A vibrational spectroscopic investigation on benzocaine molecule

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Vibrational Spectroscopy 48 (2008) 215–228 www.elsevier.com/locate/vibspec

A vibrational spectroscopic investigation on benzocaine molecule K. Balci a,*, S. Akyuz b a b

Istanbul University, Faculty of Science, Department of Physics, Vezneciler, 34134, Istanbul, Turkey Istanbul Kultur University, Faculty of Science and Letters, Department of Physics, Istanbul, Turkey Received 17 July 2007; received in revised form 5 February 2008; accepted 7 February 2008 Available online 16 February 2008

Abstract The stable conformers of free benzocaine molecule in electronic ground state were searched by means of successive single point energy calculations carried out at B3LYP/3-21G level of theory. The obtained calculation results have indicated that the molecule has three different stable conformers (one trans and two gauche) at room temperature. The resultant equilibrium geometrical parameters of these stable conformers were determined through the geometry optimizations performed at B3LYP/6-31G(d), B3LYP/6-31++G(d,p), B3LYP/aug-cc-pvTZ and MP2/631++G(d,p) levels of theory, separately. The vibrational normal modes of each conformer and associated wavenumbers, IR intensities and Raman activities were calculated in the harmonic oscillator approach at B3LYP/6-31G(d), B3LYP/6-31++G(d,p), B3LYP/aug-cc-pvTZ levels of theory. In the fitting of the calculated harmonic wavenumbers to the experimental ones, two different scaling procedures, called ‘‘Scaled Quantum Mechanics Force Field (SQM FF) methodology’’ and ‘‘scaling wavenumbers with dual scale factors’’, were proceeded independently. Both procedures have yielded results in very good agreement with the experiment and thus proved the necessity of proceeding an efficient scaling procedure over the calculated harmonic wavenumbers for performing a correct vibrational spectroscopic analysis on the basis of B3LYP calculations. In the light of the obtained scaled theoretical spectral data, a successful assignment of the fundamental bands observed in the recorded IR and Raman spectra of the free molecule was achieved. # 2008 Elsevier B.V. All rights reserved. Keywords: Benzocaine; Ethyl 4-aminobenzoate; Scaled frequencies; IR and Raman spectra; Vibrational modes; SQM (Scaled Quantum Mechanics)

1. Introduction Benzocaine (see Fig. 1a), called in the literature with different synonyms such as ethyl p-aminobenzoate, ethyl 4aminobenzoate, 4-aminobenzoic acid ethyl-ester, p-aminobenzoic acid ethyl-ester, is known as a substance used in local anesthetic applications. Today, one can easily reach many papers published on its anesthetic effects [1–4]. Besides, it is also possible to found papers published on the other important pharmacological effects of this substance; (1) its agonist and blocking effects [5], (2) its effects on a cardiac K+ channel cloned from human ventricle [6] and on the human erythrocyte membrane [7], (3) as a UV filter, its estrogenic activity in vivo and in vitro [8] as well as its important roles as a hydrophilic block in the synthesized polymeric structures which exhibit physicochemical properties in vivo studies [9,10] are only few

* Corresponding author. E-mail addresses: [email protected], [email protected] (K. Balci). 0924-2031/$ – see front matter # 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.vibspec.2008.02.001

of them. Nowadays, synthesizing of the Schiff base ligands and their metal complexes which can show antibacterial, anticancer and herbicidal activities has become an area attracting great interest [11–13]; in this aspect, benzocaine has been reported as one of the preferable substances used in synthesizing of these type of structures. The structural properties of the molecule have been investigated by various workers; the polymorphic and pseudopolymorphic crystal forms of the molecule were investigated by Schmidt by means of FT-IR, FT-Raman, SSNMR spectroscopy and powder X-ray diffraction methods [14,15]. On the other hand, the experimental geometrical parameters of benzocaine in crystal form were determined in a crystallographic study carried out by Sinha and Pattabhi [16]. In a conformational study carried out by Fernandez et al. [17], water complexes of benzocaine were investigated with a combined approach of laser spectroscopic techniques and ab initio calculations performed using B3LYP method [18,19] with 6-31+G(d) basis set. Another conformational study based on the determination of the possible stable conformers of ethyl 4-aminobenzoate (benzocaine), methyl 4-aminobenzoate, ethyl

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Fig. 1. (a) The schematic view of benzocaine molecule, (b) trans conformer (T1), (c) gauche conformer (G1), (d) gauche conformer (G2). The dihedral angle values given in the figures were obtained from the geometry optimizations performed at B3LYP/aug-cc-pvTZ level of theory.

3-aminobenzoate and methyl 3-aminobenzoate molecules, was carried out by McCombie et al. [20] by means of the experimental LIF spectroscopy and molecular modeling performed at semi-empirical MNDO and molecular mechanics MM2 levels of theory. To our best knowledge, the first theoretical vibrational spectroscopic studies on interpretation of the experimental IR and Raman spectral data of free benzocaine were carried out by Palafox in the light of the theoretical calculations performed at semi-empirical CNDO/2 level of theory [21,22]. In addition to these, two theoretical vibrational spectroscopic studies on free benzocaine, based on calculations performed at AM1, MNDO and MNDO/3 levels of theory [23,24], and another one on benzocaine hydrochloride molecule, based on calculations performed at semi-empirical AM1 level of theory [25], were carried out by the same author. Although each of these studies have supplied very valuable information on analyzing of the vibrational normal modes of benzocaine molecule and associated IR and Raman spectral data with them, according to our view, some of the assignments proposed in these studies for the fundamental bands of the molecule should be reconsidered because of the well known deficiencies of the semi-empirical methods used by the author in frequency calculations. The most recently published vibrational spectroscopic study for free benzocaine in the literature, based on the ‘‘dispersed emission’’, ‘‘HP’’, ‘‘Resonance Enhanced Multi Photon Spectroscopy (REMPI)’’ experimental techniques and DFT calculations performed at B3LYP/6-31+G(d) level of theory, was carried out by Longarte et al. [26]. As is well known from the literature, the theoretical spectral data obtained from frequency calculations performed in the harmonic oscillator approach at B3LYP/6-31G(d) level of theory should be improved by proceeding an efficient scaling procedure to reduce the systematical errors due to several

negative factors such as the anharmonicity of the vibrational normal modes which is neglected in the harmonic oscillator approach, basis set truncation effect and deficiencies arising from the calculation method itself, if they will be used as a tool in the assignment process of the fundamental bands observed in the recorded experimental spectra. Unfortunately, Longarte et al. have not considered these factors and given their assignments directly with respect to the harmonic wavenumbers they obtained from frequency calculations. On this basis, we concluded that some of the assignments proposed by these authors need to be reconsidered too. In addition to this, the authors have not proposed any assignment for the CH stretching vibrations of the molecule, where the anharmonicity character is considerably greater and therefore proceeding an efficient scaling procedure on the calculated harmonic wavenumbers is necessary. This situation strongly motivated us to perform a new comprehensive vibrational spectroscopic investigation on free benzocaine molecule. 2. Methods and calculations 2.1. Experimental part Benzocaine was reagent grade (Aldrich) and used as received. The IR spectra (400–4000 cm1) of KBr discs of benzocaine, were recorded on a Jasco 300E FT-IR spectrometer (2 cm1 resolution) based on averaging 200 samples and 16 background scans. The Raman spectrum of the sample in solid phase was taken with a JY Jobin Yvon Horiba HR(800) spectrometer using 632.8 nm excitation from a He–Ne laser in the 100–4000 cm1 region with 4 cm1 resolution. In order to obtain the resultant IR and Raman spectra of the molecule, baseline corrections were carefully performed on both of the recorded experimental spectra.

