Journal of Molecular Structure 1037 (2013) 393–401

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Journal of Molecular Structure

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An experimental and theoretical study on the hydration in aqueous mediumof the antihypertensive agent tolazoline hydrochloride

Elida Romano, Alicia Beatriz Brizuela, Karina Andrea Guzzetti, Silvia Antonia Brandán ⇑Cátedra de Química General, Instituto de Química Inorgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471,4000-S. M. de Tucumán, Argentina

h i g h l i g h t s

" Tolazoline hydrochloride in aqueousmedium was characterized by IR andRaman spectra.

" The monocation, chloride anddimeric structures in aqueoussolution were studied.

" The solvent effects were investigatedby using the Onsager and PCMmodels.

" The monocation, chloride anddimeric forms were detected in theIR spectrum.

" The topological properties for thethree structures were studied.

0022-2860/$ - see front matter � 2013 Elsevier B.V. Ahttp://dx.doi.org/10.1016/j.molstruc.2013.01.028

⇑ Corresponding author. Tel.: +54 381 4247752; faxE-mail address: sbrandan@fbqf.unt.edu.ar (S.A. Bra

g r a p h i c a l a b s t r a c t

a r t i c l e i n f o

Article history:Received 19 December 2012Received in revised form 10 January 2013Accepted 11 January 2013Available online 23 January 2013

Keywords:Tolazoline hydrochlorideVibrational spectraMolecular structureForce fieldDFT calculations

a b s t r a c t

Tolazoline hydrochloride was characterized by infrared and Raman spectroscopies in aqueous solutionphases. Optimized geometries and relative stabilities for the monocation (protonated), chloride (depro-tonated) and dimeric forms of the compound in aqueous solution have been calculated by means ofthe Density Functional Theory (DFT) method using the hybrid functional B3LYP together with the 6-31G� basis set. The solvent effects were investigated in terms of the self-consistent reaction field (SCRF)by using the Onsager and polarized continuum (PCM) models. For a complete assignment of the IR andRaman spectra in aqueous solution phases, the calculations were combined with Pulay’s Scaled QuantumMechanics Force Field (SQMFF) methodology in order to fit the theoretical frequency values to the exper-imental ones. An agreement between theoretical and available experimental results was found. The pres-ence of tolazoline monocation, chloride and dimeric forms in aqueous solution was detected in theinfrared spectrum by means of the characteristic bands at 2988, 2705, 1610, 1590, 1293 and1046 cm�1. Also, the possible charge-transfer and the topological properties for tolazoline hydrochloridewere studied by means of Natural Bond Orbital (NBO) and Atoms in Molecules theory (AIM) investigation.

� 2013 Elsevier B.V. All rights reserved.

1. Introduction

The tolazoline hydrochloride compound is of great pharmaco-logical importance because is a non-selective competitive a-adren-ergic receptor antagonist and a vasodilator being broadly used inhypertensive therapy [1]. Recently, the theoretical structural and

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vibrational properties of this compound were studied by usingDFT calculations in gas phase [2]. The experimental structuralstudies by means of X-ray diffraction methods [3] have shown thatthe monocation form is the existent structure in the solid statewhere the imidazol group is involved in a protonation processand the positive charge is dispersed over both nitrogen atoms ofthe imidazoline ring. On the other hand, the vibrational study haverevelled that there are three intense characteristic bands in theexperimental infrared spectrum assigned to the monocation

Fig. 2. (Upper) Experimental Raman spectra of tolazoline hydrochloride compoundin aqueous solution and (botton) in solid phase.

394 E. Romano et al. / Journal of Molecular Structure 1037 (2013) 393–401

species of the compound in solid phase [2]. However, so far, thereare no published high-level theoretical studies on the geometriesand spectroscopic parameters of this compound in aqueous solu-tion. The knowledge of these properties in aqueous medium isimportant for to know if the solvent affects the structure and thechemical and vibrational properties of this interesting compoundbecause often can to result in alterations of its biological activities,which sometimes may be useful or no. The aim of this paper is tostudy the theoretical structures of tolazoline hydrochloride, suchas the monocation, chloride and dimeric forms, and the experi-mental vibrational spectra in aqueous solution. For this purpose,the geometry of the monocation species of the compound was fullyoptimized in aqueous solution by using the B3LYP/6-31G� level oftheory and taking into account the solvent effects by means of theSCRF method with the polarized continuum (PCM) model [4,5]. Onthe other hand, the solvent effects of the chloride and dimericforms of this compound were investigated in terms of the SCRFmethod by using the Onsager model [6,7]. Then, the results wereanalyzed and compared with those previous reported for the com-pound in gas phase [2]. Afterwards, a complete assignment of allobserved bands in the IR and Raman spectra in aqueous solutionwas performed by using DFT calculations combined with Pulay’sSQMFF methodology [8,9]. Moreover, to analyze the energies, geo-metrical parameters, magnitude of the intramolecular interactionsand frontier orbitals of the different forms of this compound inaqueous solution, NBO [10,11] and AIM [12,13] calculations wereperformed. Furthermore, the possible charge-transfer and theintermolecular bonds of the monocation, chloride and dimericforms of tolazoline hydrochloride were analyzed. Here, the struc-tural and vibrational properties of all the forms of tolazoline hydro-chloride in aqueous solution are shown and discussed. Goodagreement between theoretical results in aqueous solution andexperimental harmonic vibrational frequencies were found.

