Determination of Acid Dissociation Constants of Some Substituted Salicylideneanilines by Spectroscopy

Home , Hammett equation, Inductive effect

Arabian Journal of Chemistry (2014) xxx, xxx–xxx

King Saud University Arabian Journal of Chemistry

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ORIGINAL ARTICLE Determination of acid dissociation constants of some substituted salicylideneanilines by spectroscopy. Application of the Hammett relation

R. Hadjeb *, D. Barkat

Department of Industrial Chemistry, Faculty of Science and Technology, Biskra University, Algeria

Received 22 August 2013; accepted 5 April 2014

KEYWORDS Abstract A series of ten Schiff bases were synthesized by condensation of salicylaldehyde and Schiff bases; substituted anilines. The acid dissociation constants (Ka) of salicylideneaniline and methyl- , chloro- Acidity constant; and nitro-substituted salicylideneanilines have been determined in ethanol–water and dioxan–water Substituent effect; binary mixtures (60% (v/v)) by a spectrophotometric (UV–Vis) method at constant ionic strength Solvent effect; and at 25 C. The calculated acidity constants, pKa values were evaluated in protonation–deproto- Hammett equation nation mechanism. In order to investigate the effects of substituent on the acidity of hydroxy Schiff bases; the applicability of the Hammett equation to the results in two systems of solvent was discussed. ª 2014 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction synthesis of these compounds has been well developed since 1960s, and many improved methods have been reported A large number of Schiff bases have emerged as an important (Cohen and Schmidt, 1962; Hadjoudis et al., 1977; Higelin class of antioxidant compounds; o-N-salicylideneanilines have and Sixl, 1983; Kownacki et al., 1993; Johmoto et al., 2009). received much attention in a wide variety of ﬁelds due to their In addition, it is also important for us to understand the different applications owing to their characteristic properties molecular and chemical properties of such Schiff bases. For such as biological activities, pharmacological and catalytic instance, these are of crucial importance in understanding properties (Thorat et al., 2012; Montielli et al., 1988; Dash the distribution, receptor binding and mechanism of action et al., 1984; Casaszar et al., 1985; Ko¨ seoglu et al., 1995). The of certain organic preparations (Yoke-Leng et al., 2013; Kaufman et al., 1975; Fleuren et al., 1979; Shamsipur et al., * Corresponding author. Tel.: +213 550524403. 1993; Almasifar et al., 1997), as well as in many analytical pro- E-mail address: [email protected] (R. Hadjeb). cedures, such as acid–base titration, solvent extraction and Peer review under responsibility of King Saud University. complex formation (Jime´nez-Lozano et al., 2002; Popovic et al., 2000; Falcomer et al., 2006; Gasowska, 2005; Evagelou et al., 2003). Production and hosting by Elsevier

Please cite this article in press as: Hadjeb, R., Barkat, D. Determination of acid dissociation constants of some substituted salicylideneanilines by spectroscopy. Application of the Hammett relation. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.04.002 2 R. Hadjeb, D. Barkat