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

2.2. Computational part All the electronic structure calculations were carried out using Gaussian03# program suite [27]. In order to determine the number of the possible stable conformers of the free molecule, a theoretical conformational search, called ‘‘scan type of calculation’’ which corresponds to successive energy calculations, was performed using B3LYP method with 3-21G basis set. In this iterative calculation, the optimized geometrical parameters (calculated at B3LYP/6-31+G(d) level of theory) reported by Longarte et al. for free benzocaine [26] were used as initial input geometrical data. During the calculation, only the dihedral angles about the C3–C11, C11–O13, O13–C14 single bonds in the aliphatic chain (see Fig. 1a), were changed by 45o in each iteration by fixing all other coordinates of the molecule. The first geometry optimization and frequency calculations were performed again at the same level of theory, as used in the conformational search, over each of the determined appropriate structures in order to determine all the possible stationary points for the free molecule and also to check whether they really correspond to local minima or saddle points. Afterwards, new geometry optimization and frequency calculations were performed at B3LYP/6-31G(d) level of theory to obtain the more accurate geometrical parameters and harmonic wavenumbers for each determined stable conformer. Considering the fact that the use of a higher level basis set which includes additional diffuse and polarization functionals generally leads to theoretical results in much better agreement with the experimental data in particular in the electronic structure calculations performed for the conjugated systems where electrons are highly delocalized, we repeated the same calculations for each of the determined stable conformers of the molecule first at B3LYP/6-31++G(d,p) and then at B3LYP/augcc-pvTZ level of theory, respectively. In order to correctly determine the relative position of the amino group to the phenyl ring and thus to check whether the plain on which the amino group locates is co-planar with that of the phenyl ring or not, additional geometry optimizations were performed for each stable conformer by using Moller-Plesset Second Order Perturbation Theory (MP2) method [28,29] and 631++G(d,p) basis set, which is expected to lead to relatively more correct calculation results in the determination of the amino group position. However, the relative failure of the MP2 with respect to B3LYP method in frequency calculations is clear in the literature; considering this and also that MP2 is a too much time consuming method in frequency calculations, all the frequency calculations in the study were carried out using B3LYP method. In order to reduce the overestimations occurred at the calculated harmonic wavenumbers, two different types of scaling procedures, referred to as scaling procedure-1: ‘‘scaling wavenumbers with dual scale factors [30]’’ and scaling procedure-2: ‘‘Scaled Quantum Mechanics Force Field (SQM FF) methodology [31–33]’’, were proceeded, independently. In procedure-1 in which two different empirical scale factors are used to directly scale the calculated harmonic wavenumbers, one empirical scale factor for scaling of the wavenumbers under 1800 cm1 (the scale factors 0.967,

217

0.977 and 0.978 for B3LYP/6-31G(d), B3LYP/6-31++G(d,p) and B3LYP/aug-cc-pvTZ levels of theory, respectively) and another one for those over 1800 cm1 (the scale factor 0.955 for B3LYP/6-31G(d) and B3LYP/6-31++G(d,p) levels of theory, while another one 0.960 for B3LYP/aug-cc-pvTZ) were used; the dual scale factors used in scaling of the wavenumbers calculated at B3LYP/6-31G(d) level of theory were derived from the single scale factor 0.9614 (reported by Scott and Radom for the B3LYP/6-31G(d) level of theory [34]) by optimizing it so as to reach the smallest root-mean-square (r.m.s.) error values for the obtained set of scaled wavenumbers. Similarly, the dual scale factors used in scaling of the harmonic wavenumbers calculated at B3LYP/6-31++G(d,p) and B3LYP/ aug-cc-pvTZ levels of theory were derived from the dual scale factors 0.9781 and 0.950 proposed by Frosch et al. for B3LYP/ 6-31++G(d,p) level of theory [35]. On the other hand, in procedure-2, the scaled wavenumbers were calculated over the geometrical and harmonic force constant parameters which were calculated through the frequency calculations performed at B3LYP/6-31G(d) level of theory. In this procedure proceeded by using the software FCART01 written by Collier [36–38], the original scaling factors proposed by Baker et al. (see Table S1 given as a supplementary material) [33] were used without making any modification. The determination of the internal coordinate contributions to the normal modes is of vital importance in achieving a correct assignment of the fundamental bands observed in the experimental spectra. Considering this, the mode descriptions of the calculated normal modes of benzocaine were given with respect to the potential energy distributions (PEDs), obtained in SQM methodology [31–33] by utilizing FCART01 program over the geometrical and force constant parameters calculated at B3LYP/6-31G(d) level of theory. 3. Results and discussion 3.1. Conformational analysis The theoretical results obtained from the ‘‘scan’’, ‘‘geometry optimization’’ and ‘‘frequency’’ type of calculations performed at different levels of theory have showed that at room temperature, free benzocaine molecule has only three different stable conformers, referred to here as trans T1, and gauche G1 and G2. As is easily seen from Fig. 1b–d, the only difference between the two gauche conformers (G1 and G2), results from the different positions of the amino groups; the hydrogen atoms in the amino group in conformer G1 locate under the phenyl ring plain so as to be in the opposite side to the methyl group, whereas in conformer G2, the two hydrogen atoms locate over the phenyl ring plain and in the same side as the methyl group. The dihedral angles obtained for the gauche conformers G1 and G2 from the geometry optimizations carried out at B3LYP/631G(d), B3LYP/6-31++G(d,p), B3LYP/aug-cc-pvTZ and MP2/ 6-31++G(d,p) levels of theory, have clearly demonstrated that in both conformers, the plain of the amino group is not coplanar with the phenyl ring; which means that at room temperature both gauche conformers in theory should exist in

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the sample under spectroscopic investigation and accordingly contribute to the resultant experimental spectra of the free molecule, although only one possible gauche conformer for the molecule has been reported by McCombie et al. [20] as well as Longarte et al. [26]. According to the SCF energies obtained from both B3LYP and MP2 calculations, the trans T1 is the most stable one among the three stable conformers of free benzocaine. As the relative energies of the conformers (see Table 1) are considered, it is seen that all of them are either lower or slightly higher than the kT energy (0.6 kcal/mol at room temperature and 1 atm. pressure); this is another important indication which shows that both the trans conformer (T1) and gauche conformers (G1 and G2) can have considerable populations in the sample under spectroscopic investigation. Comparisons between the corresponding SCF energies calculated using B3LYP method with 6-31G(d), 631++G(d,p) and aug-cc-pvTZ basis sets have showed that including additional polarization and diffuse functionals to the basis set used leads to small but important improvements at the calculated SCF energies of the three conformers; the differences between the corresponding SCF energies calculated for the gauche and trans conformers using 6-31G(d) and 631++G(d,p) basis sets are about 0.1 and 0.4 kcal/mol, respectively. On the other hand, the use of ‘‘aug-cc-pvTZ’’ basis set has not led to any meaningful improvements on the SCF energies with respect to those calculated with 631++G(d,p) (please see Table 1). Comparatively a little bit more definitive results were obtained at MP2/6-31++G(d,p) level of theory; the energy differences between the corresponding SCF energies of the trans and gauche conformers are about 0.65 kcal/mol, and are in agreement with the results obtained from the B3LYP calculations. 3.2. Geometry and force field In the geometry optimizations, B3LYP/6-31++G(d,p) and B3LYP/aug-cc-pvTZ levels of theory have yielded very close results; for the trans conformer T1, the maximum deviation between the values calculated at these two levels of theory for ˚ for bond the corresponding geometrical parameters is 0.005 A lengths, 0.28 for angles and 0.18 for dihedral angles. The dependencies of the calculated bond length and angle parameters on the conformational structure of the free molecule ˚ are very weak (only very small deviations of 0.001–0.005 A have been determined for the bond lengths of the CC and CO bonds in the aliphatic ethyl-ester chain), while those associated with the phenyl ring are almost completely insensitive to

