaled) Raman intensities spectra of acetazolamide in the regions 3600–2800 cm−1 (a) and1800–200 cm−1 (b), respectively.

vibrational modes of monomer and dimer (I) forms ofacetazolamide and acetazolamide-H

2O cluster (VI and X)

are given in Table 3, in comparison with the experimentalvibrational spectra of the investigated molecule. The calcu-lated wavenumbers of the four low energy dimers of acetazo-lamide are given in Table S3 comparatively. The assignmentprocedure for the dimers was done according to the potentialenergy distribution of dimer I.

When acetazolamide goes from themonomer form to thedimer or to the water cluster, alterations in the vibrationalspectra, due to formation of H-bonds, are estimated. TheNH2, NH, C=O, and SO

2vibrational modes provide useful

information on the intermolecularH-bonding interaction forthe acetazolamide. On the other hand, NH stretching vibra-tions have anharmonic behavior [30–32]. Thus, in harmonicapproximation procedure, NH

2stretching wavenumbers are

overestimated due to neglect of anharmonicity [33]. Thecalculated values of ](NH) stretching wavenumbers were3451, 3035–2995 and 3221 cm−1 and 3099 cm−1 for monomerand dimer (dimer I) forms and water cluster (VI and X),respectively. As seen from Table 3, due to the participationof the −NH group in hydrogen bonds, ](NH) in dimerI (with two N⋅ ⋅ ⋅H bonds; Figure 2) and water clustersVI and X (Figure 3) showed negative shifts, 456–416 and230 cm−1 and 352 cm−1, respectively. The highest shifts (456and 416 cm−1) were obtained for the dimer I. The calculatedvalues suggest the presence of relatively strong N⋅ ⋅ ⋅H andNH⋅ ⋅ ⋅N hydrogen bond interactions in dimer I. The dif-ferences in hydrogen bonding strengths are responsible forthese different wavenumber shifts. On the other hand C=O,and SO

2groups do not involve hydrogen bonding interaction

in both dimer I form and water cluster VI, and we do notobserve a remarkable change in this wavenumber on goingfrom monomer form to dimer or cluster form.

The acetazolamide C–N ring stretching modes wererecorded at 1540 cm−1, 1425 cm−1, and 1275 cm−1 as strong

intense bands in the IR and at 1425 cm−1 and 1260 cm−1 inRaman spectra of solid acetazolamide by Chufan et al. [19].However, in other studies, these modes were obtained at1498 cm−1 and 1450 cm−1 [11] and at 1571 cm−1 and 1452 cm−1[34]. In the present study, the 1550, 1420, 1384, and 1311 cm−1in IR and 1555, 1428, 1370, and 1308 cm−1 in Raman spectrumof solid acetazolamide are assigned to C–N stretching vibra-tions. The 1550 cm−1 (IR) C–N stretching mode is estimatedto shift to higherwavenumber in both dimer andwater clusterforms due to contribution of 𝛿CNH mode.

The ]as(SO2) stretching mode was observed at 1345 cm−1and 1347 cm−1 in IR andRaman spectra, respectively, andwascalculated at 1312 cm−1, 1314 cm−1, 1296 cm−1, and 1319 cm−1for monomer, clusters (VI and X), and dimer structure,respectively. Cami et al. [11] observed this mode at 1342 cm−1andBaraldi recorded thismode at 1343 cm−1 and at 1348 cm−1in IR and Raman spectra, respectively [13].

The mixing of 𝛿CNH + ](C–N) modes was observed at1234 and 1226 cm−1 as a strong band in the IR spectrum andat 1241 cm−1 in Raman spectrum as a medium band. Thismode is calculated at 1197, 1223, 1319, and 1232–1226 cm−1 forfree, clusters (VI and X), and dimer forms of acetazolamide,respectively.