Acid dissociation constant (pKa value) is an important 2. Materials and methods parameter to estimate the extent of ionization of molecules at different pH values. It is worth mentioning that there have All Schiff bases were prepared by condensing salicylaldehyde been a number of studies regarding this parameter (Yurdakoç with aniline and substituted anilines in the 2-, 3- and 4-position ¨ and Ozcan, 1993; Akay et al., 2002; Kiliçet al., 1998; Gu¨ ndu¨ z by methyl, chloro and nitro groups in ethanol on a water bath ¨ et al., 1993; Ogretir et al., 2009), in order to produce the effect for 2–5 h (Issa et al., 2005; Saw, 1967). The Schiff bases were of several electron donating and withdrawing substituents; and purified and filtered off by recrystallization from ethanol. Sal- also the effect of solvent on the acidity of a number of Schiff icylaldehyde, aniline and substituted anilines were purchased bases (Ko¨ seoglu et al., 1995; Asuero et al., 1986; Yurdakoç from Merck Millipore and were used as received. Stock solu- ¨ and Oscan, 1990). tions of our compounds were prepared in double distilled The present work therefore reports on the determination water. of the acid dissociation constants of salicylideneaniline The concentration of stock solutions of perchloric acid (Schiff base taken as the standard), salicylidene-2-methylan- (BIOCHEM) and sodium hydroxide (BIOCHEM) was 0.1 M iline, salicylidene-3-methylaniline, salicylidene-4-methylani- and was prepared as described elsewhere (Gu¨ ndu¨ z et al., line, salicylidene-2-chloroaniline, salicylidene-3-chloroaniline, 1993). The ionic strength was maintained constant by means salicylidene-4-chloroaniline, salicylidene-2-nitroaniline, salicy- of sodium perchlorate (NaClO4) as 0.1 M. All test solutions lidene-3-nitroaniline and salicylidene-4-nitroaniline. Various were freshly prepared before taking the measurement. methodologies have been used for the experimental determination of acid dissociation constants (Poole et al., 2004; 2.1. pH and spectrophotometer Lachenwitzer et al., 2002; Rouhani et al., 1995; Moghimi et al., 2003; Albert and Serjeant, 1984). Among these techniques potentiometry and spectrophotometry are the pH measurements were performed using an Nahita model NO. preferred methods due to their simplicity and ease of appli- 903 pH-ionmeter equipped with a combined pH electrode cation. For this work the UV–Vis spectroscopic method has (ingold). been employed because of its high sensitivity. The spectra and absorbance measurements were recorded Moreover, the purpose of this research was to use the Ham- on a SHIMADZU UV mini 1200 spectrophotometer over mett equation to predict the effect of substituent on the acidity the wavelength range of 200–500 nm. of salicylideneaniline, which has been a relationship between Spectrophotometric measurements were made in aqueous the effect of meta and para substituents on either rates of reac- ethanol and dioxane media containing 60% (v/v) at tions or equilibrium constants. 25.0 ± 0.1 C. During titration the absorbance (A) reading and pH values were taken after a suitable time (normally 2– 3 min) for equilibration after each addition of titrant. pK0 pKa ¼ rq ð1Þ 3. Experimental

where pK0 and pKa are the acid dissociation constants of sal- Titration was performed at a constant temperature and in a icylideneaniline (Schiff base taken as the standard) and some nitrogen atmosphere with sodium hydroxide, in concentration of their derivatives, r is a constant that characterizes the sub- of 0.02 M, in 50 ml solutions containing 0.1 M NaClO4 with: 4 4 stituent and q is a constant of reaction and is independent of (i) 2.10 M HClO4 (for cell calibration) plus (ii) 2.10 M 4 the substituent. HClO4 + 2.10 M Schiff bases.

Figure 1 UV absorption spectra of salicylidene-4-chloroaniline (2.10–4 M) in 60% ethanol–water at different PH values.

Figure 2 UV absorption spectra of salicylidene-3-methylaniline (2.104 M) in 60% dioxane–water at different pH values.

Figure 3 UV absorption spectra of salicylidene-2-nitroaniline (2.104 M) in 60% ethanol–water at different pH values.