conformation. Considering this situation, and also aiming to keep the paper size shorter, only the geometrical parameters of the conformers trans T1 and gauche G1 calculated at B3LYP/ aug-cc-pvTZ level of theory are presented in Table 2 in comparison to the experimental data reported by Sinha and Pattabhi [16]. However, an interested reader can receive the optimized geometrical data of the three conformers given in Cartesian coordinate terms in Table S2 (supplementary material). In Table 2, the relatively much shorter bond lengths of the C1–C2 and C5–C6 bonds to those of the other CC bonds in the phenyl ring exhibit a very good agreement with the experimental data reported by Sinha and Pattabhi [16], although the bond length values calculated for these bonds considerably differ from the experimental values reported by the authors. Our calculation results have clearly demonstrated that the magnitudes of the calculated amino inversion angle values depend considerably on the level of theory used but very slightly on the conformational structure of the conformer; the values calculated at B3LYP/6-31G(d) level of theory for the conformers T1, G1 and G2 are 34.958, 34.898 and 34.878, respectively. The corresponding values calculated at B3LYP/631++G(d,p) level of theory are 30.728, 30.678 and 30.718, and are also very close to those obtained from B3LYP/aug-cc-pvTZ level of theory (please see Table 2), while the values calculated at MP2/6-31++G(d,p) level of theory (36.158, 36.358 and 36.308) considerably differ from those calculated at the other three levels of theory based on B3LYP. As can be readily seen, all of the amino inversion angle values given above for the three stable conformers of free benzocaine are considerably lower than the value (40.08), calculated at B3LYP/6-31G(d) level of theory by Vaschetto et al. [39] for that of aniline (the parent molecule of benzocaine). The experimental bond length value reported by Sinha and Pattabhi [16] for the CN bond in ˚ and remarkably lower than those benzocaine is 1.35(2) A calculated by us for this bond of the three stable conformers of ˚ ). However, both the the free molecule (all are equal to 1.383 A experimental value reported by Sinha et al. and the ones calculated by us are remarkably smaller than those reported by ˚: the other authors for the CN bond in aniline molecule (1.402 A ˚: a an experimental value reported by Lister et al. [40]; 1.400 A theoretical value calculated by Vaschetto et al. at B3LYP/631G(d) [39]) and thus clearly indicate the higher electron density through the CN bond in this molecule, which results from the charge transfers due to the delocalizations of the lone pair electrons on the nitrogen atom, and also the higher double bond character of this bond to that in aniline. The scaled force ˚ , see Table S3 given as a constant values (about 6.150 mdyn/A

Table 1 The relative energies of the three stable conformers of free benzocaine moleculea Conformers

B3LYP/6-31G(d)

B3LYP/6-31++G(d,p)

B3LYP/aug-cc-pvTZ

MP2/ 6-31++G(d,p)

Trans (T1) Gauche (G1) Gauche (G2)

0.000 0.109 0.113

0.000 0.416 0.421

0.000 0.430 0.434

0.000 0.641 0.651

a

The relative energies of the three stable conformers of benzocaine are given in kcal/mol unit with respect to the SCF energy values calculated for the trans conformer T1; the SCF energies calculated for the conformer T1 at B3LYP/6-31G(d), B3LYP/6-31++G(d,p), B3LYP/aug-cc-pvTZ and MP2/6-31++G(d,p) levels of theory are 348145.019, 348172.516, 348281.320, 346042.940 kcal/mol, respectively.

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

219

Table 2 The experimental and optimized geometrical parameters (calculated at B3LYP/aug-cc-PvTZ level of theory) for the trans conformer T1 and gauche conformer G1 of benzocaine molecule ˚) Bonds (A

Angles (8)

a

a

Parameter

1–2 1–6 1–7 2–3 2–23 3–4 3–11 4–5 4–10 5–6 5–9 6–8 8–16 8–17 11–12 11–13 13–14 14–15 14–20 14–21 15–18 15–19 15–22

Exp. [16]

Conformers

X-ray

T1

1.35(2) 1.37(2) – 1.36(2) – 1.38(2) 1.45(2) 1.32(2) – 1.41(2) – 1.35(2) – – 1.18(2) 1.34(1) 1.45(2) 1.47(3) – – – – –

NH2 inversion angle Tilt angle of C–NH2 moiety a

Parameter G1

1.382 1.402 1.083 1.398 1.080 1.398 1.479 1.381 1.081 1.403 1.083 1.383 1.001 1.001 1.212 1.353 1.443 1.512 1.090 1.090 1.090 1.090 1.091

1.382 1.402 1.083 1.398 1.080 1.398 1.479 1.381 1.081 1.403 1.083 1.383 1.001 1.001 1.212 1.354 1.445 1.517 1.088 1.088 1.090 1.090 1.091

1-2-3 2-3-4 3-4-5 4-5-6 5-6-1 1-6-8 5-6-8 3-11-12 3-11-13 12-11-13 11-13-14 13-14-15 4-5-9 3-4-10 2-1-7 3-2-23 6-8-16 6-8-17 13-14-20 13-14-21 14-15-22 14-15-18 14-15-19

30.978 2.468

30.918 2.478

20-14-21 18-15-19 18-15-22

Dihedral angles (8) Parametera

Exp. [16]

Conformers

X-ray

T1

G1

124(1) 116(1) 119(1) 128(1) 109(1) 124(1) 126(1) 124.5(9) 113.6(9) 121.8(8) 120.2(9) 112(1) – – – – – – – – – – –

121.8 118.5 121.0 120.5 118.6 120.7 120.7 124.6 112.7 122.7 116.2 107.8 120.0 118.6 119.9 119.5 117.1 117.1 108.7 108.7 109.7 111.1 111.1

120.6 118.5 121.0 120.5 118.5 120.7 120.7 124.5 112.5 123.0 117.0 111.6 120.0 118.6 119.9 119.5 117.1 117.2 108.9 104.3 109.6 110.9 110.9

107.6 108.4 108.2

109.4 108.9 108.2

– – –

Conformers T1

G1

1-2-3-4 2-3-4-5 3-4-5-6 4-5-6-1 5-6-1-2 6-1-2-3 1-2-3-11 1-6-5-9 1-6-8-16 1-6-8-17 2-1-6-8 2-3-11-12 2-3-11-13 2-3-4-10 3-2-1-7 3-11-13-14 4-3-11-12 4-3-11-13 4-3-2-23 11-13-14-15 11-13-14-20 11-13-14-21 12-11-13-14

0.0 0.0 0.1 0.1 0.1 0.0 179.9 179.7 161.6 21.2 177.6 179.8 0.2 179.9 179.8 180.0 0.2 179.8 180.0 179.9 58.3 58.6 0.0

0.1 0.1 0.0 0.1 0.1 0.0 179.8 179.7 161.6 21.1 177.6 179.8 0.1 180.0 179.8 179.9 0.0 179.8 180.0 87.1 36.0 152.7 0.4

13-14-15-18 13-14-15-19 13-14-15-22

60.4 60.4 180.0

64.6 56.6 176.0

The numeration of the atoms are as given in Fig. 1a.

supplement) obtained for the CN bond stretching coordinate, which are remarkably higher than those (from 4.624 to ˚ ) obtained for the ring CC bond stretching 5.247 mdyn/A coordinates of the phenyl ring, can also be seen as another clear indication which reveals the dominant double bond character of the CN bond in benzocaine molecule. As the values calculated for C4–C3–C11–O13, C2–C3–C11–O13 and C3–C11–O13– C14 dihedral angle parameters of the trans and gauche conformers (each takes value about 08, 1808 or +1808, see Table 2) are considered, it is seen that the C3–C11–O13–14 moiety in the ethyl-ester chain of the free molecule is almost co-planar with its phenyl ring plain. The values calculated for the C11–O13–C14–C15 dihedral angle parameter of conformer T1 (each equals to 179.98, which is very close to the experimental value 1788(1) reported by Sinha and Pattabhi [16].) shows the co-planarity of the C11–O13–C14–C15 moiety of this conformer with its phenyl ring. On the other hand, the values calculated for the same dihedral angle parameters of the gauche conformers G1 and G2 all equal to 87.1o and indicate that in both conformers, the C11–O13–C14– C15 moiety locates in a perpendicular position to the phenyl ring plain. As the CO bond length parameters of the three stable conformers are compared, it is immediately seen that the values calculated for the C11–O13 bond are considerably smaller than ˚, those calculated for the O13–C14 bond by about 0.1 A

depending on the relatively higher electron density through the C11–O13, which results from the charge transfers due to the delocalization of the lone pair electrons on both oxygen atoms in the ethyl-ester chain. Accordingly, the scaled force constant values of the C11–O13 bonds stretching coordinates of the three conformers are grater than those obtained for their O13– ˚. A C14 bond stretching coordinates by about 1.09 mdyn/A comparison done over the obtained scaled force constants has revealed the very weak dependency of the force field of this molecule to its conformational structure at room temperature; ˚ are only very small deviations of 0.017–0.077 mdyn/A determined for the corresponding CO bond stretching force constants of the trans and gauche conformers. Comparatively ˚ are little bit larger deviations of 0.010–0.096 mdyn/A determined for the corresponding ethyl-ester chain CH stretching coordinates, however, the largest one is determined for the C14–C15 stretching coordinates of the conformers by a ˚. value of 0.146 mdyn/A 3.3. Normal modes and calculated spectral data The unscaled IR and Raman spectral data of the three stable conformers of benzocaine, calculated in harmonic oscillator approach at B3LYP/6-31G(d), B3LYP/6-31++G(d,p) and B3LYP/aug-cc-pvTZ levels of theory, are presented in Table

