Spectroscopic studies on the formation of charge transfer complexes of l -phenylalanine with 2,3,5-trichloro-6-alkoxy-1,4-benzoquinones in aqueous medium

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

King Saud University

Arabian Journal of Chemistry www.ksu.edu.sa www.sciencedirect.com

ORIGINAL ARTICLE

Spectroscopic studies on the formation of charge transfer complexes of L-phenylalanine with 2,3, 5-trichloro-6-alkoxy-1,4-benzoquinones in aqueous medium K. Ganesh, C. Balraj, A. Satheshkumar, Kuppanagounder P. Elango

*

Department of Chemistry, Gandhigram Rural Institute (Deemed University), Gandhigram 624 302, India Received 26 October 2012; accepted 6 October 2014

KEYWORDS Charge transfer; L-Phenylalanine; Substituent effect; Fluorescence; Theoretical studies; Taft correlation

Abstract UV–Vis, FT-IR, LC–MS and fluorescence spectral techniques were employed to investigate the mechanism of interaction of L-phenylalanine with new p-acceptors, 6-alkoxy-2,3, 5-trichloro-1,4-benzoquinones. The interaction of these quinones with L-phenylalanine (LPA) yielding radical ion pair was found to proceed through the formation of donor–acceptor complex. The stoichiometry of the complexes was determined by Job’s continuous variation method and was found to be 1:1 in all the cases. Kinetic and thermodynamic properties of the complexes were determined in aqueous medium at physiological conditions (pH = 7). Fluorescence quenching studies indicated that the interaction between the donors and the acceptor is spontaneous. Correlation of association constants of the CT complexes with Taft’s polar and steric constants indicated that the electronic effects of the substitutions play a significant role in governing the reactivity of the quinones when compared to steric factors. ª 2014 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction Charge transfer complex formed between donor and acceptor pairs is of fundamental importance in nature and governs a * Corresponding author. Tel.: +91 451 245 2371; fax: +91 451 2454466. E-mail address: [email protected] (K.P. Elango). Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

number of pivotal processes such as photosynthesis and vision (Krokos et al., 2012). Due to its wide applications and implications, charge transfer (CT) or electron donor acceptor (EDA) complexes were studied extensively in various fields like solar cells (Guldi, 2003), molecular electronics (Carroll and Gormon, 2002), non linear optics (Selby et al., 2010), sensors (Jakle, 2010) and analytical estimation of drugs (Gouda, 2009). In certain cases EDA complexes act as reaction intermediates in the nucleophilic substitution or addition reactions (Kochi, 1991). Drug–receptor mechanisms can also be explained by CT phenomenon in addition to weak interactions such as hydrogen bonding and hydrophobic interactions together with van der Waal’s forces like dipole–dipole, dipole

http://dx.doi.org/10.1016/j.arabjc.2014.10.020 1878-5352 ª 2014 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). Please cite this article in press as: Ganesh, K. et al., Spectroscopic studies on the formation of charge transfer complexes of L-phenylalanine with 2,3,5-trichloro-6alkoxy-1,4-benzoquinones in aqueous medium. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.10.020