2. Experimental methods

A pure MP Biomedicals commercial sample of tolazoline hydro-chloride (T) was used. The infrared and Raman spectra in solidphase were taken from a previous study reported by us [2], whichare presented in Figs. 1 and 2 compared with the correspondingexperimental spectra obtained in this work in aqueous solution.The IR spectrum of a saturated aqueous solution of the sample be-tween AgCl windows was registered from 4000 to 400 cm�1, withan FT-IR Perkin Elmer spectrometer provided with a Globar sourceand a DGTS detector, and then the corresponding bands due to thesolvent were subtracted. The Raman spectrum of the saturated

Fig. 1. (Upper) Experimental infrared spectra of tolazoline hydrochloride com-pound in aqueous solution and (botton) in solid phase.

aqueous solution was measured in a glass capillary between3500 and 10 cm�1 with a Bruker RF100/S spectrometer equippedwith a Nd:YAG laser (excitation line of 1064 nm, 800 mW of laserpower) and a Ge detector cooled at liquid nitrogen temperature.All spectra were recorded with a resolution of 1 cm�1 and 200scans.

3. Computational details

For SCRF calculations, the B3LYP/6-31G� method [14,15], asimplemented in the GAUSSIAN 03 program [16], was employedto fully optimize the monocation, chloride and dimeric structuresof (T). Fig. 3 shows those structures of (T) and labeling of the atoms.In this study, the solvent effects were simulated considering thecavity of series of spheres using the self-consistent Onsager andPCM models, as implemented in the GAUSSIAN 03 program [16].Natural charges and bond orders were also calculated at the sametheory levels from NBO calculation by using the NBO 3.1 program[17], as implemented in the GAUSSIAN 03 package [16]. The elec-tronic charge density topological analyses were performed forthe monocation, chloride and dimeric structures, by using theAIM200 program package [13]. The same approximation levelswere used to calculate the harmonic frequencies and the valenceforce field in Cartesian coordinates. Then, the resulting force fieldswere transformed into ‘‘natural’’ internal coordinates by using theMOLVIB program [18]. The natural internal coordinates for themonocation form were previously reported [2] while those corre-sponding to the chloride form are listed in Table S1 (Supportingmaterial). The harmonic force fields for the monocation and chlo-ride structures were evaluated at B3LYP/6-31G� level, followingthe SQMFF procedure [8,9], and later the potential energy distribu-tion components (PEDs) higher than or equal to 10% were subse-quently calculated with the resulting SQM. The nature of all thevibration modes corresponding to the dimeric form of (T)(Fig. 3c) in aqueous solution at B3LYP/6-31G� level was carriedout by means of the GaussView program [19]. The total energyfor the dimeric species by using the 6-31G� basis set was correctedfor Basis Set Superposition Error (BSSE) by the standard Boys–Ber-nardi counterpoise method [20].

4. Results and discussion

4.1. Geometry optimization

The optimized structures for the monocation, chloride and di-meric forms of (T) are presented in Fig. 3. Tables 1 and 2 showsthe comparisons of the calculated geometrical parameters for the

Fig. 3. Theoretical structures and atoms numbering for the monocation, chloride and dimeric forms of tolazoline hydrochloride in aqueous solution.

E. Romano et al. / Journal of Molecular Structure 1037 (2013) 393–401 395

monocation and chloride forms in aqueous solution, respectivelywith those corresponding ones calculated in gas phase and fromX-ray diffraction [3] by means of the root mean of square devia-tions (rmsd) values. It is important note that the calculation inaqueous solution reproduce reasonably well the theoretical bondlengths (0.023–0.020 Å) using the 6-31G� basis sets. Here, the cal-culation predicts for the monocation that the C5@N4 and C3AN4distances in aqueous solution by using both basis sets are slightlylower than the values in gas phase while the C5AN1 distance in-crease in aqueous solution. The C5@N4 and C5AN1 distances arelower than the C3AN4 distance because the two N atoms of theimidazoline ring are protonated, in accordance with the X-ray dif-fraction [3] and the calculations in gas phase [2]. In aqueous solu-tion, the decreasing in those distances is justified by the hydrationdue to the hydrogen bonds formation. For the chloride form, con-trary results for those distances are observed due to the presenceof the Cl atom. In this form, the H25ACl26 distances using both ba-sis sets increase the values with the hydration, as observed inTable 2.