220

Table 3 The experimental wavenumbers obtained from the IR and Raman spectra of benzocaine and corresponding scaled theoretical wavenumbers of the trans T1 and gauche G1 conformers of this molecule Modes a Observed bands Scaled wavenumbers and PEDs obtained for the trans conformer (T1) Scaled wavenumbers nC (cm1)

na (cm1) nb (cm1) nx (cm1) nd (cm1)

Potential energy distribution (PED) [%]

nC (cm1)

– – –

44 75 85

45 75 85

46 76 86

46 78 84

tE(CO)[57], tE(CC) [31] tE(CO) [57], tE(CC) [12] tE(CC) [50], tE(CO) [20], gE(CC) [15] dE(COC,CCC,COC) [69], dC(O = CO) [21] tE(CO)[52], tR(CC) [28] dE(COC,CCC,CCO) [76]

– – –

4#

107a

99

103

99

101

5# 6#

– 240a

140 239

142 248

141 239

141 241

7# 8#

258b –

252 295

254 297

250 295

247 296

9

306a

300

305

302

302

10 11

322a 378b

332 367

335 378

333 368

344 371

12

–

379

392

382

383

13 14

– –

408 486

412 489

414 447

418 455

15

502b

489

504

492

494

16 17

532b 614c

534 612

533 626

506 614

511 617

18 19

638b 694b

632 680

648 686

637 687

640 699

20

770c

743

750

759

773

–

792

795

793

797

22

815a

800

812

805

809

23 24 25

– 840c 861a

802 821 842

809 829 849

809 831 846

818 846 848

26

881d

874

873

872

872

27 28

957e 967a

932 950

940 958

954 965

968 981

t(CH3) [77] gE(CC) [33], tR [26], tE(CO) [16] nE(CC) [31], dE(COC) [22], dR[17] t(NH2) [94] dE(CCO,COC) [38], d(CN) [14] d(CN) [46], dE(CCO) [20] tR [72], gR(CH) [26] tR [17], wag(CN) [56], gE(CC) [15] dE(CCO,CCC) [39], dC(O = CO) [20] wag(NH2) [57], tR [13] dR [23], nE(CC) [15] dR [62] tR [35], gR(CH) [20], gC(C = O) [21] gC(C = O) [40], gE(CC) [18], tR [18] r(CH2) [50], r(CH3) [41] nR [24], dE(COC) [15], n(CN) [18] gR(CH) [95] gR(CH) [73] nR [21], nE(CO) [21], dE(COC) [15] nE(CO,CC) [57], d(CH3) [21] gR(CH) [92] gR(CH) [89]

Scaled wavenumbers na (cm1) nb (cm1) nx (cm1) nd (cm1) 48 54 93

49 54 95

48 54 87

48 55 87

142a

139

144

138

139

– –

122 326

123 340

121 325

121 327

– –

228 276

232 279

218 276

215 278

306a

302

307

303

304

322a 418f

334 419

332 430

333 419

345 421

–

373

385

375

378

– –

408 483

412 488

414 447

417 454

502b

489

501

489

490

532b 614c

532 611

532 626

507 614

512 616

638b 694b

631 681

647 687

636 686

639 699

770c

744

751

759

773

–

754

761

756

759

815a

806

815

811

815

– 840c 861a

801 821 837

808 828 843

808 830 840

817 847 842

881d

864

862

863

863

957e 967a

931 949

940 957

953 965

967 980

Potential energy distribution (PED) [%]

D

tE(CO) [55], tE(CC) [31] tE(CO) [50], gE(CC) [19] tE(CC) [51], tE(CO) [31] dE(COC,CCC) [60], d(O = CO) [10], tR [13] tE(CO) [41], tR(CC) [33] dE(COC) [33], t(NH2) [33], t(CH3) [10] t(CH3) [77] gE(CC) [32], tR [27] nE(CC) [31], dR [13], gE(CC) [11] t(NH2) [67], dE(COC) [11] dE(CCO) [36], d(CN) [10] d(CN) [43], dE(CCO,COC) [11], dR [10] tR [72], gR(CH) [26] tR [16], wag(NH2) [40], gE(CC) [15] dE(CCO,CCC) [33], dC(O = CO) [15] wag(NH2) [64], tR [13] dR [29], nE(CC) [15], dC(O = CO) [13] dR [61], dR(CH) [19] tR [35], gR(CH) [20], gC(C = O) [20] gC(C = O) [40], gE(CC) [17], tR(CC) [18] r(CH2) [40], r(CH3) [24], nE(CO) [10] nR [24], dR [13], n(CN) [15] gR(CH) [95] gR(CH) [73] nR [17], nE(CO) [18], dE(COC) [14] nE(CO,CC) [63], d(CH3) [19] gR(CH) [92] gR(CH) [89]

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

1 2# 3

21#

Observed bands Scaled wavenumbers and PEDs obtained for the gauche conformer (G1) D

29

–

1010

1000

1006

1153

dR [25], nR [13], nE(CC,CO) [44] nE(CC,CO) [54], nR [19], dR [10] r(NH2) [58], nR [26], dR(CH) [10] r(CH3) [38], nE(CC,CO) [29], dE(CCO) [12] nE(CO) [54], nR [14] dR(CH) [60], nR [19], r(NH2) [13] r(CH2) [58], r(CH3) [38]

30

1018c

1019

1015

1019

1017

31

1062b

1055

1059

1047

1048

–

1108

1118

1107

1112

1107c 1135f

1112 1125

1110 1129

1115 1126

1104 1127

–

1154

1158

1151

36

1174c

1168

1170

1171

1171

37# 38 39

– 1270c –

1262 1264 1292

1267 1264 1292

1263 1267 1292

1268 1257 1289

40

1309c

1303

1310

1307

41

1329b

1338

1334

42

1369c

1370

43

1390b

44 45 46

nR [32], dR [32], dR(CH) [23]

997

996

997

1018c

1007

1013

1007

1008

nE(CC,CO) [80]

1062c

1054

1058

1046

1048

–

1087

1092

1086

1087

1107c 1135f

1104 1124

1108 1129

1104 1126

1099 1126

–

1168

1175

1171

1173

dR(CH) [72], nR [17]

1174c

1170

1170

1169

1170

– 1270c –

1298 1265 1292

1304 1266 1292

1298 1267 1292

1303 1258 1289

1310

r(CH2) [88] nE(CC,CO) [56], nR [11] n(CN) [51], dR(CH) [22], nR [10] dR(CH) [63], nR [22]

1309c

1304

1310

1307

1310

1343

1331

nR [71], dR(CH) [13]

1329b

1337

1334

1342

1331

1370

1367

1371

1369c

1373

1368

1369

1372

1404

1399

1399

1395

1390b

1394

1394

1391

1387

– 1435c 1464b

1438 1467 1478

1451 1444 1454

1440 1457 1467

1440 1455 1466

– 1435c 1464b

1438 1465 1468

1451 1442 1447

1440 1455 1461

1439 1453 1459

47

1472c

1496

1477

1486

1487

1472c

1487

1464

1475

1473

48

1514c

1515

1525

1517

1516

1514c

1514

1524

1519

1515

49 50

1579b 1604b

1573 1614

1575 1598

1579 1615

1574 1610

1579b 1604b

1573 1614

1574 1597

1578 1615

1573 1610

51 52 53 54 55

1624c 1735c 2909c 2945c 2972f

1639 1729 2922 2933 2968

1620 1723 2929 2940 2975

1632 1712 2910 2926 2963

1625 1706 2916 2927 2957

1624c 1735c 2909c 2945c 2985c

1638 1726 2918 2947 2992

1620 1720 2928 2957 3002

1631 1717 2905 2938 2982

1624 1708 2915 2942 2981

56 57

2985c –

2989 2998

2996 3005

2978 2989

2976 2985

2972f –

2980 3011

2990 3020

2970 3000

2969 3000

n(CH3) [87], n(CH2) [12] n(CH3) [62], n(CH2) [38]