2 induced dipole, dispersion interactions etc.(Raza Khan et al., 2010). In general, vast studies on CT complexes of a variety of acceptors have been carried out in non-aqueous solvents only (Mostafa and Bazzi, 2011; AlQaradawi et al., 2012; Refat, 2011; Ganesh et al., 2012). In spite of a large number of studies, the real understanding of drug–receptor interactions is still a far cry as the matter is complex and no consideration of water molecule in drug–receptor interaction is made till now. Water constitutes 80% of our body weight and is the predominant biological solvent. Unless the role of water in drug–receptor interactions is properly understood, understanding the possibility of drug–receptor interaction is remote. As a primary step, the charge transfer complexes of drugs with acceptors in physiological condition i.e. in aqueous medium should be studied. Quinones are important molecules in biology/nature which notably play an essential role in redox reactions such as photosynthesis and respiration (Bernardo et al., 2007; Crofts and Wraight, 1983). They are oxidants and electrophiles since a nucleophile (drugs, amino acids) addition represents a formal two electron reduction and these properties are interrelated. Quinone accepts one or two electrons to form corresponding radical-anion (Q) and hydroquinone dianion (Q2). These species interact with crucial cellular molecules such as DNA, proteins and oxygen, tuning their biological activity by accepting the electrons in the correct site (Crofts and Wraight, 1983; Remy et al., 2003; Okamura et al., 2000; Monks et al., 1992; Wei-Ma et al., 2011). The ability of the quinones to accept one or two electrons depends directly on their chemical structures and their biological action (Izumi et al., 2005). Thus, the mechanism of interaction of quinone with biologically important amino acids, in general, is a research topic of significant interest and hence the present study. The main objective, therefore, of the present article is to study the spectral, thermodynamic and kinetic aspects of the interaction of 1,4-benzoquinones possessing variable alkoxy groups with L-phenylalanine (LPA) with an aim to investigate the mechanism of the interaction and to characterize the complex formed in these interactions. L-Phenylalanine is chemically known as (S)-2-amino-3-phenylpropanoic acid which is an essential amino acid used in the treatment of endogenic depression symptoms (Heller, 1978), attention deficit disorder (Wood et al., 1985) and as an enhancer of opium analgesics used in the conditions of chronic pain (Kamruzzaman et al., 2012). In the presence of phenylalanine hydroxylase enzyme, LPA is biologically converted into another amino acid, tyrosine. LPA has also been reported to reduce the calories with its ability to burn fat and suppress appetite (Hoeger et al., 1999). Carbon labeled LPA has been used to assess basal muscle protein synthesis rates in vivo in humans by the single biopsy approach (Burd et al., 2012). The quinone cofactor 2,4,5-trihydroxy phenylalanine (THP) is found in copper amine oxidase (CAO) which actively involved in wound healing in plants and functions as a regulatory enzyme in mammals (Murie, 2004). Thus the pharmaceutical and biological importance of LPA emphasizes the need to study the actual site of attack during the formation of charge transfer complexes with quinones. Such a study would undeniably shed some light on the mechanism of the drug/amino acid action in real pharmacokinetic study. Though these 1,4-benzoquinones are known to organic chemists as intermediates, it is the first systematic attempt to investigate the CT complexes formed by them as acceptors

K. Ganesh et al. with the amino acid as donor in aqueous medium. Such a structural variation of the quinones would certainly help to tune their redox chemistry and hence their biological activity. In the frame of Density Functional Theory (DFT) we have also performed the complete optimization of the geometry for these quinones, donor and their CT complexes. Attempts have also been made to investigate the effect of substituents on the CT interaction using the techniques of correlation analysis by employing Taft’s substituent constants (Shorter, 1982). 2. Experimental 2.1. Material and methodology The electron acceptors viz. different alkoxy substituted 1, 4-benzoquinones were synthesized and purified by the reported method (Richard and Paul, 1974). The electron donor, L-phenylalanine, was obtained from Merck, India and was used as received. The purity of the amino acid was checked by its melting point (observed 274 C; literature 273 C) and FT-IR spectrum. Double distilled water was used throughout the study. The second distillation was carried out using alkaline permanganate. Disodium-monohydrogen phosphate and monosodium dihydrogen phosphate buffer (AR grade, Merck, India) were used to keep the pH at 7. The structure of the amino acid and acceptors is shown below.

O

H2N

OH

Chemical structure of phenylalanine 1

O R

6

O

1

3

5

Cl

Cl 2

4

Cl

2O

Structure of acceptors

where R = methyl (MQ); ethyl (EQ); isopropyl (IPQ) and n-butyl (BQ). Solutions for the spectroscopic measurements were prepared by dissolving accurately weighed amounts of donor (D) and acceptor (A) in the appropriate volume of solvent immediately before running the spectra in phosphate buffer at pH = 7. The electronic absorption spectra were recorded on a JASCO (V 630, Japan) UV–Vis double beam spectrophotometer using 1 cm matched quartz cells by using aqueous phosphate buffer. The temperature of the cell holder was controlled with a water flow (±0.2 C). The steady state fluorescence spectra were obtained on a JASCO (FP 6200, Japan) spectrofluorimeter. The emission slit width (5 nm) and the scan rate (250 nm) were kept constant for all of the experiments. FT-IR spectra were recorded on a JASCO (FT-IR 460 Plus, Japan) spectrometer.