A comparison of the total energies and the corresponding dipolemoment values for the monocation and chloride forms of (T),

determined using the B3LYP/6-31G� method, are given inTable S2. The results show that the monocation form is most stablein gas phase while the chloride form is stable in aqueous solutionand also, show that the values of the dipole moments for bothforms increase with the hydration. On the other hand, the dimericform is also more stable in aqueous solution. The calculated molec-ular volumes with both methods for all the forms of (T) in gas andaqueous phases using the MOLDRAW program [21] are presentedin Table S3. The results show a volume change for the monocationform between 0.2 and 1.3 Å3 on moving from the gas phase to solu-tion, for the chloride form between 1.8 and 2.5 Å3 and for the di-meric form of 4.3 Å3. This large change in the volume of thechloride and dimeric forms in solution is related to the increasein the distances and in the dipole moment values as consequenceof the hydration, as seen in Table S2. These differences in the vol-umes and in the calculated van der Waals radii for the three spe-cies in solution (4.70, 4.99 and 6.0 Å for the monocation, chlorideand dimeric species, respectively using 6-31G� basis set) indicatinga hydration different for each form. The solvation energies valuesfor the monocation (240.27 and 247.62 kJ/mol using 6-31G� and6-311++G�� basis sets, respectively) and the notable increasing of

Table 1Comparison of calculated geometrical parameters for the monocation form oftolazoline hydrochloride in aqueous solution with the corresponding experimentalvalues.

B3LYP/6-31G� methoda

Parameter Gas phase Aqueous solution/PCM Exp.b

Bond lengths (Å)C5@N4 1.326 1.323 1.289 (8)C3AN4 1.477 1.472 1.491 (8)C5AN1 1.319 1.321 1.352 (8)C2AN1 1.474 1.474 1.472 (8)C2AC3 1.558 1.554 1.532 (10)C5AC11 1.504 1.503 1.509 (9)C14AC11 1.517 1.515 1.481 (9)C14AC15 1.401 1.402 1.415 (10)C15AC16 1.395 1.396 1.383 (11)C16AC17 1.396 1.397 1.360 (12)C17AC18 1.396 1.397 1.421 (10)C18AC19 1.396 1.397 1.392 (10)C19AC14 1.402 1.401 1.405 (9)RMSD 0.023 0.022

Bond angles (�)C11AC5AN1 124.2 125.7 120.5 (6)C11AC5AN4 124.8 122.9 123.7 (6)C5AC11AC14 113.6 115.3 115.1 (6)C3AN4AC5 112.2 112.1 109.3 (5)C2AN1AC5 112.5 111.9 107.2 (5)N1AC5AN4 110.8 111.3 115.8 (6)N1AC2AC3 102.1 102.4 104.6 (6)N4AC3AC2 102.0 102.1 102.8 (5)RMSD 2.5 2.5

Dihedral angles (�)C15AC14AC11AC5 80.4 85.7 89.3 (2)

a This work.b Ref. [3].

Table 2Comparison of calculated geometrical parameters for the chloride form of tolazolinehydrochloride in aqueous solution with the corresponding experimental values.

B3LYP/6-31G� methoda

Parameter Aqueous solution/Onsager Gas phase Exp.b

Bond lengths (Å)C5@N4 1.314 1.301 1.289 (8)C3AN4 1.471 1.467 1.491 (8)C5AN1 1.333 1.354 1.352 (8)C2AN1 1.470 1.475 1.472 (8)C2AC3 1.555 1.554 1.532 (10)C5AC11 1.505 1.501 1.509 (9)C14AC11 1.517 1.522 1.481 (9)C14AC15 1.401 1.402 1.415 (10)C15AC16 1.395 1.395 1.383 (11)C16AC17 1.397 1.397 1.360 (12)C17AC18 1.396 1.395 1.421 (10)C18AC19 1.397 1.396 1.392 (10)C19AC14 1.402 1.399 1.405 (9)H25ACl26 1.967 1.803RMSD 0.021 0.020

Bond angles (�)C11AC5AN1 123.2 123.6 120.5 (6)C11AC5AN4 124.5 123.8 123.7 (6)C5AC11AC14 113.1 110.5 115.1 (6)C3AN4AC5 110.7 110.9 109.3 (5)C2AN1AC5 111.2 109.3 107.2 (5)N1AC5AN4 112.2 112.4 115.8 (6)N1AC2AC3 101.4 101.5 104.6 (6)N4AC3AC2 103.0 102.8 102.8 (5)RMSD 2.006 2.121

Dihedral angles (�)C15AC14AC11AC5 88.4 80.4 89.3 (2)

a This work.b Ref. [3].

396 E. Romano et al. / Journal of Molecular Structure 1037 (2013) 393–401

the dipole moment values in aqueous solution probably suggestthat the monocation is slightly most hydrated than the other ones,as expected because an ion is a species highly hydrated in solution.

The atomic charges derived from the ESPs (MK) for (T) [22–24]by using 6-31G� basis set and the natural charge values in gas andaqueous phases are given in Table S4. The results for the monoca-tion form show that the N1 and N4 atoms have approximately thesame values while, for the chloride form there are significant dif-ferences due to the Cl atoms. Thus, in aqueous solution some val-ues decrease due to the hydration while the charge on the Clatom increases, stabilizing the neutral form in aqueous solution.The bond orders, expressed by Wiberg’s index, are given inTable S5. Again for the monocation form, the bond order valuesof the N1 atoms are approximately similar to the values of theN4 atoms as well gas as in aqueous solution phases. On the con-trary, the differences observed between those atoms for the chlo-ride form are justified by the presence of the Cl atoms, this way;there are differences between the N1AH6 and N4AH25 bonds be-cause in the N4AH25 bond the H25 is linked to a Cl atom, as ob-served in Table S4. Another important change is observed on thebond orders corresponding to the N and Cl atoms of the chlorideform because the values in gas phase are different from the valuesin aqueous solution. The lower values observed on the N4 and Clatoms in aqueous solution are related with the weakly of theN4AH25 and H25ACl26 bonds as consequence of the hydration.These results are in accordance with the lower bond order valueobserved on the H25 atom linked to the N4 in aqueous solution.