The bands at 1174 cm−1 and 1140 cm−1 were assignedto ](N–N)ring stretching and ]SO

2symmetric stretching

vibrations, respectively, by Cami et al. [11]. In this study weobserved a strong band at 1167 cm−1 in IR and 1165 cm−1in Raman spectra and assigned it to ]SO

2+𝜐(N–N) mode

according to PED calculations..The PED result of this

mode shows us that SO2stretching and (N–N) stretching

contributions are 59% and 44%, respectively.The strong band at 1095 cm−1 in the IR and Raman

spectra is assigned to NH2rocking mode, in agreement with

PED.The correspondingmode was assigned at 1097 cm−1 [11]and at 1090 cm−1 [34] in previous studies. But Baraldi et al.


Table 2: The intra- and interhydrogen bonds of the dimer conformers (I–IV) and H2O clusters (I–X) of acetazolamide.

(a)

Dimer IIntramolecular

H-bonds

Dimer IIIntramolecular

H-bonds

Dimer IIIIntramolecular

H-bonds

Dimer IVIntramolecular

H-bondsAtoms Bond (A) Atoms Bond (A) Atoms Bond (A) Atoms Bond (A)3N–10H 3.377 3N–10H 3.342 3N–10H 3.148 4N–13H 2.4683N–11H 2.975 3N–11H 2.962 3N–11H 2.816 20H–25N 2.4688O–10H 2.698 8O–10H 2.717 8O–10H 2.7007O–11H 2.696 7O–11H 2.694 7O–11H 2.7154N–13H 2.512 4N–13H 2.467 4N–13H 2.48829N–37H 3.377 29N–37H 3.196 29N–37H 3.14129N–38H 2.975 29N–38H 2.766 29N–38H 2.85735O–37H 2.968 35O–37H 2.689 35O–37H 2.69734O–38H 2.696 34O–38H 2.717 34O–38H 2.71320H–25N 2.512 20H–25N 2.476 20H–25N 2.458

IntermolecularH-bonds




13H–25N 1.889 10H–34O 1.973 10H–35O 4.141 15O–37H 1.9714N–20H 1.889 11H–35O — 11H–34O 4.363 15O–38H —

13H–26O 2.022 10H–26O 1.97211H–26O —

(b)

Cluster IIntramolecular

H-bonds

Cluster IIIntramolecular

H-bonds

Cluster IIIIntramolecular

H-bonds

Cluster IVIntramolecular

H-bonds

Cluster VIntramolecular

H-bondsAtoms Bond (A) Atoms Bond (A) Atoms Bond (A) Atoms Bond (A) Atoms Bond (A)3N–10H 3.103 3N–10H 2.838 3N–10H 3.092 3N–10H 3.068 3N–10H 3.0413N–11H 2.786 3N–11H 3.340 3N–11H 2.791 3N–11H 2.846 3N–11H 3.5938O–10H 2.696 8O–10H 2.767 8O–10H 2.695 8O–10H 2.696 8O–10H 2.7337O–11H 2.715 7O–11H 2.630 7O–11H 2.716 7O–11H 2.715 7O–11H 2.6594N–13H 2.474 4N–13H 2.472 4N–13H 2.475 4N–13H 2.472 4N–13H 2.472






7O–22H 2.004 7O–20H 2.068 7O–22H 1.983 15O–22H 1.954 3N–22H 2.00610H–21O 1.893

Cluster VIIntramolecular

H-bonds

Cluster VIIIntramolecular

H-bond

Cluster VIIIIntramolecular

H-bonds

Cluster IXIntramolecular

H-bonds

Cluster X(5 H2O)

IntramolecularH-bonds

Atoms Bond (A) Atoms Bond (A) Atoms Bond (A) Atoms Bond (A) Atoms Bond (A)3N–10H 3.175 3N–10H 3.591 3N–10H 2.999 3N–10H 3.068 3N–10H 2.8373N–11H 2.850 3N–11H 3.041 3N–11H 2.859 3N–11H 2.845 3N–11H 3.2298O–10H 2.694 8O–10H 2.659 8O–10H 2.711 8O–10H 2.695 8O–10H 2.7817O–11H 2.712 7O–11H 2.732 7O–11H 2.693 7O–11H 2.716 7O–11H 2.6364N–13H 2.487 4N–13H 2.472 4N–13H 2.478 4N–13H 2.472 4N–13H 2.463