Please cite this article in press as: Ganesh, K. et al., Spectroscopic studies on the formation of charge transfer complexes of L-phenylalanine with 2,3,5-trichloro-6alkoxy-1,4-benzoquinones in aqueous medium. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.10.020

Formation of charge transfer complexes of L-phenylalanine

3

2.2. Synthesis and characterization of substituted quinones

2.3. Kinetic procedure

1,4-Benzoquinones possessing different alkoxy substituents were synthesized and purified as reported elsewhere (Richard and Paul, 1974). The percentage yields of various quinones obtained by this method are shown in Scheme 1. The quinones were characterized using conventional analytical CHN and various spectral techniques (Balraj et al., 2013). The reported results are collected here for easy understanding.

The kinetics of the interaction of LPA with acceptors (MQ, EQ, IPQ, and BQ) of different quinones was followed at three different temperatures in aqueous medium at physiological pH 7 under pseudo-first-order conditions, keeping [D]  [A]. The increases in absorbance of the new peak appeared at 340 nm for LPA–MQ, LPA–EQ, LPA–IPQ and LPA–BQ with elapse of time being recorded. The pseudo-first-order rate constants (k1) were calculated from the gradients of log (A1  At) against time plots, where A1 and At represent the absorbance at infinity and time t, respectively. The second order rate constants were calculated by dividing k1 by [D] (Ganesh et al., 2012).

2.2.1. 2,3,5-Trichloro-6-methoxycyclohexa-2,5-diene-1,4-dione (MQ) 1

H NMR (DMSO-d6, 300 MHz; Fig. 1Sa), d (ppm) 4.19 (s, 3H), FT-IR (KBr, cm1): 1680 (C‚O), 1668 (C‚O), 1567 (C‚C), UV–Vis in ethanol (kmax): 419 nm (n-p*), log e 2.50, Anal. Calcd. for C7H3Cl3O3: C, 34.82; H, 1.25; found: C, 36.17; H, 1.74; m.p. 172 C.

3. Results and discussion 3.1. Stoichiometry of the interaction

2.2.2. 2,3,5-Trichloro-6-ethoxycyclohexa-2,5-diene-1,4-dione (EQ) 1

H NMR (DMSO-d6, 300 MHz, Fig. 1Sb), d (ppm) 1.39 (t, J = 7.20 Hz, 3H), 4.45–4.53 (m, 2H); FT-IR (KBr, cm1): 1676, 1608 (C‚O); UV–Vis in ethanol (kmax): 419 nm, log e 2.62, Anal. Calcd. for C8H5Cl3O3: C, 37.61; H, 1.97; found: C, 36.87; H, 1.84; m.p. 112 C. 2.2.3. 2,3,5-Trichloro-6-isopropoxycyclohexa-2,5-diene-1,4dione (IPQ) 1 H NMR (DMSO-d6, 300 MHz, Fig. 1Sc), d (ppm) 1.34 (d, J = 6.00 Hz, 6H), 4.98–5.10 (m, 1H); FT-IR (KBr, cm1): 1670, 1648 (C‚O), UV–Vis in ethanol (kmax): 419 nm, log e 2.62, Anal. Calcd. for C9H7Cl3O3: C, 40.11; H, 2.62; found: C, 40.81; H, 2.56; m.p. 74 C.

The stoichiometry of the CT complex formed, in all the cases, was determined by applying Job’s continuous variation method using absorption spectral data (Job, 1928). In all the cases (LPA–MQ, LPA–EQ, LPA–IPQ, LPA–BQ) the symmetrical curve with a maximum at 0.5 mol fraction indicated the formation of a 1:1 (D:A) CT complex (Fig. 1). The photometric titration measurements were also performed for the determination of the stoichiometry in these interactions. The results of the photometric titration studies (Fig. 2) confirmed the observed stoichiometry of the interaction (Gaber and Al-Shihry, 2005). The stoichiometry of the systems is further confirmed by Job’s continuous variation method using emission spectral data also (Laia et al., 2003) [(Fig. 2S) Supplemental information]. 3.2. Characterization of CT complexes

2.2.4. 2,3,5-Trichloro-6-butoxycyclohexa-2,5-diene-1,4-dione (BQ) 1

H NMR (DMSO-d6, 300 MHz, Fig. 1Sd), d (ppm) 0.9 (t, J = 6.00 Hz, 3H), 1.35–1.48 (m, 2H), 1.63–1.74 (m, 2H), 4.45 (t, J = 6.30 Hz, 2H); FT-IR (KBr, cm1): 1672, 1649 (C‚O), UV–Vis in ethanol (kmax): 419 nm, log e 2.62, Anal. Calcd. for C10H9Cl3O3: C, 42.36; H, 3.20; found: C, 42.14; H, 3.18; m.p. 88 C.