Simple titration spectra (absorbance (A) vs. wavelength) pH 1 1 ðAk AkLÞ10 ¼ Ak þ AkHL ð3Þ resulting from spectrophotometric titration of Schiff bases at K2 K2 different pH values are given in Figs. 1–3. where AkH2L,AkHL and AkL are the absorbance for the species The spectra of all the Schiff bases studied except the spec- H L, HL and L respectively at k wavelength.From these equa- trum of salicylidene-2-nitroaniline that follows two isosbestic 2 tions, pKa values of all compounds were calculated at least at points, show that the deprotonation of nitrogen atom and three different fixed wavelengths. The values of AkH2L calcu- naphtholic hydrogen atom is completely dissociable in sepa- lated with the protonation constants of Schiff bases were rate steps (Figs. 1 and 2). But for the nitro group in the ortho recorded with the absorbance values at the start of the titration position the absorption spectrum does not present significant (at acidic region), and the values of AkL were recorded with the changes throughout the titration, which could be due to the absorbance at the end of titration where the titration solution presence of the keto form (Fig. 3). was sufficiently basic. pKa values of substances were calculated from this method and pH measurement data according to the procedure defined 4. Results in the literature (Asuero et al., 1986; Yurdakoçand O¨ scan, 1990) based on the following equations (Akay et al., 2002; Polster and Lanchmann, 1989): The o-hydroxy Schiff bases, where a highly stable hydrogen (H)-bridged, quasi six-membered ring exists due to intramolec- pH ðAk AkH2LÞ10 ¼K1 Ak þ K1 AkHL ð2Þ ular H-bonding between the H-atom of the hydroxyl group

protonation site We note that the values of pK1 for protonated Schiff bases bearing the substituent R from para to ortho, follow an order of increasing acidity. N The interpretation of classification could be obtained tak- OH ing into account the electronic effect of the substituent on R the one hand and the spatial configuration of our legends on the other hand. Our compounds tend to adopt a configuration deprotonation site in space of two aromatic rings are hardly coplanar. This geom-

R = H, CH3, Cl2 and NO2 etry results in two types of resonance in the molecule, the ﬁrst taking place between phenol and the double bond of the imine,

Scheme 1 Structure of the Schiff bases in which R: H, CH3,Cl2 the second relating to the lone pair of the nitrogen and the phe- and NO2 in three different positions. nyl part of the aniline. The order of acidity of salicylide` neaniline derivatives com- and the N-atom of the imine linkage (Polster and Lanchmann, pared to the reference molecule SA (salicylideneaniline) is as 1989; Blagus et al., 2010; Krygowski et al., 2008; Filarowski, follows: 2005; Dominiak et al., 2003). The advantage of these systems The methyl group with an inductive effect donor leads to is that they show two tautomer forms, enol-imine (OH) and pK1 whose values are relative to the salicylideneaniline follow- keto-enamine (NH) forms. These tautomers are awaited to ing descending order of acidity: be in equilibrium with each other, but it is the (OH) that is 2 CH3 < SA < 3 CH3 < 4 CH3 commonly found (Scheme 1). Considering the structures of the Schiff bases, we can We note that the salicylidene-2-methylaniline has a pK1 lower deduce that they have two protonation sites; the ﬁrst one is than in the meta and para positions.if R is a nitro group the the imino-nitrogen atom and the second one is OH group of order of the acidity is as follows: the phenol ring. The log K1 and log K2 values are related to 3 NO2 < 4 NO2 < SA the dissociation acid of imine nitrogen and phenolate respec- Similarly, we also note that the salicylidene-3-nitroaniline has tively, as follows: apK1 lower than in the para position. LH Hþ þ þ ½ ½ As in the case of the methyl group and nitro, order of acid- H2L HL þ H ; K1 ¼ þ ð4Þ ½H2L ity for the chloro substituent group is as follows: 2 Cl < 3 Cl < 4 Cl < SA ½Hþ½L HL L þ Hþ ; K ¼ ð5Þ 2 ½HL For this substituent it is observed that the acidity is high when the substituent is in the ortho position.In addition to the The numerical pK1 and pK2 values of ten Schiff bases deter- inductive effect of donor or attractor for the three substituents, mined in ethanol–water and dioxane–water mixtures are given another effect can be added to better interpret these results, in Table 1. which is the character of the electron-withdrawing or electron

DpK1 ¼ pK1 pK1ð0Þ ð6Þ mesomeric substituent. Indeed, the values of pK1 Schiff bases substituted in the ortho, meta and para-nitro in both systems dioxane–water 5. Discussion and ethanol–water are quite similar and are signiﬁcantly lower than those substituted by chloro and methyl groups. This The acid dissociation constants given in Table 1 are considered becomes obvious if one considers only the character of the in more detail in order to gain more information about the spe- nitro group mesomeric electron which strongly attracts the ciﬁc effect of the substituent and the effect of solvent on the electronic charge at the nitrogen which generates high acidity basicity of the Schiff bases. that facilitates the deprotonation.