58 59 60 61 62

3030f 3042c 3070c 3089a 3420c

3036 3038 3078 3086 3405

3043 3045 3086 3093 3427

3033 3035 3071 3078 3428

3035 3036 3070 3079 3435

umb(CH3) [52], wag(CH2) [39] wag(CH2) [32], umb(CH3) [45] nR [44], dR(CH) [14] d(CH3) [90] Scissor (CH3) [69], Scissor (CH2) [26] Scissor (CH2) [75], Scissor (CH3) [21] nR [30], dR(CH) [43], n(CN) [11] nR [64], dR(CH) [12] nR [49], dR(CH) [18], Scissor (NH2) [13] Scissor (NH2) [85] nc(C = O) [78] n(CH3) [100] n(CH2) [98] n(CH2)[82], n(CH3) [18] n(CH3) [99] n(CH3) [82], n(CH2) [18] nR(CH) [99] nR(CH) [99] nR(CH) [99] nR(CH) [99] n(NH2) [100]

r(NH2) [58], nR [25], dR(CH) [10] r(CH3) [27], nE(CC,CO) [36], nR [10] nE(CO) [45], r(CH3) [19] dR(CH) [62], nR [20], r(NH2) [15] r(CH2) [39], r(CH3) [33], dR(CH) [10] dR(CH) [63], nR [15], nE(CO,CC) [10] r(CH2) [75], dR(CH) [12] nE(CC,CO) [56], nR [12] n(CN) [50], dR(CH) [22], nR [10] dR(CH) [53], nR [17], r(CH2) [16] nR [72], dR(CH) [13], r(NH2) [11] umb(CH3) [76], wag(CH2) [17] wag(CH2) [59], umb(CH3) [24] nR [43], dR(CH) [36] d(CH3) [89] Scissor(CH2) [80], Scissor(CH3) [15] Scissor(CH3) [82], Scissor(CH2) [13] nR [30], dR(CH) [45], n(CN) [11] nR [65], dR(CH) [11] nR [50], dR(CH) [19], Scissor(NH2) [20] Scissor(NH2) [85] nc(C = O) [77] n(CH3) [100] n(CH2) [96] n(CH2) [53], n(CH3) [47]

3030f 3042c 3070c 3089a 3420c

3034 3035 3076 3082 3401

3044 3045 3087 3093 3427

3031 3032 3068 3076 3425

3036 3036 3071 3080 3435

nR(CH) [99] nR(CH) [99] nR(CH) [99] nR(CH) [99] n(NH2) [100]

33 34 35#

221

991

32#

–

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

995

a

r.m.s. r.m.s.2

14.1 13.2

8.3 9.2

10.8 11.1

10.6 11.2

n(NH2) [100] 3524

3535

3533 3501 3508c

1

na (cm1) nb (cm1) nx (cm1) nd (cm1)

Potential energy distribution (PED) [%] Scaled wavenumbers

nC (cm1)

63

C

r.m.s. r.m.s. 2

14.4 13.5

9.5 11.1

12.3 11.9

12.7 12.3

n(NH2) [100] 3534 3532 3524 3497 3508c

1

na (cm1) nb (cm1) nx (cm1) nd (cm1)

Potential energy distribution (PED) [%] Scaled wavenumbers nC (cm1)

Observed bands Scaled wavenumbers and PEDs obtained for the gauche conformer (G1)

D

Modesa Observed bands Scaled wavenumbers and PEDs obtained for the trans conformer (T1)

Table 3 (Continued )

a: Raman-solid phase [23], b: IR-solution phase [41], c: IR-gas phase [41], d: IR-KBr [this study], e: Raman-solid phase [this study], f: Raman-solution phase [23]. Obtained from the wavenumbers calculated at B3LYP/6-31G(d) using scale factors 0.967 (for wavenumbers under 1800 cm1) and 0.955 cm1 (for those over 1800 cm1). b Calculated in SQM FF methodology from the force constants calculated at B3LYP/6-31G(d) level of theory using the force constant scale factors proposed by Baker at [33]. x Obtained from the wavenumbers calculated at B3LYP/6-31++G(d,p) using scale factors 0.977 (for wavenumbers under 1800 cm1) and 0.955 cm1 (for those over 1800 cm1). d Obtained from the wavenumbers calculated at B3LYP/aug-cc-pvTZ using scale factors 0.978 (for wavenumbers under 1800 cm1) and 0.960 cm1 (for those over 1800 cm1). D Calculated in SQM FF methodology using FCART01 software [36–38] from the calculation data obtained at B3LYP/6-31G(d) level of theory. The PEDs lower than 10% were not included. n: bond stretching, d: inplain angle bending, g: out-of-plain angle bending, t: torsion, r: rocking, tw: twisting, wag: wagging, umb: umbrella, R: ring, E: ethyl-ester chain, C: carbonyl group. 1 root-mean-square calculated for the region 0–1800 cm1 over the experimental wavenumbers given in column 1 and corresponding scaled wavenumbers. 2 root-mean-square calculated for the region 0–3700 cm1 over the experimental wavenumbers given in column 1 and corresponding scaled wavenumbers. a The corresponding normal modes of the trans T1 and gauche G1 conformers are given with the same mode numbers and in the same order. For the illustrations of the normal modes of the trans conformer T1, please see Figs. S1–S3 given as supplementary data. # Denotes the normal modes which are remarkably sensitive to the conformational structure.

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228 D

222

S4 as a supplementary material. In addition to this, the illustrations of the normal modes of the trans conformer (T1) calculated at B3LYP/aug-cc-pvTZ level of theory are given in Fig. S1 (‘‘ethyl-ester chain modes’’), Fig. S2 (‘‘ring modes’’) and Fig. S3 (‘‘amino group modes’’) for the interested reader as another useful supplementary material. The insignificant amount of deviations of 0–3 cm1 between the corresponding harmonic wavenumbers of the conformers G1 and G2 have clearly demonstrated that from the vibrational spectroscopic point of view, both gauche conformers of benzocaine can be assumed as almost identical. Accordingly, the individual contributions of these two conformers to the recorded IR and Raman spectra of the molecule cannot be easily distinguished from each other. To our view, this clearly explains why both McCombie et al. [20] and Longarte et al. [26] have reported only one gauche conformer for the free molecule. A comparison done over all the harmonic wavenumbers given in Table S4 has demonstrated that the torsion and angle bending modes with number 2, 4 through 8, 11 and four rocking modes with number 21, 32, 35, 37 (all are associated with the ethyl-ester aliphatic chain) show remarkable sensitivities to conformation, while the remained all normal modes show either very weak sensitivities or almost insensitivities to the conformational structure of the conformers; this determination is in agreement with that of Longarte et al. [26] which states that the low-frequency normal modes with wavenumber under 400 cm1 (torsion and bending vibrations associated with the ethyl-ester aliphatic chain) should be regarded as characteristic fingerprint for the trans and gauche conformers. As the harmonic wavenumbers given for free benzocaine in Table S4 are compared with the bands observed in the experimental IR and Raman spectra of the molecule, it is immediately seen that in particular the harmonic wavenumbers calculated for the fingerprint and high-frequency normal modes significantly deviate from the experimental ones and accordingly they need to be scaled appropriately, although increasing of the level of theory used in the calculation lead to some considerable improvements. The scaled wavenumbers and PEDs obtained for the conformers trans T1 and gauche G1 are given in Table 3 in comparison with the corresponding experimental wavenumbers. In the table, three different sets of scaled wavenumbers obtained by proceeding the scaling procedure-1 (‘‘scaling wavenumbers with dual scale factors [30]’’) from the harmonic wavenumbers calculated at B3LYP/ 6-31G(d), B3LYP/6-31++G(d,p) and B3LYP/aug-cc-pvTZ levels of theory are labeled with na, nx and nd, respectively, while another set of scaled wavenumbers obtained by proceeding the scaling procedure-2 (‘‘SQM FF methodology [31–33]’’) from the geometrical and force constant parameters calculated at B3LYP/6-31G(d) level of theory are labeled with nb. The root-mean-square error values (see Table 3), calculated over each set of scaled wavenumbers and corresponding experimental ones, have showed that the set nb exhibits the best agreement with the experiment, while the set na exhibits the poorest one. However, all of the obtained r.m.s. values are below 15 cm1 and sufficiently prove both the obvious success of the two scaling procedures used in this study and the