4.2. NBO and AIM studies

On the other hand, the monocation and chloride forms of (T)were also studied by means of NBO and AIM calculations. The sec-ond order perturbation energies E(2) (donor ? acceptor) that in-volve the most important delocalization were analyzed by meansof NBO calculations [10,11] and the results are given in Table S6.The contributions of the stabilization energies for the DETr?r�charge transfers of the benzyl ring are the most important delocal-izations observed in the monocation form while in the chlorideform in gas phase the DETLP?LP� and DETLP?BD� charge transfersdue to the lone pairs of the N1, N4 and Cl26 atoms are more impor-tant than the DETr?r� charge transfers. Thus, the results supportthe high stability found in aqueous solution for the chloride formin relation to the monocation one, as observed in Table S6.

The topological analysis [12,13] for the monocation of (T) hasshown in the previous study [2] that the electron density, q(r)and the Laplacian values, »2q(r) for the Ring Critical Point (RCP)of the imidazoline ring have higher values than those correspond-ing to the benzyl ring. Both results were explained since there is agradation of the positive charge distribution from one N atom tothe other N atom in the same region of the imidazoline ring[2,3]. The results for the chloride forms of (T) in aqueous solutionare given in Table S7 compared with the observed for the dimericform in gas and aqueous solution phases. The results for the chlo-ride and dimeric forms using both basis sets show different BCPs.These BCPs have the typical properties of the closed-shell interac-tion and for this, the values of q(r) are relatively low, the relation-ship |k1|/k3 are <1 and r2q(r) are positive indicating that theinteraction is dominated by the charge contraction away fromthe interatomic surface toward each nucleus. In the chloride formit is possible to observe three BCPs related to the Cl26� � �H12,Cl26� � �H20 and Cl26� � �H25 halogen bonds, as shown in Fig. S1.Here, the bonds between the Cl26 and H20 atoms using B3LYP/6-31G� level and between Cl26 and H12 atoms using B3LYP/6-311++G�� approximation show ellipticity values larger than 1.1,indicating that those bonds tend to distort to a more stable form,whereas the values for the bond Cl26� � �H25 suggest stable bond.

E. Romano et al. / Journal of Molecular Structure 1037 (2013) 393–401 397

The previous AIM analysis for the dimeric species in gas phase [2]shows five (BCPs), as in aqueous solution, they are the Cl26� � �H12,Cl26� � �H20, Cl26� � �H25, Cl26� � �H27 and Cl26� � �H39 halogenbonds. In this case, the ellipticity values for the bonds Cl26� � �H20,Cl26� � �H25 and Cl26� � �H27 suggest stable bonds.

5. Vibrational analysis

The recorded infrared and Raman spectra for the compound inaqueous solution compared with the corresponding in the solidphase can be seen in Figs. 1 and 2, respectively. The monocationand chloride forms of (T) have respectively 69 and 72 normalvibration modes and all modes are active in both spectra. Table 3show the experimental and SQM frequencies for the expected nor-mal vibration modes of the monocation and chloride forms of (T),in solid and aqueous solution phases, by using 6-31G� basis set to-gether with the complete assignments, while its correspondingPED contributions are shown in Tables S8 and S9. The optimizeddimeric structure of (T) by using the B3LYP/6-31G� level has C1

symmetry and 150 normal vibration modes, all active in the infra-red and Raman spectra. The assignment of the experimental bandsto the 150 expected normal vibration modes was made by meansof Gaussview program [19] by analyzing the nature of the vibra-tions. The vibrational assignment of the experimental bands tothe normal vibration modes is based on the comparison with theprevious assignment for (T) in solid phase [2], with related mole-cules [23–35] and with the results of the calculations performedhere. In this work we have considered the obtained results by usingB3LYP/6-31G� calculations because the Pulay’s scaling factors aredefined for this basis set. Fig. 4 shows the experimental infraredspectrum in aqueous solution compared with the correspondingtheoretical of the monocation, chloride and dimeric forms of tolaz-oline hydrochloride at B3LYP/6-31G� level. It is important to noticethat the very strong band calculated for the monocation form inaqueous solution at 1606 cm�1 (see Tables 3 and S8) is in agree-ment with the broad and very intense band observed in the exper-imental spectrum at 1610 cm�1. Moreover, the very strong bandcalculated for the chloride form in aqueous solution at2538 cm�1 (see Tables 3 and S9) is associated with the strong IRband observed in the experimental spectrum at 2705 cm�1. Onthe other hand, the three bands more intense in the theoreticalIR spectrum of the dimer at 3201, 3015 and 2897 cm�1 are inagreement with the broad and very intense band observed in theexperimental spectrum at 2988 cm�1. These observations clearlysupport that the three forms of (T) can be present in an aqueoussolution of (T). The SQM force fields for monocation and chlorideforms of the compound can be obtained at request. The discussionof assignment for the compound is presented as follows.