4N–22H 2.023 3N–22H 2.007 7O–20H 1.978 15O–22H 1.954 7O–25H 2.19313H–21O 1.907 11H–21O 1.892 8O–32H 1.926

3N–30H 2.27310H–29O 1.7084N–22H 2.03613H–21O 1.83415O–28H 1.9858O–23H 2.474

8 Journal of SpectroscopyTa

ble3:Ex

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(solid

andaqueou

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andRa

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andcalculated

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acetazolam

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Cluster

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ClusterX

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] sca.

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Int.

Mon

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Int.Dim

erI

] as(N–H

)] a

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3339

vs—

3337

vw3331m

a ;3301sb

—3473

3637

631

3474

3433

3484;

3484

1169;22

] NH2(asym,)(100)

](N–H

)]N

–H3234

s3193

3225

m3227

ma ;

3179

mb

3230

wa ;

3183

shb

3451

3614

1980

3221

3099

3035;

2995

28;4931

] NH(100)

] 𝑠(N

–H)

] 𝑆N–H

3151s

—3145

w3148

ma ;

3093

wb

3152

wa ;

3089

sb3361

3520

1690

3360

3334

3364

;3364

119;3162

] NH2(sym)(100)

] as(CH

3)]C

H3

3004

s—

—3001vw

a ;3014vw

b3014

b3007

3149

1564

3011

3018

3015;

3014

181;26336

] CH3(asym,)(100)

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3)]C

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2948

m—

2979

sh2916wa ;

2985

vwb

2941

vsa ;

2985

b2996

3138

1759

2995

2982

2992;

2992

3199;575

] CH3(asym,)(99)

] 𝑠(C

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32923

m—

2933

vs2932

b2932

b2924

3061

5191

2924

2914

2923;

2923

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1699

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1707

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1680

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1677

wb

1724

1765

3123

1720

1719

1721;

1720

45;5313

] OC(77)

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C(6)+𝛿CN

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2(scis,)

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ip1558

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wb

1571

b1562

1599

173

1560

1619

1554;

1554

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N)+𝛿CN

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ring

1550

vs1552

s1555

m1542

vsa ;

1553

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1558

b1519

1554

6783

1546

1575

1581;

1565

2005;15

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+𝛿CN

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shb

1455

shb

1460

1494

749

1459

1479

1463;

1462

72;1099𝛿CH

H(74)

+𝛿CH

C(13)

𝛿as(C

H3)

] 𝑠C=

N+

𝛿aC

H3

1437

s1435

1442

vs1436

ma ;

1437

mb

1443

vsa ;

1434

mb

1440

1474

932

1443

1451

1449;

1448

611;204𝛿CH

H(81)+𝛿CH

C(8)+

] CN(8)

] as(C=

N) ri

ng] 𝑠C=

N𝛿aC

H3

1420

sh1418

1428

sh1426

shb

1422

b1442

1476

2472

1449

1443

1456;

1456

7540

;1329

] CN(77)

+𝛿CH

H(6)

] 𝑠(C

=N) ri

ng𝛿𝑠CH

31384

sh1387

1370

w1376

shb

1386

b1409

1442

5198

1424

1428

1439;

1435

72;164

12] C

N(54)

+𝛿CN

H(23)

+𝛿CN

N(6)

𝛿𝑠(C

H3)

] asSO2

1365

s1363

—1368

vsb

1373

b1376

1409

1144

1377

1388

1379;

1379

1312;42𝛿CH

H(92)

+] C

C(6)

] as(SO

2)] a

sC–N

–C1346

vs1344

1347

m1343

vsa ;

1322

sb1348

a1312

1343

750

1314

1296

1319;1319

1226;690

] SO2(asym,)(90)

+𝛿SN

H(6)

](C–

N)