In all the cases, the CT complexes were obtained by allowing the reactants (5 mmol of LPA and 5 mmol of the corresponding acceptors in water) to react for 24 h under stoichiometric conditions. The FT-IR spectra of the pure LPA, acceptors and their CT complexes were recorded and the peak assignments for important peaks are given in Tables 1–4. The results

O Cl

O Cl

O

Cl

Cl O

exce

ss e met q. NaO han CH ol 3,

70°C , 12

1 (72%)

C H 5, NaO 2 1 eq. thanol e

O Cl

O

Cl

Cl

h

h 90°C, 12

O

,2 ml l IPA 10 m a CO 3 N 2 H 2O,

12 90°C,

Cl h

3 (64%)

Cl

Cl

10 m 2 m l n-B uta lH Cl n 2 O, Na ol, 90° 2 CO C, 12

h

Cl O

Cl

O

O

O Cl

O

3

Cl

Cl O

O

2 (68%)

Scheme 1

4 (67%)

Preparation method for alkoxy substituted quinones.

Please cite this article in press as: Ganesh, K. et al., Spectroscopic studies on the formation of charge transfer complexes of L-phenylalanine with 2,3,5-trichloro-6alkoxy-1,4-benzoquinones in aqueous medium. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.10.020

4

K. Ganesh et al. 0.28

Table 1 FT-IR wave numbers (cm1), intensitya and tentative band assignments for the LPA and its complex with MQ.

LPA-MQ LPA-EQ LPA-IPQ LPA-BQ

LPA

Absorbance

MQ

3066w

0.24

1684s 1671 1615

0.20

LPA–MQ complex Assignments 3029b 1737 1679s 1629

1625 1602 1562 1492 1482

0.16

1409 1270m 1099s 909m 778m 722m

0.12 0.2

0.3

0.4

0.5

0.6

0.7

0.8

mole fraction of the donor

Figure 1 Job’s continuous variation plots for LPA with MQ, EQ, IPQ and BQ in water at 298 K.

0.24

744 698 a

744 700

0.16

0.12

1625

0.08

1562 1492

LPA–EQ complex

Assignments

1675s 1621

3029b 1735 1671m 1631

m(ANH+ 3 ); m(C‚O) m(C‚O)

1600

1481 1409 0.04

1.0

Mono substituted Benzene

EQ

3066w

0.5

m(CACl)

s, strong; m, medium; w, weak; m, stretching; d, bending.

LPA

0.0

d(ANH+ 3 ); asymmetric m(NAH); asymmetric m(C‚O); asymmetric d(ANH+ 3 ); symmetric m(NAH); symmetric m(C‚O); symmetric m(OACH3)

Table 2 FT-IR wave numbers (cm1), intensitya and tentative band assignments for the LPA and its complex with EQ.

LPA-MQ LPA-EQ LPA-IPQ LPA-BQ

0.20

Absorbance

1229m 1079m 823w 732

m(ANH+ 3 ); m(C‚O) m(C‚O)

1.5

2.0

2.5

3.0

3.5

1270m 1101s 784m 723m

4.0

Volume of acceptor (ml)

Figure 2 Photometric titration plots for LPA with MQ, EQ, IPQ and BQ in water at 298 K.

indicated that the shifts in positions of some of the peaks could be attributed to the symmetry and electronic structure modifications in both donor and acceptor units in the formed CT complex relative to the free molecules. In the FT-IR spectrum of free LPA molecule, the broad and overlapped bands observed in the region of 3300– 2300 cm1 are the characteristic common feature when the spectrum was recorded in KBr pellet. The main broad band at 3066 cm1 is due to the ANH+ 3 stretching band of LPA molecule in the solid state (Silverstein et al., 1981). The peaks at 1625 and 1492 cm1 are due to asymmetric and symmetric bending vibrations of the ANH+ 3 group of the LPA. The strong bands in the spectrum at 1562 and 1409 cm1 are assigned to asymmetric and symmetric stretching vibrations of the carboxyl group (ACOO). This observation suggests

744 698 a

1224m 1079m 732 700 740 700

d(ANH+ 3 ); asymmetric m(NAH); asymmetric m(C‚O); asymmetric d(ANH+ 3 ); symmetric m(NAH); symmetric m(C‚O); symmetric m(OACH2CH3) m(CACl) Mono substituted Benzene

s, strong; m, medium; w, weak; m, stretching; d, bending.