5.1. Band assignments

5.1.1. NH modesIn the previous assignment for the monocation form of (T) in so-

lid phase [2], the two NAH stretching vibrations were assigned tothe broad band observed in the IR spectra at 3440 cm�1. That bandin the Raman spectrum in aqueous solution decrease its intensityand also, it is shifted toward lower frequencies, hence, the verystrong IR band located at 3317 cm�1 is easily assigned to the twoNAH stretching vibrations for that form of (T). The NAH stretchingmodes in the chloride and dimeric forms are easily assigned, inaccordance to the calculations, to the strong IR bands at 3317and 2705 cm�1. Note that the shifting of a these modes towardlower frequencies are justified due to the Cl atoms in both struc-tures. The corresponding in-plane deformation modes for the mon-ocation and chloride forms could be associated to the weak Raman

bands at 1390 and 1240 cm�1 according to previous assignment [2]and to the theoretical calculations while for the dimeric form thosemodes are associated with the strong IR bands at 1457 and1293 cm�1. In the monocation form, the weak IR bands at 690and 589 cm�1 are assigned to the out-of-plane deformation modeswhile in the chloride form those modes are associated respectivelywith the shoulder and weak IR band at 846 and 438 cm�1. In thedimeric form, the shoulders at 846 and 815 cm�1 and the IR bandat 832 cm�1 are assigned to out-of-plane deformation modes. Thebroad band between 2500 and 1900 cm�1 can be attributed tothe NAH� � �N hydrogen bonding formed by the spatial arrangementof molecules in the lattice crystal [3], as observed in the molecularpacking of the 2-(20-furyl)-4,5-1H-dihydroimidazole molecule [27].

5.1.2. CH modesThe broad and intense band at 3068 cm�1 in the IR spectra of (T)

in aqueous solution can be easily assigned, due to their position, tothe CAH stretching modes for the monocation and chloride forms,as shown in Table 3. Note that those modes in solution are ob-served at lower frequencies due to the hydration while for the di-meric form those modes are calculated at higher frequencies and,for this, they are assigned to the broad Raman band at3101 cm�1. The in-plane deformation modes are clearly predictedfor the monocation and chloride forms in the 1501–1149 cm�1 re-gion [6], hence, they are assigned in that region, as observed in Ta-ble 3 while, for the dimeric form, those modes are assigned in the1396–1105 cm�1 region. The modes corresponding to out-of-planedeformations were assigned taking into account the results of thetheoretical calculations and the assignments for similar molecules[2,29–36]. Thus, for the monocation and chloride forms thosemodes were assigned to the bands observed between 1031 and776 cm�1 while for the dimeric form those modes are assigned tothe bands observed between 1004 and 728 cm�1, as seem inTable 3.

5.1.3. CH2 modesThe antisymmetric and symmetric stretching modes of these

groups for all the forms of (T) can be clearly assigned to the verystrong band and shoulder respectively at 2988 and 2928 cm�1, asindicated in Table 3, being the symmetric modes more intense inthe Raman spectrum as expected. The scissoring modes for thethree forms of (T) are assigned, in agreement with heterocycliccompounds containing the imidazoline ring [2,23–28], to the IRand Raman bands between 1556 and 1415 cm�1, as observed in Ta-ble 3. As predicted by the calculation for the three forms of (T), thewagging modes are easily assigned to the shoulders and the IRbands located between 1437 and 1168 cm�1, while the expectedrocking modes are assigned according to the PED contribution be-tween 1332 and 1206 cm�1. The twisting modes are predicted bythe calculations between 1141 and 793 cm�1; thus, these modesare associated with the IR and Raman bands between 1157 and797 cm�1, as indicated in Table 3.

5.1.4. Skeletal modesHere, the skeletal stretching modes are strongly mixed among

them as can be seen in Tables S8 and S9. The very strong bandsat 1610 and 1590 cm�1 are mainly associated with the C@C andC@N stretching modes for all of forms of (T) in accordance withsimilar compounds [2,24–35] and with our theoretical results(see Table 3). The strong band at 1497 cm�1 is associated withthe C@C stretching modes of the dimeric form, while the remainingCAC and CAN stretching modes are associated with the bands andshoulders located in both spectra between 1157 and 661 cm�1, asobserved in Table 3. Note that these vibration modes for the mon-ocation form in the spectra in aqueous solution are observed shiftedas consequence of the hydration. The benzyl ring deformations (bR)

Table 3Observed and calculated frequencies (cm�1) and assignments for tolazoline hydrochloride.