]C–N

ring

1282

s—

1308

w1280

ma ,

1286

mb

1242

wa ,

1289

a1291

1322

109

1299

1249

1300;

1298

11;186

] CN(62)

+] C

S(13)

+𝛿NCN

(7)

+𝛿CC

N(5)

𝛿CN

H—

1234

s1234

1241

m1227

sa1197

1225

629

1223

1319

1232;

1226

2041;15

] CN(29)

+𝛿CN

H(19

)+] C

C(13)

+𝛿NCO

(12)

+𝛿CC

H(9)

] 𝑠(SO2)+

] 𝑠(N

–N) ri

ng] 𝑠SO

2116

8vs

1166

1165s

1163v

sa;

1176v

sb116

7sa ,

1168b

1121

1147

1022

1133

1100

1134;113

2186;1905

] OS(59)

+] N

N(34)

] 𝑠(SO2)+

] 𝑠(N

–N) ri

ng𝛿ipCN

NC

1105m

1106

1103sh

1122

mb

1121

b110

0112

65630

1104

1140

1105;110

410516;439

] OS(42)

+] N

N(39)

𝜌(N

H2)

“Ringmod

e”1096

s1097

1094

s1095

sa;

1087

mb

1097sa;

1085m

b1071

1096

323

1070

1171

1063;

1063

14;778𝜌NH2(91)

𝛿rin

g+] ring

“Ringmod

e”1038

w1038

—1045

ma ,

1045

mb

1041

b1042

1066

538

1045

1048

1046

;1045

139;1528𝛿SC

N(44)

+] C

S(42)

𝜌(C

H3)

——

——

1011a

,1014

b1016

b1031

1055

101033

1045

1036;

1036

9;29𝛿CC

H(72)

+𝛿CH

H(10)

+𝛾CN

CO(16)


Table3:Con

tinued.

Assignm

ent

Thiswork

Thisworkcalculated

byDFT

/6-31++G

(d,p)

PED(≥5%

)Free

acetazolam

ide

Thiswork

[13]

Experim

ental

Experim

ental

Free

Cluster

VI

ClusterX

Dim

erI

IRsolid

IRaq

Raman

IRsolid

Raman

] sca.

] uns

Raman

Int.

Mon

o] sca.

] sca.

] sca.

Raman

Int.Dim

erI

𝜌(C

H3)

]N–N

996m

995

998w

975m

b955m

a ,968b

993

1016

276

1000

1014

1009;

1007

198;1𝛿CC

H(55)

+] C

C(18)

](C–

N)+

](C–

C)]S–N

944s

947

956m

939s

a ,913m

b916b

949

971

854

954

963

953;949

2;2584

] CN(25)

+] C

C(18)

+] N

N(9)+

𝛿CC

N(15)

+𝛿CC

H(8)+

𝛿OCN

(7)+𝛿NCN

(6)

](S–N

)“R

ingmod

e”813m

807v

w813w

a ,844w

b—

824

843

2623

821

829

817;817

573;6259

] SN(55)

+𝛾S–NH2(15)

𝛿rin

g+] ring

“Ringmod

e”783m

—780m

a ,817m

b821b

786

805

24792

793

798;786

9;201

] CS(17)

+] C

C(7)+𝛿CC

N(12)

+𝛿NNC(42)

] as(C–

S)rin

g] 𝑎(C

–S) ri

ng705m

719

709s

705w

a ;710w

b712m

a ;711b

672

688

1385

681

682

683;681

3652;11

] CS(58)

+] C

C(9)+𝛿NCO

(9)

+𝛿NCC

(12)

w(N

H2)

] 𝑠(C

–S) ri

ng675s

668

680v

s674s

a ,673s

b684v

sa,

680b

668

684

408

667

988

626;624

5395;178𝛾S–NH2(36)

+] S

N(19

)+] C

S(16)

+𝛿NSO

(13)

] 𝑠(C

–S) ri

ng+𝛿rin

g—

644m

643

647sh

643a;