that phenylalanine is in the zwitter ionic form. The two intense bands at 744 and 698 cm1 are the pattern of the mono substituted benzene ring of LPA (Slifkin and Walmsley, 1969; Moxon and Slifkin, 1972; Silverstein et al., 1981; Cao and Fischer, 2000). As a representative case, the FT-IR spectrum of LPA–MQ complex is shown in Fig. 3. In this spectrum, a strong peak at 1737 cm1 corresponds to the presence of the free carboxyl group (ACOOH). This indicates that LPA is not in Zwitter ionic form during complexation, as it is carried out at pH 7. The isoelectric point of LPA is pH = 5.49 (Figs. 4 and 5). The asymmetric and symmetric bending vibrations of the ANH2 group occurred at 1602 and 1482 cm1 respectively. The m(C‚O), m(OACH3) and m(CACl) stretching vibrations

Please cite this article in press as: Ganesh, K. et al., Spectroscopic studies on the formation of charge transfer complexes of L-phenylalanine with 2,3,5-trichloro-6alkoxy-1,4-benzoquinones in aqueous medium. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.10.020

Formation of charge transfer complexes of L-phenylalanine

5 100

Table 3 FT-IR wave numbers (cm1), intensitya and tentative band assignments for the LPA and its complex with IPQ. IPQ

LPA–IPQ complex Assignments

1681s 1614

3023b 1732 1675s 1629

3066w

d(ANH+ 3 ); asymmetric m(NAH); asymmetric m(C‚O); asymmetric d(ANH+ 3 ); symmetric m(NAH); symmetric m(C‚O); symmetric m(OACH)

1625 1600 1562 1492 1475 1409 1255m 1076s 948m 796m 719m 744 698 a

80

m(ANH+ 3 ); m(C‚O) m(C‚O)

1207m 1033m 917w 744 701 744 701

% Transmittance

LPA

60

40

20

m(CACl) 0 4000

3500

Mono substituted Benzene

3000

2500

2000

1500

1000

500

-1

Wavenumber (cm )

s, strong; m, medium; w, weak; m, stretching; d, bending.

Figure 3

FT-IR spectrum of LPA–MQ complex.

100 1

a

Table 4 FT-IR wave numbers (cm ), intensity and tentative band assignments for the LPA and its complex with BQ. BQ

3066w 1687s 1608

LPA–BQ complex

Assignments

3035b 1731w 1629s

m(ANH+ 3 ); m(C‚O) m(C‚O)

1625 1600w 1562 1492 1484 1409 1263m 1076s 958m 788m 719m 744 698 a

1205m 1037m 908w 744 701 744 701

80

d(ANH+ 3 ); asymmetric m(NAH); asymmetric m(C‚O); asymmetric d(ANH+ 3 ); symmetric m(NAH); symmetric m(C‚O); symmetric m(OACH3)

% Transmittance

LPA

60

40

20

m(CACl) 0 4000

3500

3000

2500

2000

1500

1000

500

-1

Wavenumber (cm )

Mono substituted Benzene

Figure 4

s, strong; m, medium; w, weak; m, stretching; d, bending.

1

in the free MQ species appeared at 1684, 1270 and 909 cm , respectively. In the complex these stretching vibrations occurred at 1679, 1229 and 823 cm1, respectively. Such a bathochromic shift could be indicative of a higher charge density on the carbonyl and chloro groups of the MQ molecule (Ganesh et al., 2011). Two intense peaks from the mono substituted benzene ring found at 744 and 698 cm1 in the free LPA referred no significant shifts in the CT complexes indicating non participation of the benzene ring in CT complex formation with these acceptors. These observations suggested that the NH2 moiety of LPA participated in the complex formation with the quinones through charge transfer transition. The results obtained further support the fact that, in the amino acid–chloranil CT process, the lone pair of electrons on a nitrogen atom interacts with carbon–oxygen p-orbital in the

FT-IR spectrum of LPA.