Table 1 The acid dissociation constants of substituted salicylideneaniline at 25.0 ± 0.1 C for two different solvent mixtures and the Hammett constants Isaacs (1986). 60% Ethanol + 40% water 60% Dioxane + 40%water

r pK1 DpK1 pK2 pK1 DpK1 pK2 Salicylideneaniline – 4.34 – 8.51 3.75 – 9.90 Salicylidene-2-methylaniline – 4.09 – 9.06 3.53 – 9.80 Salicylidene-3-methylaniline 0.07 4.51 0.17 9.35 4.02 0.27 9.83 Salicylidene-4-methylaniline 0.16 4.61 0.27 9.47 4.20 0.45 9.85 Salicylidene-2-nitroaniline – – – – – – – Salicylidene-3-nitroaniline 0.71 2.69 1.65 9.81 2.61 1.14 9.70 Salicylidene-4-nitroaniline 0.79 2.73 1.61 9.93 2.63 1.12 9.78 Salicylidene-2-chloroaniline – 3.86 – 10.34 3.14 – 9.72 Salicylidene-3-chloroaniline 0.37 4.02 0.32 9.23 3.23 0.52 9.92 Salicylidene-4-chloroaniline 0.23 4.15 0.19 9.49 3.48 0.27 9.96

We note that, during the transition from ortho to para of We note that the variation of the acid dissociation con- the chloro pK1 values increased signiﬁcantly compared with stants with the nature of solvent follows the same trend for nitro. This is probably due to the inductive effect attractor that other anilinesalicylidenes differently substituted. We can say strongly attracts the electron density at the nitrogen when the that the effect of solvent on the protonation constants remains substituent is in the ortho position, that is to say, a high the same for all the hydroxy Schiff bases studied. acidity. It is observed that the values of pKa follow the following The methyl group with an inductive effect donor leads to a order: value of pK lower when the substituent is in the ortho posi- 1 pK ðdioxaneÞ < pK ðethanolÞ tion. If we consider the hypothesis that greater electron density 1 1 at the nitrogen, that is to say, the deprotonation is difﬁcult pK2ðethanolÞ < pK2ðdioxaneÞ (low acidity), this disagrees with the result. Another effect that can add to interpret these results is probably the steric effect of A difference between the values of pK1 equal to 0.41 is the methyl group. observed when going from ethanol to dioxane. The difference As to the variation of the pK2 regarding the values of these between the values of pK1 is due to the difference in polarity of compounds, we have not observed any order between these the two solvents. values and the type or position of the substituents. This lack For values of pK2 a difference of 0.38 is obtained. This can of regularity can probably be attributed to the fact that the be explained, in addition to the difference in polarity of the substituent was far from the OH group (Ko¨ seoglu et al., two solvents, by establishing hydrogen bonds between the sol- 1995; Gu¨ ndu¨ z et al., 1993). vent and the phenolic OH group. This study is also concerned with the effect of solvent on the By using the data listed in Table1 Hammett relations, acid dissociation constants. This effect has been studied by sev- (r DpK1) of substituted salicylideneaniline in 60% ethanol– eral authors (Kwan-Kit et al., 1974; Gu¨ ndu¨ z et al., 1986). water and 60% dioxane–water mixtures are given in Figs. 4 and 5 respectively.