651w

b64

5b645

660

5062

648

661

661;659

8007;3𝛿CS

C(23)

+] C

S(23)

+𝛾S–NH2(16)

+]NS(6)+𝛿NSO

(6)

Γas(ring)

𝛿ipN–C

=O621vs

618

637w

620s

a ,622s

b636w

a ,624b

624

639

225

639

636

635;635

225;69ΓNNCS

(44)

+𝛾NNCS

(30)

+𝛾CC

NO(11)

𝛾OCN

C—

608s

h610v

w613b

607b

608

622

16778

591

597;595

89;52

𝛾CN

CO(24)

+𝛾NNCS

(16)

+ΓNNCS

(20)+ΓCN

CO(13)

+ΓNCN

H(11)+𝛾CC

NH(8)+

𝛿CH

C(7)

Γ𝑠(rin

g)𝛿SO

2582m

580w

584m

b588b

588

602

65593

575

578;576

123;36ΓNCS

C(50)

+𝛾NNCS

(10)

+𝛾SC

SN(21)+𝛿CS

O(6)

𝛿(C

–C=O

)573m

575

—574m

b578m

a ,574b

573

586

392

576

611

573;570

28;565𝛿CC

O(19

)+𝛾S–NH2(10)

+] C

S(16)

+] C

C(8)+𝛿OSC

(7)+

𝛿NCN

(5)

w(SO2)+w(N

H2)𝛿O=C

–C—

—554m

b560b

535

547

279

535

524

532;531

106;670𝛿NSO

(34)

+𝛿CC

O(10)

+𝛿CS

N(10)

+𝛾S–NH2(12)

+] N

S(5)

𝛾(N

–H)

—508s

881

507w

520s

b507b

531

544

97778

878

881;864

3;47𝛾CN

CH(25)

+ΓOCN

H(20)

+𝛾CC

NO(16)

+ΓNNCS

(10)

+ΓNCN

H(8)

𝛿sciss(SO2)

wag

SO2

457v

w545

453w

458m

b450w

a ,453b

467

478

1731

469

514

470;470

702;110

7𝛿OSO

(40)

+𝛿NSO

(25)

+] N

S(11)+] C

S(5)

𝜌(SO2)+t(N

H2)

𝜌SO

240

6vw

413w

411w

b417w

a ,40

6b432

442

208

435

468

433;433

559;16𝛿NSO

(48)

+𝛾S–NH2(16)

+ΓNCN

H(7)+ΓCS

CN(7)+

𝛿SN

H(7)

t(NH

2)+t(S

O2)

——

—398b

395shb

393

403

245

406

440

400;40

035;1655𝛿NSO

(51)+ΓOSN

H(18)

+ΓNSC

N(9)

𝛿CC

O+𝛿OSO

Latic

evib.

—373w

—374m

a ,368b

386

395

1489

388

404

386;384

2455;190𝛿CC

O(21)+𝛿NCN

(18)

+𝛿OSO

(16)

+𝛿SC

S(7)+

𝛿CC

N(13)

+] C

S(7)+

] CN(6)


Table3:Con

tinued.

Assignm

ent

Thiswork

Thisworkcalculated

byDFT

/6-31++G

(d,p)

PED(≥5%

)Free

acetazolam

ide

Thiswork

[13]

Experim

ental

Experim

ental

Free

Cluster

VI

ClusterX

Dim

erI

IRsolid

IRaq

Raman

IRsolid

Raman

] sca.

] uns

Raman

Int.

Mon

o] sca.

] sca.

] sca.