1,4-benzoquinone (Foster, 1969; Beth and Cheng, 1980; Silverstein et al., 1981). The results are comparable with the reactions of amino acids with p-benzoquinones, thereto the band at 1730 cm1, corresponds to carbonyl stretch of the un-ionized carboxy  group and the absence of ANH+ 3 and ACOO indicated the non-Zwitterionic structure in the formed CT complex (Slifkin and Walmsley, 1969; Moxon and Slifkin, 1972). 3.3. Interaction of LPA with the quinones The electronic spectra of MQ in the presence of large excess of donor i.e., [D]/[A] >100 were recorded as a function of time in aqueous phosphate buffer medium (Fig. 6). Immediately after mixing aqueous solutions of colorless LPA and pale yellow colored MQ, a pink colored solution resulted whose electronic

Please cite this article in press as: Ganesh, K. et al., Spectroscopic studies on the formation of charge transfer complexes of L-phenylalanine with 2,3,5-trichloro-6alkoxy-1,4-benzoquinones in aqueous medium. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.10.020

6

K. Ganesh et al. 100

90

% Transmittance

80

70

60

50

40 4000

3500

3000

2500

2000

1500

1000

500

-1

Wavenumber (cm )

Figure 5

FT-IR spectrum of MQ.

1.2

1.0

0.8

0.6

Absorbance

1.0

0.4

0.2

D

0.8

0.0 200

300

400

500

600

700

800

Absorbance

Wavelength (nm)

0.6

0.4

0.2

A

spectrum showed absorption band in 430–540 nm range. This is characteristic absorption band of quinone radical ion (Hasani and Rezaei, 2006; Balraj et al., 2011). It is observed that with elapse of time the intensity of these bands at 291 nm decreased with a concurrent increase in the intensity of bands at 360 nm and 540 nm (Fig. 6). These peaks are the characteristic bands of the CT interaction of phenylalanine with p-chloranil at pH = 7.4 (Birks and Slifkin, 1963; Beth and Cheng, 1980). A clear isosbestic point is observed at 302 nm. These observations indicated that initial reactants were converted into CT complex. For comparison the electronic spectrum of the complex is also shown in Fig. 6. Similar electronic spectra were obtained for other systems viz. LPA–EQ, LPA–IPQ and LPA–BQ [(Fig. 3Sa, Sb and Sc) Supplemental information]. It is concluded that amino groups in the amino acid form CT complexes with substituted quinones in aqueous medium (Birks and Slifkin, 1963; Beth and Cheng, 1980). The kinetics of the interaction of LPA with the acceptors has been followed by monitoring the increase in absorbance of the peak at 360 nm in water as a function of time under pseudo-first-order conditions i.e., [D]  [A]. The pseudofirst-order rate constant (k1) values for the formation of the complex as a function of [D] and [A] are collected in Table 5. It is evident from the results that in all the cases the rate is independent of initial concentration of A indicating first order dependence on [A]. For all the systems, a plot of log k1 versus log [D] is linear with a slope of unity (r >0.995; slope range 0.951–1.00) [(Fig. 4S) Supplemental information] indicating unit order dependence on [D]. This was further supported by the constancy in k2 values (Balraj et al., 2011). The pseudo first-order rate constants, for all the systems, were measured at three different temperatures and the thermodynamic parameters computed are collected in Table. 6. A large negative value of entropy of activation indicated the involvement of polar transition state. This may be due to the fact that there is some charge separation in the transformation of reactants to the CT complex. Also the negative entropy of activation indicated a greater degree of ordering in the transition state than in the initial state, due to an increase in solvation during the activation process. Based on the foregoing results and discussions the following plausible mechanism for the interaction of LPA with these acceptors has been proposed (Scheme 2).

C 0.0 200

400

600

800

3.4. Characteristics of the CT complexes

Wavelength (nm)

Figure 6 Electronic spectra of LPA with MQ in water at 298 K D: LPA; A: MQ; C: CT complex; Inset LPA–MQ complex peak.

Table 5

In all the systems, an attempt was made to characterize the CT complexes formed in these interactions. For that the absorbance of the new bands was measured using constant acceptor

Effect of concentration of donor and acceptors on the rate of the interaction at 298 K.