Solid phasec Aqueous solutiona

Experimental Monocation Chloride Dimer

IRc Ramanc SQMb Assignmentc IRa Ramana SQMd Assignmenta SQMe Assignmenta Calcf Assignmenta

3440 w, br 3492 mN4AH25 3452 sh 3358 mN1AH6 3459 mN1AH6 3664 mN1AH63440 w, br 3200 vw 3456 mN1AH6 3317 vsbr 3355 m, br 3312 mN4AH25 3214 mC7AH223110 w br 3160 sh maCH2 imid.dimer 3176 mC47AH503100 w 3101 sh 3093 mC17AH22 3101 w 3088 mC17AH22 3167 mC19AH24

3082 sh 3083 mC16AH21 3140 maCH2 imid.

3070 sh 3075 mC18AH23 3065 mC18AH23 3076 mC18AH23 3133 maCH2 imid.

3055 br 3053 mC15AH20 3068 s,br 3056 mC16AH21 3069 mC16AH21 3130 maCH2 imid.

3047 br 3047 (100) msCH2 dimer 3047 mC17AH22 3126 maCH2

3044 br 3035 (48) msCH2 dimer 3031 mC19AH24 3050 mC19AH24 3125 maCH2

3026 (30) 3049 mC19AH24 3030 mC15AH20 3046 mC15AH20 3116 maCH2

2996 (23) 3027 maCH2 imid. 3008 sh 3016 ma CH2 imid. 3012 ma CH2 imid 3079 ms CH2

2982 sh 2982 (39) 3011 maCH2 imid. 3000 sh 3000 ma CH2 imid. 3076 ms CH2

2970 w br 2970 (45) 2975 msCH2 imid. 2988 vs 2985 m,br 2964 ms CH2 imid. 2998 ma CH2 imid. 3075 ms CH2 imid.

2967 w mNAAHdimer 2954 m 2961 ms CH2 imid. 2987 ma CH2 3073 ms CH2 imid.

2958 w 2958 (47) 2972 msCH2 imid. 2954 m 2959 ma CH2 2955 ms CH2 imid 3070 ms CH2

2938 w 2968 maCH2 2954 m 2949 ms CH2 imid. 3062 ms CH2

2925 sh 2924 (48) 2926 msCH2, msNAHdimer 2928 sh 2921 m 2921 ms CH2 2935 ms CH2 3009 msN4AH25� � �Cl262885 w 2885 (28) mNAH� � �N (see text) 2705 s 2732 vw 2478 mN4AH25 2895 msN34AH511621 vs 1615 (15) 1606 mC15AC16 1610 vs 1607 m,br 1606 m C15AC16 1635 mC5AN11599 s 1600 (26) 1595 mC5AN1 1590 vs 1590 m 1596 mC5AN1 1609 m C15AC16 1630 mC30AN281585 s 1583 (16) 1589 mC16AC17 1590 m 1588 mC19AC14 1603 mC5AN41585 s 1583 (16) 1571 mC5AN4 1580 sh 1584 mC5AN4 1587 mC16AC17

1556 vw 1560 mC5AN1 1556 dCH2 imid.

1497 s 1497 (4) 1498 bC16AH21 1497 s 1501 bC16AH21 1499 bC15AH20 1503 mCAC1482 sh 1486 dCH2 imid. 1489 sh 1486 m 1489 dCH2 imid. 1484 dCH2 imid.

1473 (19) 1471 dCH2 imid. 1472 m 1473 dCH2 imid. 1479 bmAHop1468 sh bNAHop dimer 1468 sh 1462 sh 1469 dCH2 imid.

1451 m 1451 (18) 1456 bC17AH21 1457 s 1457 bC17AH22 1454 bC18AH23 1449 bmAHop1437 w 1424 w 1390 wagCH2 imid.

1426 s 1425 (23) 1415 dCH2 1415 m 1415 dCH2 1416 dCH2 1386 wagCH2 imid.

1396 sh 1390 w 1397 bN4AH25 1379 bNAH 1378 bCAH1360 w 1362 (10) 1383 qCH2 1357 m 1358 w 1344 wagCH2 imid. 1335 bC19AH24 1338 wagCH2 imid

1350 sh 1349 sh 1337 wagCH2 imid. 1346 sh 1328 w 1340 bC19AH24 1327 wagCH2 imid. 1327 wagCH2

1334 w 1335 (5) 1335 bC15AH20, bC19AH24 1332 sh 1311 w 1310 qCH2 1309 qCH2

1307 vs 1301 (10) 1309 mC14AC15 1293 vs 1297 w 1308 mC14AC15 1303 mC14AC15 1296 bmAHip1286 s 1287 (8) 1295 bN1AH6 1270 sh 1271 w 1288 wagCH2 imid. 1273 wagCH2 imid. 1273 qCH2 imid.

1270 sh 1271 sh 1284 wagCH2 imid. 1257 w 1259 qCH2 imid. 1249 qCH2 imid. 1247 qCH2 imid.

1246 sh 1245 (4) 1254 qCH2 imid. 1240 w 1219 bN1AH6 1220 bN1AH6 1229 qCH2 imid.