Raman

Int.Dim

erI

𝛿CC

N—

—326w

—328w

a ,330b

346

354

298

353

364

360;355

15;364𝛿CC

N(41)+𝛿NCS

(23)

+] C

S(5)

t(NH

2)—

—267m

—270s

a ,270b

291

298

503

302

386

316;315

34;594𝛿CS

N(19

)+𝛿OSN

(19)+

ΓHNSO

(19)+ΓNNCS

(6)

t(NH

2)—

—253sh

—256m

a ,258b

274

280

363

274

—275;275

12;952ΓHNSC

(23)

+𝛿CS

N(17)

+𝛿CS

O(9)+𝛿NSO

(8)+ΓCS

CN(9)

] C–S

——

——

230b

235

241

4727

237

270

237;233

5884;325

] CS(42)

+𝛿CS

N(25)

+𝛿NCC

(13)

+𝛿CS

O(6)

ΓCS

NH

——

195w

—192b

219

224

291

230

231

243;241

4402;112𝛿OSN

(32)

+ΓHNSC

(32)

+ΓNSC

S(18)

𝛿CS

N—

—160w

—136b

163

166

425

176

197

165;163

1835;12𝛿CS

N(55)

+𝛿CN

C(29)

𝛾C–

S—

—116

—118

b123

126

1587

127

133

138;132

4227;114𝛾CS

NS(33)

+𝛿CS

O(27)

+𝛾CC

NH(15)

+ΓOCN

H(10)

𝛿SC

S—

—105

—105b

9092

887

87130

102;100

567;764𝛿SC

S(44)

+𝛿CN

C(13)

+ΓCN

CN(14

)

ΓNCN

H—

——

——

8890

295

98104

118;104

57;25ΓNCN

H(54)

+ΓCN

CO(9)+

𝛾NCS

N(7)+𝛿CS

N(6)

t(CH

3)—

——

——

5657

1122

50116

78;62

817;1641𝛾S–NH2(36)

+ΓNCC

H(18)

+𝛾NCC

H(10)

+𝛾NCS

N(6)+

ΓNNCS

(6)

t(CH

3)—

——

——

3940

2415

43106

51;48

459;3691ΓNCC

H(69)

+𝛾NCC

O(17)

+𝛿HCH

(6)

ΓSC

SN—

——

——

1111

1622

2113

31;12

572;4369ΓSC

SN(65)

+𝛾SC

SN(15)

a Ref[13],bRe

f[24].


assigned this strong intense band at 1095 cm−1 to a “ringmode” (1,3,4 thiadiazolic ring) [13]. Our assignments are inagreement with those of Cami et al. [11, 34].

Cami et al. [11] assigned the 1058 cm−1 and 795 cm−1bands to ring bending vibrations with contribution from](C–S) [11]. In this study, ring bending and ring stretchingmodes were found to bemixed and assigned to 1038 cm−1 and782 cm−1 bands observed in IR spectrum as weak bands. Wedo not observe any band in the Raman spectrum attributableto these modes.

We assigned the ](S–N) mode to the medium and weakbands observed at 812 cm−1 and 807 cm−1 in the IR andRaman spectra, respectively, according to the calculatedresults. This mode was assigned to the medium band at872 cm−1 in [34], whereas Cami et al. [11] assigned the ](S–N)+wagging (NH

2) complicated mode to 944 cm−1 [11] and

Baraldi et al. assigned it to 939 cm−1 [13].The ]as(C–S)ring was observed at 704 cm−1 as a medium

band in the IR and at 709 cm−1 as strong band in theRaman spectra. The ]

𝑠(C–S)ring stretching was mixed with

ring bending and observed at 644 cm−1 and 647 cm−1 in IRand Raman spectra, respectively. The bands at 782 cm−1 and679 cm−1 were assigned to ](C-S) asymmetric and symmetricstretchings, respectively, by Cami et al. [34].

In this study, the band located at 675 cm−1 in the IR andat 680 cm−1 in the Raman spectrum was assigned to w(NH

2)

mode. This mode with a contribution of CH bending vibra-tion was assigned to 636 cm−1 by Cami et al. [11]. There wasno assignment corresponding to the w(NH

2) mode in [13].