[D] (103 M)

[A] (105 M)

1.3 1.9 2.5 3.1 3.1 3.1 3.1

3.1 3.1 3.1 3.1 2.5 1.9 1.3

k1 (104), s1

k2 (101) s1 mol1 dm3

LPA–MQ

LPA–EQ

LPA–IPQ

LPA–BQ

LPA–MQ

LPA–EQ

LPA–IPQ

LPA–BQ

1.52 2.07 2.84 3.41 2.92 2.91 2.94

1.27 2.08 2.51 3.21 2.58 2.60 2.62

1.09 1.69 2.11 2.64 2.04 2.01 2.02

1.31 1.94 2.61 3.27 2.44 2.44 2.41

1.1 1.1 1.1 1.1

1.0 1.1 1.0 1.0

0.8 0.9 0.8 0.8

1.0 1.0 1.0 1.1

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Formation of charge transfer complexes of L-phenylalanine Table 6 Systems

LPA–MQ LPA–EQ LPA–IPQ LPA–BQ

7

Kinetic and thermodynamic parameters for the interaction of LPA with acceptors in aqueous medium. k1 (104) sec1

k nm 541 540 540 540

298

305

313 K

3.41 3.19 2.64 3.27

4.16 4.52 3.92 4.13

5.85 5.61 5.12 5.94

DH#

DS#

DG#

25 26 32 28

226 223 205 217

93 93 93 93

DH# kJ mol1; DS# J K1 mol1; DG# kJ mol1.

O

O

NH2

Cl

Cl

Cl

O R

+ O

O

Cl NH2 O

OH

Cl

Cl

O R

O

OH

Acceptors LPA R= Me, Et, i-Pr and n-Bu

CT- Complex

O Cl NH2 O

Cl

Cl

OH

O

O R

radical ion pair

Scheme 2

Table 7

Mechanism of interaction of LPA with acceptors.

Spectral properties of the CT complexes formed between LPA and acceptors in water at 298 K.

Property

LPA–MQ

LPA–EQ

LPA–IPQ

LPA–BQ

Formation constant K (dm3 mol1) Abs. method Extinction coefficient log e (dm3 mol1 cm1) Abs. method Association constant Kf (mol L1) emission method Stern–Volmer constant KSV emission method

4150 2.65 1.74 · 105 9.52 · 104

2680 2.56 7.25 · 104 6.70 · 104

1820 2.53 3.77 · 104 5.83 · 104

2210 2.37 6.93 · 104 6.32 · 104

concentration in aqueous medium and varying concentrations of the donor but always [D][A]. Representative spectra are shown in [(Fig. 5S) Supplemental information] for LPA–MQ system. The nature of the spectra indicated that the interaction between the donor and the acceptor is of CT type. Formation constants (K) and molar extinction coefficients (e) of the CT complexes were determined spectrophotometrically using the Scott equation (Scott, 1956).

information] and the values of K and e thus determined are given in Table 7. The observed high values of K suggested that the formed CT complexes are of a strong type (Balraj et al., 2011) and the linearity of the Scott plots further supports this result.

½D½A=d ¼ ½D=e þ ð1=KeÞ

The nature and magnitude of the interaction of LPA with receptors play an important role in the pharmacokinetics of the drugs. CT interaction is one of the non covalent binding forces which explains the drug–receptor mechanism. In the present study, an attempt was made to study the CT interaction of LPA with the quinones by means of the fluorescence study. Fluorescence spectra were recorded at room

ð1Þ

where [D] and [A] are the initial molar concentration of the donor and acceptor, respectively and d is the absorbance. The values of K and e are determined from the gradient and intercept of the linear plot of [D][A]/d against [D]. The representative Scott plots are shown in [(Fig. 6S) Supplemental

3.5. Fluorescence studies

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8

K. Ganesh et al.

temperature in water in the range of 300–700 nm using an excitation at 255 nm for LPA. It was observed that the fluorescence of LPA was quenched by the quinones at 287 nm as a result of formation of CT complex. The experimental results indicated that the quenching efficiency increased with increasing concentration of electron acceptors (Figs. 7–10) and with increasing time. The fraction of acceptors bound to the donors was determined by using the following Eq. (2).

h ¼ ðF0  FÞ=F0

ð2Þ

where F and F0 denote the fluorescence intensities of the donor in the presence of acceptor and in the absence of acceptor, respectively. From the resulting values of h, the association constant (Kf) for LPA–MQ, LPA–EQ, LPA–IPQ and LPA– BQ systems was computed using the method described by D

D

a

b

Fluorescence intensity (AU)

Fluorescence intensity (AU)

a

c d e f

300

400

500

600

300

Figure 7 Fluorescence spectra for LPA–MQ system in water at fixed concentration of [D] = {7.8125 · 104 (curve D)} and variable concentration of [A] · 106 = {7.8125 (curve a), 1.5625 (curve b), 2.3437 (curve c), 3.125 (curve d), 3.9063 (curve e), 4.6875(curve f)} mol L1 at 298 K.