1213 sh 1212 (7) 1209 qCH2 imid. 1206 m,br 1214 qCH2 imid. 1195 qCH2 imid. 1194 bCAH1203 s 1204 sh 1197 bN4AH25 1202 w 1196 m,br 1194 bC15AH20 1191 mC19AC14 1193 bCAH1189 sh 1188 (25) 1188 mC11AC14 1184 vw 1186 sh 1185 bC18AH231180 w 1182 bC16AH21 1184 vw 1186 sh 1178 wagCH2 1181 bC16AH211170 m 1170 wagCH2 1168 w 1162 w 1170 mC17AC18 1167 wagCH2

1160 w 1154 (12) 1166 bC18AH23 1157 vw 1149 sh 1079 mC18AC19 1161 bC17AH22 1141 sCH2 imid.

1148 w 1079 mC18AC19 1105 vw 1108 vw 1029 mC1AN2 1076 mC18AC19 1117 bCAH1077 w 1077 (3) 1025 bR1 imid. 1078 m 1078 w 1026 mC16AC17 1026 mC17AC18 1073 mCAN1046 w 1050 (3) 1024 bR1 benc. 1046 s 1032 s 1019 sCH2 imid. 1022 mC1AN2 1059 bR1 benc.

1030 w 1030 (27) 1014 sCH2 imid. 1031 m 1010 sh 1019 cC18AH23 1016 sCH2 imid. 1037 bR1 imid.

1015 sh 1015 (10) 1012 mC1AN2 1010 sh 1014 mC11AC5 1014 bR2 imid.

1000 vw 1000 (81) 1010 cC17AH22 1004 w 1005 vs 1000 bR1 benc. 1011 cC16AH21999 sh 998 cC16AH21 1009 cC41AH44

995 sh 998 mC17AC18 999 sh 997 bR1 benc. 995 bR1 imid.

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986 vw 988 (5) cCAHdimer 992 sh 980 cC16AH21 985 mC3AN4 981 cC45AH49974 sh 971 cC18AH23 972 sh 974 vw 976 mC3AN4 966 cC18AH23 980 cC15AH20941 w 961 mC3AN4 955 vw 940 cC15AH20 956 sCH2

925 w 924 (33) 933 c C19AH24 932 m 932 s 927 c C19AH24 935 c C19AH24899 vw 896 m(C2AC3)imid. 893 m(C2AC3)imid. 880 sCH2 imid.

888 vw 890 (2) 888 m(C2AC3)imid. 875 vw 866 c C19AH24 863 sCH2 872 cC42AH46863 vw 863 sCH2 861 vw 859 sCH2 855 cC15AH20 867 cC15AH20855 vw 858 (2) 853 cC15AH20 846 sh 848 cNAH 844 cNAH822 m 825 (10) cNAHdimer 832 m 820 m C11AC14 843 cNAH810 m 812 (12) 815 c(C11AC14) 815 sh 814 m C11AC14 814 cNAH778 m 786 sCH2 imid. 797 vw 793 sCH2 imid. 793 sCH2 imid. 790 sR1 benc.

778 m 771 sR1 benc. 776 sh 779 w 779 cC17AH22 771 cC17AH22 789 sR1 benc.

757 sh 764 (5) bRimid. dimer 749 w 745 bR2 imid. 748 bR2 imid.

745 vs 744 (4) 745 bR2 imid. 728 sh 728 w 715 bR2 imid. 735 cC16AH21698 m 698 (2) 702 cC16AH21 704 w 705 sR1 benc. 705 sR1 benc. 710 sR1 benc.

693 m cCAHdimer 690 w 698 cN1AH6 688 bR2 imid.

681 w 685 (1) cNAHdimer 674 w 665 mC11AC5643 m 644 (14) 656 mC11AC5 661 w 656 bR1 imid. 642 mC11AC5636 sh 629 bR2 benc. 636 m 631 bR2 benc. 631 bR2 benc. 633 bR2 benc.

614 w 611 (14) 617 cN1AH6 627 vw 622 m 590 bR3 benc. 603 bR3 benc. 629 bR3 benc.

589 (1) 586 bR3 benc. 589 w 583 cN4AH25561 w 565 c(C11AC5) 546 mC30AC35

528 m 529 c(C11AC5) 542 sh 540 c(C11AC5) 545 bR3 benc.

520 m 520 (7) cNAHdimer 527 vw463 s 464 (3) 469 c(C11AC14), sR3 benc., sR2 benc. 473 w 472 m 481 c(C11AC14) 482 c(C11AC14)438 sh 435 cN4AH25 438 vw 448 w 467 c(C11AC14) 462 cN1AH6419 vvw sRbenc.dimer 426 vw409 vvw 409 (2) 402 sR2 benc. 419 vw 411 w 406 sR2 benc. 404 sR2 benc. 418 sR2 benc.

331 (4) bCACdimer 412 vw 325 sh 324 b(C11AC14) 394 b(C40AC35)327 311 b(C11AC14) 313 m 308 b(C11AC14) 300 b(C11AC5) 282 b(C30AC55)303 (23) 275 dC4AC11AC5) 275 sh 274 dC4AC11AC5) 277 b(C11AC5)241 (4) 204 sR3 benc. 235 s,br 232 sR3 benc. 258 sR3 benc.206 (16) 187 sR2 imid. 212 s,br 204 sR3 benc. 193 sR3 benc. 215 sR3 benc.