The ring torsion modes were expected in the region 530–650 cm−1. We assigned the 621 cm−1 and 582 cm−1 bands inIR spectrum and 637 and 580 cm−1 bands in the Ramanspectrum to the ring torsion modes. These modes wereobserved at 650 cm−1 and 534 cm−1 byCami et al. [11]. Baraldiet al. did not assign ring torsion modes [13]. However, thebands at 621 cm−1 in the IR spectrum and at 637 cm−1 inRaman spectrum were identified as 𝛿ip(N–C=O) mode [13],and the band at 584 cm−1 in IR spectrum and at 588 cm−1 inthe Raman spectrum was assigned to 𝛿SO

2[24].

The acetazolamide SO2waggingmode, coupledwithNH

2

wagging mode, was calculated at 535 cm−1 for free form.We did not observe this mode in the experimental IR orRaman spectra, but it was observed at 588 cm−1 [34] and at552 cm−1 [11] in previous studies. This mode was assigned to458 cm−1 in IR and 453 cm−1 in Raman spectra [24]. Rockingand twisting SO

2vibrations were situated at 416 cm−1 and

315 cm−1 [11]. In this study, corresponding values of thesemodes were assigned at 406 cm−1 and at 413 cm−1.

The assignment in the range of 500–250 cm−1 is difficultdue to the presence of several overlapping weak bands.Thesebands are associated with vibrational and lattice modes andmost of them are strongly overlapped.

The experimental micro-Raman (solid) and calculated(scaled) Raman intensity spectra and the experimental FT-IR(solid) and calculated (scaled) absorption intensity spectra ofacetazolamide dimer (I–IV) are given in Figures 7 and 8.

Ram

an in

tens

ity

Exp.

−1)Raman shift (cm1800 1600 1400 1200 1000 800 600 400 200

I

II

IV

III

Figure 7: Experimental micro-Raman (solid) and calculated(scaled) Raman intensity spectra of acetazolamide dimer (I–IV) inthe region 1800–200 cm−1, respectively.

Exp.

1800 1600 1400 1200 1000 800 600 400

I

II

IV

III

Exp.

I

II

IV

IIIAb

sorp

tion

inte

nsity

Wavenumber (cm−1)

Figure 8: Experimental FT-IR (solid) and calculated (scaled)absorption intensity spectra of acetazolamide dimer (I–IV) in theregion 1800–400 cm−1, respectively.

]C=O, ]C=N, ]aSO2, and ]sSO2 vibrations are observedat 1699, 1550, 1346, and 1168 cm−1, respectively, in the IRspectrum of solid acetazolamide, but they are observed at1694 (Δ = ]aq. − ]solid = −5 cm

−1), 1552 (Δ = ]aq. − ]solid =+2 cm−1), 1344 (Δ = ]aq. − ]solid = −2 cm

−1), and 1166 (Δ =]aq. − ]solid = −2 cm

−1) respectively, in that of aqueoussolution.The water cluster structure (X) of Figure 3 simulatesbest the aqueous environment for the molecule. The exper-imental FT-IR (solid and aqueous solution) and calculated(scaled) absorption intensity spectra of H

2O clusters (I–X)

of acetazolamide in the region of 1800–800 cm−1 are given inFigure S2.

3.3. HOMO-LUMO and NBO Analysis. The frontier molec-ular orbitals are important in determining the molecularreactivity. The highest occupied molecular orbital (HOMO)energy characterizes the ability of electron giving, the lowestunoccupied molecular orbital (LUMO) energy characterizesthe ability of electron accepting, and the gap betweenHOMOand LUMO characterizes the molecular stability.TheHOMO


and LUMO energies of acetazolamide are calculated by DFTmethod at B3LYP/6-31G∗∗ level of theory, and the atomicorbital compositions of the frontier molecular orbitals foracetazolamide are shown in Figure S3. LUMO is located overthe ring, the methyl group, and C–N bond which is locatedon the chain of the molecule. The HOMO is located over thering, carbonyl group, and amine group, and consequently thehomo-lumo transition implies an electron density transfer toring, methyl group, and C–N bond from the carbonyl groupand amine group. The computed low HOMO-LUMO energygap (−5.497 eV) shows the charge transfer interactions, takingplace within the molecule.