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

223

Fig. 2. A comparison of the gas phase experimental IR spectrum of free benzocaine with the theoretical IR spectra obtained for the trans conformer T1 of this molecule; (a) the experimental gas phase IR spectrum taken from ref. [41], (b) the scaled theoretical spectrum, obtained in the SQM methodology over the spectral data calculated at B3LYP/6-31G(d) level of theory, (c) the scaled theoretical spectrum obtained in the procedure ‘‘scaling wavenumbers using dual scale factors’’ over the spectral data calculated at B3LYP/aug-cc-pvTZ level of theory.

necessity of proceeding an efficient scaling procedure over the calculated harmonic wavenumbers to give a correct assignment of the fundamental bands observed in the experimental spectra of benzocaine molecule. The scaled theoretical IR spectra of the trans T1 and gauche G1 conformers obtained by proceeding the scaling procedure-1 from the harmonic wavenumbers calculated at B3LYP/aug-cc-pvTZ level of theory and also the ones obtained by proceeding the scaling procedure-2 from the geometrical and force constant parameters calculated at B3LYP/6-31G(d) level of theory are given in Figs. 2 and 3 in comparison with the gas phase IR spectrum of the free molecule (in 600–3700 cm1 spectral region) taken from ref. [41]. As is clearly seen, all of the scaled theoretical IR spectra given in the figures, are in very good agreement with the experimental one in particular in the fingerprint region (600– 1800 cm1), however, in the high-frequency region (2700– 3700 cm1), the agreement of the scaled spectra of the trans conformer T1 with the experimental spectrum is seen considerably better than that of the gauche conformer G1. 3.4. Assignments for the fundamental bands The solid phase experimental IR and Raman spectra of bezocaine molecule recorded in this study are given in Fig. 4 in

comparison to the gas phase and solution phase (in CS2 + CCl4 solvents) IR spectra of the molecule, taken from ref. [41]; only the wavenumbers of the bands assigned as ‘‘fundamental’’ are labeled in the figure. The wavenumbers of the fundamental bands assigned from the IR and Raman spectra given in Fig. 4 and corresponding ones collected from the studies of Alcolea Palafox [21–24] and Longarte et al. [26] are given in Table 4 in comparison. Our calculation results given in Table 3 have clearly demonstrated that a good number of the fundamental bands of benzocaine have been wrongly assigned by either Alcolea Palafox [21–24] or Longarte et al. [26] or both. In the light of these results, we propose reassignments for the fundamentals due to the normal modes with number 4, 6, 7, 9, 10, 11, 15, 33, 36, 46, 47, 54, 59, 60, which are marked with a star character (*) in Table 4. To continue the discussion only on the conformation sensitive normal modes of the molecule will be much more preferable for both keeping the paper size shorter and determining the individual contributions of the trans and gauche conformers to the experimental vibrational spectra of benzocaine molecule. As has been exposed in the previous part of the text, only few ethyl-ester chain modes which locate in the low-frequency region (0–400 cm1) and four rocking modes of the methyl and ethyl groups located in the fingerprint region (400–1800 cm1) show remarkable sensitivities to the

224

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

Fig. 3. A comparison of the gas phase experimental IR spectrum of free benzocaine with the theoretical IR spectra obtained for the gauche conformer G1 of this molecule; (a) the experimental gas phase IR spectrum taken from ref. [41], (b) the scaled theoretical spectrum, obtained in the SQM methodology over the spectral data calculated at B3LYP/6-31G(d) level of theory, (c) the scaled theoretical spectrum obtained in the procedure ‘‘scaling wavenumbers using dual scale factors’’ over the spectral data calculated at B3LYP/aug-cc-pvTZ level of theory.

conformational structure, while all the other remaining normal modes of the molecule either show very weak sensitivities or are almost insensitive to conformation. Unfortunately, the fundamental bands due to the conformation sensitive methyl and ethyl rocking modes of the molecule which locate in the fingerprint region could not be observed in the experimental spectra since either they are too weak or are overlapped with the relatively more strong bands, while five bands could be observed in the low-frequency region of the recorded solid phase Raman spectrum of the molecule. The medium band at 110 cm1 is one of them; the corresponding bands were observed at 107 cm1 by Alcolea Palafox (in solid phase Raman spectrum [22,23]) and at 100 cm1 by Longarte et al. (in solid phase dispersed emission spectrum [26]), respectively. In agreement with the assignment proposed by Longarte et al. [26], we assign these three bands as the fundamentals due to the normal mode 4 of the trans conformer T1 (the rocking vibration of ethyl-ester chain; r(Ph-E)). The weak band at 142 cm1 in the solid phase Raman spectrum of the molecule [22,23] is assigned by Alcolea Palafox as the fundamental band due to the torsion mode about the CC bond linking ethyl and methyl groups. However, the theoretical IR and Raman spectral data

presented in Tables 3 and S4 indicate that this band should be reassigned as the fundamental due to the mode 4 of the gauche conformers G1 and G2 (r(Ph-E). The very weak band at 240 cm1 in solid phase Raman spectrum [22,23] is assigned by Alcolea Palafox as the fundamental due to the amino wagging mode, while the corresponding one observed at 243 cm1 in solid phase dispersed emission spectrum [26] is assigned by Longarte et al. as the fundamental due to the phenyl ring mode referred to as ‘‘15’’ in Wilson notation [42]. In contrast to these two different assignments, we propose to assign these two fundamental bands to the mode 6 of the conformer T1 (COC,CCC,CCO angle bending vibrations in the ethyl-ester chain). The very weak band observed at 261 cm1 in solid phase Raman spectrum [22,23] is assigned by Alcolea Palafox as the fundamental due to the rocking modes of the amino group and ethyl-ester chain; however, this assignment is in disagreement with our calculation results, and thus we propose to assign this band reported by the authors and also the corresponding ones observed by us at 257 cm1 in solid phase Raman spectrum and at 258 cm1 in solution phase IR spectrum [41] to the mode 7 of the trans conformer T1 (the methyl torsion vibration). The two medium intensity bands observed at 306

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

225

Fig. 4. The experimental IR and Raman spectra of benzocaine molecule. Only the bands assigned as fundamental are labeled; (a) the gas phase IR spectrum of benzocaine [41], (b) the IR spectrum of benzocaine in CS2 + CCl4 solvents [41], (c) the recorded KBr disk IR spectrum of benzocaine, (d) the recorded solid phase Raman spectrum of benzocaine.

and 316 cm1 in the solid and solution phase Raman spectra [22,23] are assigned by Alcolea Palafox as an over tone of the methyl torsion mode [2t(CH3)], while the corresponding medium band observed at 305 cm1 in solid phase dispersed emission spectrum [26] is assigned by Longarte et al. as the fundamental due to the phenyl ring mode referred to as ‘‘10b’’ in Wilson notation [42], which is reported in coupling with the COC angle bending vibrations of the ethyl-ester chain. Both assignments proposed by these authors are, unfortunately, in disagreement with our calculation results; we proposed to assign these three bands and the corresponding two bands observed by us at 301 cm1 (in solid phase Raman spectrum) and at 303 cm1 (in solution phase IR spectrum [41]) as the fundamentals due to the mode 9 of the trans T1 and gauche conformers G1 and G2 (CC bond stretching + COC angle

bending vibrations in ethyl-ester chain). The two medium intensity bands observed at 318 cm1 (in solid phase Raman spectrum [21,23]) and at 322 cm1 (in solution phase Raman spectrum [22,23]) are assigned by Alcolea Palafox as the fundamentals due to the phenyl ring mode referred to as ‘‘10b’’ in Wilson notation [42], which is reported in coupling with the out-of-plain angle bending mode of the ethyl-ester chain. The corresponding bands were observed by us at 316 cm1 (in solid phase Raman spectrum) and at 326 cm1 (in solution phase IR spectrum [41]); considering our calculation results, we propose to assign these two bands and the other two reported by Alcolea Palafox as the fundamentals due to the mode 10 of the trans and gauche conformers (amino torsion mode). The two medium intensity bands at 390 and 380 cm1 (observed in solid phase [21,23] and solution phase [23,24] IR spectra, respectively) and