0,5 m-CH 3

p-CH 3 0,0 p-Cl m-Cl

-0,5 1 pK

Δ -1,0

p-NO -1,5 2

m-NO 2 -2,0 -0,2 0,0 0,2 0,4 0,6 0,8 σ

Figure 4 Plot of the DpKa of substituted salicylideneaniline against the Hammett substituted constants (r) in ethanol solvent.

p-CH 0,5 3 m-CH 3

0,0 p-Cl

1 m-Cl -0,5 pK Δ

-1,0

p-NO -1,5 m-NO 2 2

-0,2 0,0 0,2 0,4 0,6 0,8 σ

Figure 5 Plot of the DpKa of substituted salicylideneaniline against the Hammett substituted constants (r) in dioxane solvent.

As shown in Figs. 4 and 5, excellent linear correlations gov- Filarowski, A., 2005. J. Phys. Org. Chem. 18, 686–698. ern the influence of the substituent R on the acid dissociation Fleuren, H.L.J., Van Ginneken, C.A.M., Van Rossum, J.M., 1979. J. constant of the azomethine nitrogen. Pharm. Sci. 68, 1056–1058. For both solvents, the values of q are negative and lie Gasowska, A., 2005. J. Inorg. Biochem. 99, 1698–1707. Gu¨ ndu¨ z, T., Gu¨ ndu¨ z, N., Kiliç, E., Kenar, A., 1986. Analyst 111, between 1.86 for water–dioxane and 2.02 for the system 1345. water–ethanol which means that the reaction is sensitive to Gu¨ ndu¨ z, T., Kiliç, E., Canel, E., Ko¨ seoglu, F., 1993. Anal. Chim. Acta the effect of the substituent electron. 282, 489–495. We note that the value of q in the system water–dioxane is Hadjoudis, E., Milia, F., Seliger, J., Blinc, R., 1977. Solid State greater than that determined in the system water–ethanol. This Commun. 21, 541–543. difference is due to the solvent polarity. This implies that as the Higelin, D., Sixl, H., 1983. Chem. Phys. 77, 391–400. solvent polarity decreases, the role of the substituent increases Isaacs, N.S., 1986. Physical Organic Chemistry. Longman Scientific and q values increase, and this is consistent with Tokura’s and Technical, New York. results (Tokura et al., 1969). Issa, R.M., Khedr, A.M., Rizk, H.F., 2005. Spectrochim. Acta, Part A 62, 621–629. Jimeńez-Lozano, E., Marque´s, I., Barron, D., Beltran, J., Barbosa, J., 6. Conclusion 2002. Anal. Chim. Acta 464, 37–45. Johmoto, K., Sekine, A., Uekusa, H., Ohashi, Y., 2009. Bull. Chem. In summary, we have discussed and revised to understanding Soc. Jpn. 82, 50–57. of the acid–base behavior of N-salicylideneaniline (SA) and Kaufman, J.J., Semo, N.M., Koski, W.S., 1975. J. Med. Chem. 18, some substituted salicylideneaniline in ethanol and dioxane– 647–655. water binary mixtures. The determined pK values are appro- Kiliç, E., Atakol, O., Canel, E., Alibegeoglu, Z., Gu¨ ndu¨ z, T., a Ko¨ seoglu, F., 1998. Turk. J. Chem. 22, 387–391. priate for predicting the effect of different substituents in dif- Ko¨ seoglu, F., Kiliç, E., Uysal, D., 1995. Talanta 42, 1875–1882. ferent positions. Kownacki, K., Kaczmarek, L., Grabowska, A., 1993. Chem. Phys. Also, the important data extracted from this exploration Lett. 210, 373–379. are the constant of reaction (q) which can be used for other Krygowski, T.M., Zachara-Horeglad, J.E., Palusiak, M., Pelloni, S., substituent