170 vw 189 sR2 imid. 160 mH25ACl26 189 sR2 imid.

125 vw 111 sR2 imid.

139 sw CH2 imid.dimer 104 vw 79 sR1 imid. 104 sR1 imid.

112 sw CH2 imid.dimer 66 b(C11AC5) 73 dC4C11C5 79 dC4C11C543 sR1 imid. 41 sR1 imid. 49 dN4H25Cl26 44 s(C11AC14)34 s(C11AC4) 34 s(C11AC4) 37 s(C11AC14) 36 s(C40AC35)24 s(C11AC5) 24 s(C11AC5) 27 s(C11AC5)19 b(C11AC5) 9 s(C11AC5) 12 cNAH� � �Cl

m, stretching; d, angle deformation; wag, wagging; q, rocking; b, in plane deformation; c, out plane deformation; s, torsion; benc., bencene; imid., imidazoline; a, antisymmetry; s, symmetry, R, ring, s, strong; m, medium; w, weak;v, very; sh, shoulder; br, broad.

a This work.b From scaled quantum mechanics force field by using B3LYP/6-31G�.c From Ref. [2].d From scaled quantum mechanics force field by using PCM/B3LYP/6-31G�.e From scaled quantum mechanics force field by using Onsager/B3LYP/6-31G�.f From Onsager/B3LYP/6-31G�.

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401399

Fig. 4. (a) Experimental infrared in aqueous solution compared with the corre-sponding theoretical of the: (b) monocation form, (c) chloride form and, (d) dimericforms of tolazoline hydrochloride at B3LYP/6-31G� level of theory.

400 E. Romano et al. / Journal of Molecular Structure 1037 (2013) 393–401

are clearly assigned taking into account the calculated PEDcontribution and the previous assignment of (T) in solid phase[2,28–35] while the three benzyl ring torsions (sR) are calculatedstrongly coupled with others modes and, in the lower frecuenciesregion; for this reason, those modes are assigned as indicated inTable 3. The deformations ring modes corresponding to the imidaz-oline ring for the three forms of (T) are clearly predicted by the cal-culations at higher frequencies and, in different regions [2,24–28],in reference to the corresponding torsion ring modes, thus, the(bR1) and (bR2) deformations modes are assigned for the protonatedform to the Raman bands at 749 and 661 cm�1 while for the chlo-ride form those modes are assigned to the shoulders in the Ramanand IR spectra respectively at 998 and 728 cm�1.

6. Force field

The force constants for the monocation and chloride forms of(T) were estimated by using Pulay et al. [8,9] scaling procedureas mentioned before. The force constants expressed in terms ofsimple valence internal coordinates were calculated from the cor-responding scaled force fields by using the MOLVIB program [18].The force constants calculated for both forms at the B3LYP/6-31G� level in the gas phase were compared with the ones obtainedin aqueous solution by PCM and Onsager models, respectively and,the results are shown in Table S10. A very important observation isthat the calculated f(NAH) force constants values with both basissets for the monocation and chloride forms in aqueous solutionare lower than the corresponding gas phase values due to thehydration while for the chloride form the f(NAHCl) force constantsincrease its values in reference to the gas phase value. The length-ening of the HACl bond in this form as consequence of the hydra-tion justifies those differences observed. Also, the discrepancyobserved in the f(ClAH) and f(dNAHACl) force constants valuesare attributed to the lengthening of the HACl bond of the hydratedchloride form.

7. Conclusions

– The substance was characterized by infrared and Raman spec-troscopies in aqueous solution phase. The presence of tolazolinehydrochloride monocation, chloride and dimeric forms in aque-ous solution was detected in the IR spectrum by means of thecharacteristic bands at 2988, 2705, 1610, 1590, 1293 and

1046 cm�1. The bands observed in the experimental infraredspectrum in aqueous solution at 2988, 1590, 1293 and1046 cm�1 are associated with the monocation, chloride anddimeric forms, the band at 2705 cm�1 is characteristic of thechloride form while the band at 1610 cm�1 is characteristic ofthe monocation and dimeric forms.

– The theoretical molecular structures of tolazoline hydrochloridemonocation, chloride and dimeric forms in aqueous solutionwere respectively determined by the PCM and Onsager modelsemploying the B3LYP/6-31G� method.

The calculations suggest the existence of tolazoline hydrochlo-ride monocation, chloride and dimeric forms in aqueous solution,as they were experimentally observed.

– The complete assignments of the 69 and 72 normal vibrationmodes respectively for the monocation, chloride forms of tolaz-oline hydrochloride were performed.

– The SQM force fields were obtained for the monocation, chlo-ride forms of tolazoline hydrochloride by the PCM and Onsagermodels employing the B3LYP/6-31G� method.

– The NBO and AIM analyses show the high stability found inaqueous solution for the chloride form in relation to the mono-cation one.

Acknowledgements

This work was subsidized with grants from CIUNT (Consejo deInvestigaciones, Universidad Nacional de Tucumán). The authorsthank Prof. Tom Sundius for his permission to use MOLVIB.

Appendix A. Supplementary material

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.molstruc.2013.01.028.

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