226

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

Table 4 The assignments proposed for the fundamental bands observed in the experimental IR, Raman and Dispersed Emision Spectra of benzocaine molecule Experimental wavenumbers (cm1)

Modes# This study n 4T 4G 6T 7T 9 10 11 T 11 G 15 16 17 18 19 20 22 24 25 26 27 28 30 31 33 34 36 38 40 41 42 43 45 46 47 48 49 50 51 52 53 54 55 56 * 58 59 60 61 62 63 1

a

– – – – – – 400* – 503* 515 615 640 700 772 – 846 – 881 – – 1026 1079 1109* – 1172* 1281 1311 1342 1367 1393 1442 – 1475* 1515 1574 1597 1636 1684 2900 2926* 2963 2985 3026 3046* 3071* – 3342 3423

1

n

Ref. [21,22,23,24] b

110 – – 257* 301* 316* 399* – 504* 510 619 640 703 774 818 – 862 884 957 966 1027 – 1111* – 117* 1282 1312 1369 1392 1449 1461* 1477* 1517 1575 1604 1636 1681 2901 2930* 2966 2987 3027 3075* 3085 3337 3424

n

c

– – – – – 318* 390* – 510* 518 620 645 700 772 – 845 – 880 – – 1026 1082 1115* 1130 1174* 1282 1314 1341 1370 1392 1443 – 1473* 1515 1575 1600 1635 1685 2900 2940* 2960 2980 – 3045* 3070* – 3340 3420

n

d

– – – – – – 380* – 504* 535 615 640 700 – – 847 – 897 – 970 1020 – 1112* – 1172* 1275 1310 – 1370 1391 1440 1463* 1478* 1520 1578 1608 1625 1700 2900 2932* 2952 2980 – 3040* – 3100 3370 3490

2

Ref. [26] n

e

107 142* 240* 261* 306* 322* 406* – 507* 513 615 635 – 774 815 – 861 – – 967 – – 1110* 1130 1171* 1275 1302 – 1365 1388 1435 1450* – – 1573 1600 1630 1677 2898 2934* 2965 2985 3029 3058* – 3089 3344 3434

n

f

– – – – 316* – 399* 418* 503* 510 618 641 – – 822 – 862 – – – 1009 – 1113* 1135 1176* 1284 1312 – 1372 1395 1444 – – 1522 1578 1609 1627 1697 2901 2937* 2972 3030 3055* 3074* – 3393 3407

n

g

100 – 243* – 305* 383* 421* 499* – 619 641 – – 825 – 865 896 – – 1044 1065 – 1137 1187* 1286 1301 1329 1366 1390 1451 – – 1515 1558 1601 – 1715 – – – – – – – – – –

3

Ref. [41] n

h

– – – – – – – 420* 502* – 622 639 – – 826 845 865 887 – – 1045 1070 – 1132 1288 1305 1331 – – 1449 – – – – 1593 – – – – – – – – – – – –

Assignments for the observed fundamental bandsy

4

ni

nj

– – – – – – – – – – 614 – 678 770 – 840 – – – – 1018 – 1107* – 1174* 1270 1309 – 1369 – 1435 – 1472* 1514 – 1624 1735 2909 2945* – 2985 – 3042* 3070* – 3420 3508

– – – 258* 303* 326* 378* – 502* 532 614 638 694 770 – 839 868 – – 975 1010 1062 1106* – 1171* 1270 1308 1329 1366 1390 1441 1464* 1477* 1517 1579 1604 1621 1712 2902 2933* 2955 2981 3017 3039* 3063* – 3407 3499

r(Ph-E) r(Ph-E) dE(COC,CCC,CCO) t(CH3) nE(CC), dE(COC), dR t(NH2) dE(CCO,COC) + d(CN) dE(CCO,COC) + d(CN) dE(CCO,CCC) + dC(O = CO) wag(NH2) + tR 6a(dR) + nE(CC) 6b(dR) 4(tR) + gC(C = O) gC(C = O) + gE(CC) + tR 18a(nR) + dE(COC) + n(CN) 17b(gR(CH)) 1(nR), nE(CO) + dE(COC) nE(CO,CC) + d(CH3) 5(gR(CH)) 17a(gR(CH)) nE(CC,CO) + nR + dR r(NH2) + nR + dR(CH) nE(CO) [54] + nR(CC) [14] 15(dR(CH) + nR) + r(NH2) 9a(dR(CH) + nR) nE(CC,CO) 3(dR(CH) + nR) 14(nR + dR(CH)) umb(CH3) + wag(CH2) wag(CH2) + umb(CH3) CH3 anti sym. bending Scissor(CH3) + Scissor(CH2) Scissor(CH2) + Scissor(CH3) 19a(nR + dR(CH)) + n(CN) 8b(nR + dR(CH)) 8a(nR + dR(CH))+Scissor(NH2) Scissor(NH2) nc(C = O) ns(CH3) ns(CH2) nas(CH2) + nas(CH3) nas(CH3) 7b(nR (CH)) 20b(nR(CH)) 20a(nR(CH)) 2(nR(CH)) ns(NH2) nas(NH2)

a: Solid phase KBr IR data [this study], b: solid phase Raman data [this study]. c: Solid phase IR data from refs. [21,23], d: solution phase (in chloroform) IR data from refs. [23,24], e: solid phase Raman data from [22,23], f: solution phase (in chloroform) Raman data from refs. [22,23]. 3 g: Obtained from the solid phase dispersed emission spectrum of the trans conformer of benzocaine [26], h: obtained from the solid phase dispersed emission spectrum of the gauche conformer of benzocaine [26]. 4 i: Gas phase IR data from ref. [41], j: solution phase (CS2 + CCl4) IR data from ref. [41] # The numeration of the normal modes is as given in Tables S3 and S4. For the illustrations of the normal modes of the trans conformer T1, please see Figs. S1–S3. T: denotes the modes of the trans conformer T1, G: denotes the modes of the gauche conformers (G1 and G2). * The fundamental bands reassigned in this study. y The assignments of the phenyl ring modes are given in Wilson notation [42], n: bond stretching, d: in-plain angle bending, g: out-of-plain angle bending, t: torsion, r: rocking, wag: wagging, umb: umbrella, R: ring, E: ethyl-ester-chain, C: carbonyl group, Ph: phenyl moiety. 2

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other two weak bands at 406 and 399 cm1 (in solid phase and solution phase [22,23] Raman spectra, respectively) are assigned by Alcolea Palafox as the fundamentals due to the amino torsion mode, while the corresponding band observed at 383 cm1 (in solid phase dispersed emission spectrum 26]) is assigned by Longarte et al. as the fundamental due to the amino rocking mode. On the other hand, our calculation results strongly suggest that these four bands reported by the [other authors and the corresponding ones observed by us at 400 cm1 (in solid phase IR spectrum), at 399 cm1 (in solid phase Raman spectrum) and at 378 cm1 (in solution phase IR spectrum [41]) should be assigned as the fundamentals due to the mode 11 of the trans conformer T1 (CCO and COC angle bending vibrations of the ethyl-ester chain in coupling with the in-plain amino CN bending vibration; dE(CCO,COC) + d(CN)). The very weak band observed at 418 cm1 in solution phase Raman spectrum [22,23] is assigned by Alcolea Palafox as the fundamental due to the rocking modes of the carbonyl and amino groups and ethyl-ester chain, while the corresponding two strong bands at 420 and 421 cm1 in two solid phase dispersed emission spectra [26] are assigned by Longarte et al. as the fundamentals due to the phenyl ring mode referred to as ‘‘10b’’ in Wilson notation [42]. In the light of our calculation results, we confidently propose to reassign these three bands as the fundamentals due to the mode 11 of the gauche conformers G1 and G2 (dE(CCO,COC) + d(CN)).

both gauche conformers are almost identical to each other and therefore their individual contributions to the recorded vibrational spectra of the molecule cannot be easily distinguished from each other. The calculated harmonic wavenumbers have demonstrated that at room temperature, except for only few torsion and angle bending modes and four ethyl and methyl rocking modes associated with the ethyl-ester chain, the remained all normal modes of free benzocaine are either very weakly sensitive or insensitive to its conformational structure. In order to reduce the systematic overestimations, the harmonic wavenumbers calculated at B3LYP/ 6-31G(d), B3LYP/6-31++G(d,p) and B3LYP/aug-cc-pvTZ levels of theory were directly scaled by proceeding the scaling procedure referred to as ‘‘scaling wavenumbers with dual scale factor’’ and thereby three different sets of scaled wavenumbers were obtained for each of the determined three stable conformers of the molecule. On the other hand, another set was obtained in ‘‘SQM methodology’’ from the geometrical and force constant parameters calculated at B3LYP/6-31G(d) level of theory. The r.m.s. values calculated for each set of wavenumbers have clearly showed the very good agreement between our experimental assignments and the obtained scaled wavenumbers as well as the obvious superiority of ‘‘SQM methodology’’ to the other scaling procedure used in the study.