in order to determine approximately their acid dis- Lazzeretti, P., 2008. J. Org. Chem. 73, 2138–2145. sociation constants, without making calculations in the same Kwan-Kit, M., McBryde, W.A.E., Neiboer, E., 1974. Can. J. Chem. conditions. The Hammett equation represents the effect of 52, 1821. substituent on the reactivity of azomethine nitrogen of Schiff Lachenwitzer, A., Li, N., Lipkowski, J.J., 2002. Electroanal. Chem. bases in ethanol and dioxane solvents. 532, 85–98. Moghimi, A., Alizadeh, R., Shokrollahi, A., Aghabozorg, H., Shamsipur, M., Shockravi, A., 2003. Inorg. Chem. 42, 1616–1624. Acknowledgement Montielli, C., Brunora, G., Fignani, A., Marchi, A., 1988. Korroz. Figy. 28, 118. The Authors thank the University of Biskra for support of this O¨ gretir, C., Go¨ rgu¨ n, K., O¨ zku¨ tu¨ k, M., Sakarya, H.C., 2009. ARKI- work. VOC, vii, 197–209. Polster, J., Lanchmann, H., 1989. Spectrometric Titrations, Chap. 6–7. References Poole, S.K., Patel, S., Dehring, K., Workman, H., Poole, C.F.J., 2004. Chromatogr A 1037, 445–454. Popovic, Z., Pavlovic, G., Matkovic-Calogovic, D., Soldin, Z., Rajic, Akay, M.A., Canel, E., Kiliç, E., 2002. Turk. J. Chem. 26, 37–44. M., Vikic-Topic, D., Kovacek, D., 2000. Inorg. Chim. Acta 306, Albert, A., Serjeant, E.P., 1984. The Determination of Ionization 142–152. Constants. Chapman and Hall Ltd, London. Rouhani, S., Rezaei, R., Sharghi, H., Shamsipur, M., Rounaghi, G., Almasifar, D., Forghaniha, A., Khojasteh, Z., Ghasemi, J., Sharghi, 1995. Microchem. J. 52, 22–27. H., Shamsipur, M.J., 1997. Chem. Eng. Data 42, 1212–1215. Saw, H.D., 1967. J. Am. Chem. Soc. 101, 154. Asuero, A.G., Navas, M.J., Herrador, A.M., Recamales, A.F., 1986. Shamsipur, M., Ghasemi, J., Tamaddon, F., Sharghi, H., 1993. Int. J. Pharm. 34, 81–82. Talanta 40, 697–699. Blagus, A., Cincic, D., Friscic, T., Kaitner, B., Stilinovic, V., Maced, Thorat, B.R., Mandewale, M., Shelke, S., Kamat, Atram, R.G., J., 2010. Chem. Eng. 29, 117–138. Bhalerao, M., Yamgar, R., 2012. J. Chem. Pharm. Res. 4 (1), 14– Casaszar, J., Morvay, J., Herczeg, O., 1985. Acta Phys. Chem. 31, 717. 17. Cohen, M.D., Schmidt, G.M.J., 1962. J. Phys. Chem. 66, 2442–2446. Tokura, N., Kondo, Y., Matsui, T., 1969. Bull. Chem. Soc. (Japan) 42, Dash, B., Mahapotra, P.K., Panda, D., Pattnaik, J.M., 1984. J. Indian 1039. Chem. Soc. 61, 1061. Yoke-Leng, S., Noridayu, O., Niyaz Khan, M., Pratt, L.M., 2013. Dominiak, P.M., Grech, E., Barr, G., Tear, S., Mallinson, P., Tetrahedron 69, 2524–2533. Wozniak, K., 2003. Chem. Eur. J. 9, 963–970. Yurdakoç, M., O¨ scan, M., 1990. Turk. J. Chem., C13, S3, 362–396. Evagelou, V., Tsantili-Kakoulidou, A., Koupparis, M., 2003. J. Yurdakoç, M., O¨ zcan, M., 1993. Turk. J. Chem. 17, 133–137. Pharm. Biomed. Anal. 31, 1119–1128. Falcomer, V.A.S., Lemos, S.S., Batista, A.A., Ellena, J., Castellano, E.E., 2006. Inorg. Chim. Acta 359, 1064–1070.