TheNBOanalysis of acetazolamidemolecule is calculatedby DFTmethod at B3LYP/6-31G∗∗ level of theory.The natureand credibility of the intermolecular hydrogen bonding canbe analysed by searching the changes in electron densityin the environments of N⋅ ⋅ ⋅H hydrogen bonds. The NBOanalysis of acetazolamide clearly explains the evidence of theformation of strongH-bonded interaction between the LP(N)and 𝜎∗(N–H) antibonding orbitals. The hyperconjugativeinteractions CR(N

4) → 𝜎

∗(H20–N21), LP1(N4) → 𝜎

∗(H20–

N21), and CR(N

25) → 𝜎

∗(N12–H13), LP1(N25) → 𝜎

∗(N12–

H13) are obtained as 0.37, 23.34, 0.37, and 23.34 kcal/mol,

respectively, and are shown in Table S4. The differences inE2 energies are reasonably due to the fact that the accrual ofelectron density is in the N–H bonds.

The comparison of NBO analysis between dimer andmonomer forms of acetazolamide indicates the formation oftwo H-bonded interactions between nitrogen lone electronpairs and 𝜎∗(N–H) antibonding orbitals.

The magnitudes of charge transfer from lone pairs of𝑛(N4) and 𝑛(N

25) of the hydrogen-bonded N atoms into

the antibonds𝜎∗(N21–H20) and𝜎∗(N

12–H13) increased upon

dimerization (0.05298e and 0.05299e) (see Table S5). Similarconclusion can be obtained while considering the energy ofeach orbital. The electron density in the N–H antibondingorbitals 𝜎∗(N

4–C5) and 𝜋∗(N

4–C5) is increased significantly

(0.00291e and 0.04037e, resp.) because of the dimerization.The elongation (0.02 A) thereby weakens the bond. This isassociated with the downshifts of stretching frequency (TableS2 and Table 3).

The intramolecular hyperconjugative interaction 𝜎(N4–

C5) distribution to 𝜎∗(C

5–N12) and 𝜎∗(N

12–C14) caused

less stabilization of 1.09 and 2.06 kcal/mol. This interactionof 𝜋(N

4–C5) with 𝜋∗(C

2–N3) leads to strong delocaliza-

tion of 14.11 kcal/mol. There occurs a strong intramolecularhyperconjugative interaction from 𝑛(N

12) to 𝜎∗(N

4–C5) and

𝜎∗(C14–O15) with 47.21 and 54.82 kcal/mol (Table S4). The

increased electron density at the N12atom leads to the elon-

gation of N–H bond and a lowering of the N–H stretchingwavenumber (see Table S2 and Table 3).

4. Conclusion

In this study, the monomer and dimer forms and waterclusters of acetazolamide were studied by using the DFTmethod at B3LYP/6-31G++(d,p) level of theory. The effectof basis set superposition error (BSSE) on the structure and

energy of acetazolamide dimer has been investigated. Themost stable structure of the dimer (dimer I) possesses interac-tion energy of 16.116 kcal/mol after the basis set superpositionerror (BSSE) correction. The difference between the BSSEcorrected (16.116 kcal/mol) and uncorrected (17.390 kcal/mol)interaction energies indicates the magnitude of error causeddue to the basis set superposition. The energy of dimerI is found to be lower than the total energy of the twomonomer (2∗𝐸monomer) units, indicating that intermolecularhydrogen bonding plays an important role in stabilization ofthe molecule. The wavenumbers associated with the relatedmolecule are in a good agreement with [11, 34]. The compar-ison of NBO analysis between dimer and monomer formsof acetazolamide indicates the formation of two H-bondedinteractions between nitrogen lone electron pairs and 𝜎∗(N–H) antibonding orbitals. Increasing of the electron densityin the N–H antibonding orbitals upon dimerization can beassociated with the downshifts of N–H stretching frequency.

Acknowledgment

This study was supported by the Research Funds of IstanbulUniversity (Project nos. ONAP-2423, UDP-16156, and UDP-17069-N-3341).

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