4. Conclusion

This research study was supported by the Research Fund of Istanbul University. Project Numbers: UDP-915/18042007 and 409/13092005. We thank to Professor Mustafa Urgen and Dr. Ebru Devrim Sam (Faculty of Metallurgy, Istanbul Technical University) for their very kind supports in recording of the Raman spectrum of benzocaine. We also thank Professor William Collier (Department of Chemistry, Oral Roberts University) for his very kind support in providing the FCART01 software. The study has been dedicated to the memory of Professor Dr. Cakil ERK, a very valuable scientist we lost three years ago.

A theoretical conformational analysis on free benzocaine molecule was carried out by means of successive single point energy calculations performed at B3LYP/3-21G(d) level of theory; the obtained results have demonstrated that at room temperature the molecule in electronic ground state has three stable conformers (one trans and two gauche). The SCF energies calculated at B3LYP/6-31, B3LYP/6-31++G(d,p), B3LYP/aug-cc-pvTZ and MP2/6-31++G(d,p) levels of theory over the optimized geometries of each stable conformer have indicated that the trans conformer is the most stable one, and the other two gauche conformers are energetically almost equal to each other; very small differences between the calculated SCF energies of the trans and gauche conformers have demonstrated that at room temperature each conformer can have considerable population in the sample under spectroscopic investigation and accordingly contribute to the recorded experimental spectra of the free molecule. The geometrical and force constant parameters of the trans and gauche conformers were calculated at room temperature through the geometry optimization and frequency calculations performed at B3LYP/6-31, B3LYP/6-31++G(d,p) and B3LYP/ aug-cc-pvTZ levels of theory; the obtained results have demonstrated that the dependency of the geometrical and force constant parameters of the molecule to its conformational structure is in general very weak. The very close wavenumber values obtained for the corresponding normal modes of the two gauche conformers of free benzocaine have clearly demonstrated that from the vibrational spectroscopic point of view,

Acknowledgements

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.vibspec.2008.02.001. References [1] D. Nathan, A. Sakr, J.L. Lichtin, R.L. Bronaugh, Pharm. Res. 7 (1990) 1147. [2] U. Sorum, B. Damsgard, Aquaculture 232 (2004) 333. [3] A.M.M.C. Gontijo, R.E. Barreto, G. Speit, V.A.V. Reyes, G.L. Volpato, D.M.F. Salvadori, Mutat. Res. 534 (2003) 165. [4] A. Algareer, A. Alyaya, L. Andersson, J. Dent. 34 (2006) 747. [5] R. Caballero, I. Moreno, T. Gonzalez, C. Valenzuela, J. Tamargo, E. Delpon, Cardiovasc. Res. 56 (2002) 104. [6] E. Delpon, R. Caballero, C. Valenzuela, M. Longobardo, D. Snyders, J. Tamargo, Cardiovasc. Res. 42 (1999) 510. [7] M. Suwalsky, C. Schneider, F. Villenea, B. Norris, H. Cardenas, F. Cuevas, C.P. Sotomayor, Biophys. Chem. 109 (2004) 189. [8] P.Y. Kunz, K. Fent, Aquat. Toxicol. 79 (2006) 305.

228

K. Balci, S. Akyuz / Vibrational Spectroscopy 48 (2008) 215–228

[9] J.X. Zhang, L.Y. Qiu, Y. Jinn, K.J. Zhu, Colloids Surf. B: Biointerfaces 43 (2005) 123. [10] P. Mura, F. Maestrelli, M.L. Gonzales-Rodrigez, I. Michelacci, C. Chelardini, A.M. Rabasco, Eur. J. Pharm. Biopharm. 67 (2007) 86. [11] S.M. Ben-saber, A.A. Maihub, S.S. Hudere, M.M. El-ajaily, Microchem. J. 81 (2005) 191. [12] M.A. Mariggio, S. Cafaggi, M. Ottone, B. Parodi, M.O. Vannozzi, V. Mandys, M. Viale, Investig. New Drugs 22 (2004) 3. [13] M.S. Refat, I.M. El-Deen, H.K. Ibrahim, S. El-Ghool, Spectrochim. Acta Part A 65 (2006) 1191. [14] A.C. Schmidt, Int. J. Pharm. 298 (2005) 186. [15] A.C. Schmidt, Pharm. Res. 22 (2005) 2121. [16] B.K. Sinha, V. Pattabhi, Proc. Indian Acad. Sci. (Chem. Sci.) 98 (1987) 229. [17] J.A. Fernandez, A. Longarte, I. Unamuno, F. Castano, J. Chem. Phys. 113 (2000) 8531. [18] A.D. Becke, J. Chem. Phys. 107 (1997) 8554. [19] H.L. Schmider, A.D. Becke, J. Chem. Phys. 108 (1998) 9624. [20] J. McCombie, P.A. Hepworth, T.F. Palmer, J.P. Simons, M.J. Walker, Chem. Phys. Lett. 206 (1993) 37. [21] M. Alcolea Palafox, Spectrochim. Acta 44A (1988) 1465. [22] M. Alcolea Palafox, J. Raman Spectrosc. 20 (1989) 765. [23] M. Alcolea Palafox, J. Mol. Struct. (Theochem.) 236 (1991) 161. [24] M. Alcolea Palafox, Indian J. Pure Appl. Phys. 30 (1992) 59. [25] M. Alcolea Palafox, Spectrosc. Lett. 30 (6) (1997) 1089. [26] A. Longarte, J.A. Fernandez, I. Unamuno, F. Castano, Chem. Phys. 260 (2000) 83. [27] Gaussian 03, Revision C.02, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Montgomery, Jr., T. Vreven, K.N. Kudin, J.C. Burant, J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M.

[28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42]

Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, C. Gonzalez, J.A. Pople, Gaussian, Inc., Wallingford CT, 2004. M.J. Frisch, M. Head-Gordon, J.A. Pople, Chem. Phys. Lett. 166 (1990) 275. M.J. Frisch, M. Head-Gordon, J.A. Pople, Chem. Phys. Lett. 166 (1990) 281. M.D. Halls, J. Velkovski, H.B. Schlegel, Theor. Chem. Acc. 105 (2001) 413. G. Rauhut, P. Pulay, J. Phys. Chem. 99 (1995) 3093. P. Pulay, G. Fogarasi, F. Pang, J.E. Boggs, J. Am. Chem. Soc. 101 (1979) 2550. J. Baker, A.A. Jarzecki, P. Pulay, J. Phys. Chem. A 102 (1998) 1412. A.P. Scott, L. Radom, J. Phys. Chem. 100 (1996) 16502. T. Frosch, M. Schmitt, J. Popp, Anal. Bional. Chem. 387 (2007) 1749. W.B. Collier, I. Magdo, T.D. Klots, J. Chem. Phys. 110 (1999) 5710. S.E. Lappi, W.B. Collier, S. Franzen, J. Phys. Chem. A 106 (2002) 11446. W.B. Collier, QCPE Bull. 13 (1993) 19. M.E. Vaschetto, B.A. Retamal, A.P. Monkman, J. Mol. Struct. (Theochem.) 486 (1999) 209. D.G. Lister, J.K. Tyler, J.H. Hong, N.W. Larsen, J. Mol. Struct. 23 (1974) 253. http://webbook.nist.gov/chemistry/name-ser.html.en-us.en. E.B. Wilson, Phys. Rev. 45 (1934) 706.