400

500

600

700

Wavelength (nm)

Figure 9 Fluorescence spectra for LPA–IPQ system in water at fixed concentration of [D] = {7.8125 · 104 (curve D)} and variable concentration of [A] · 106 = {7.8125 (curve a), 1.5625 (curve b), 2.3437 (curve c), 3.125 (curve d), 3.9063 (curve e), 4.6875(curve f), 5.4688 (curve g)} mol L1 at 298 K.

D

D

a b

a Fluorescence intensity (AU)

Fluorescence intensity (AU)

c d e f g

700

Wavelength (nm)

c d e f g

300

b

400

500

600

700

Wavelength (nm)

Figure 8 Fluorescence spectra for LPA–EQ system in water at fixed concentration of [D] = {7.8125 · 104 (curve D)} and variable concentration of [A] · 106 = {7.8125 (curve a), 1.5625 (curve b), 2.3437 (curve c), 3.125 (curve d), 3.9063 (curve e), 4.6875(curve f), 5.4688 (curve g)} mol L1 at 298 K.

b c d e f g

300

400

500

600

700

Wavelength (nm)

Figure 10 Fluorescence spectra for LPA–BQ system in water at fixed concentration of [D] = {7.8125 · 104 (curve D)} and variable concentration of [A] · 106 = {7.8125 (curve a), 1.5625 (curve b), 2.3437 (curve c), 3.125 (curve d), 3.9063 (curve e), 4.6875 (curve f), 5.4688 (curve g)} mol L1 at 298 K.

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Formation of charge transfer complexes of L-phenylalanine

9

Ward (Ward, 1985). It has been shown that for equivalent and independent binding sites (Eq. (3)):

where n is the number of binding sites, [AT] is the total acceptor concentration and [DT] is the total donor concentration. For all the systems investigated, a plot 1/(1  h) versus [AT]/h is linear (r >0.98, for all the systems) indicating that under experimental conditions all the binding sites are equivalent and independent. The values of Kf obtained, from the plots, for LPA–MQ, LPA–EQ, LPA–IPQ and LPA–BQ systems are found to be 1.7 · 105, 7.2 · 104, 6.9 · 104, and 3.7 · 104 mol L1, respectively. The standard Gibbs energy change DG0 was calculated from the Kf values using the relation DG0 = 2.303 RT log10 Kf. DG0 values for LPA–MQ, LPA– EQ, LPA–IPQ and LPA–BQ systems were found to be 28.83, 26.78, 25.22 and 26.68 kJ mol1 respectively, indicating that the interaction between the LPA and acceptors is spontaneous in nature. Fluorescence quenching can occur by different mechanisms viz. static or dynamic or both. Stern–Volmer equation (Eq. (4)) is useful in understanding the mechanism of fluorescence quenching. F0 =F ¼ 1 þ KSV ½Q

Log10 ðF0  FÞ=F ¼ log KA þ n log10 ½Q

0.2

0.0

-0.2

-0.4

-0.6

-0.8 -5.2

-5.0

-4.8

-4.6

-4.4

-4.2

log [Q]

Figure 12 Plot of log (F0  F/F) versus log [Q] of LPA with acceptors in water at 298 K.

Table 8 Binding constants (KA) and number of binding sites (n) for LPA–MQ, LPA–EQ, LPA–IPQ and LPA–BQ systems in aqueous medium. Acceptors

KA (mol1 L)

n

LPA–MQ LPA–EQ LPA–IPQ LPA–BQ

8.1 · 106 6.2 · 105 2.1 · 105 2.7 · 105

1.3 1.2 1.2 1.1

ð5Þ where KA is the binding constant and n is the number of binding sites per donor molecule (Xu et al., 2009). In the present study, in all the cases, a plot of log10 (F0  F)/F versus log10 [Q] is linear (r >0.961 Fig. 12) and the values of KA and n are collected in Table 8. The results indicated that, the magnitude of the binding constant is in the order of LPA– MQ > LPA–EQ > LPA–BQ > LPA–IPQ. These observations are in corroboration with the results of absorption spectral and kinetic studies as enumerated earlier in this paper. The value of n, for the systems, is nearly unity indicating the presence of only one type of binding site.

6.0

F0/F

0.4

LPA-MQ r=0.98 LPA-EQ r=0.97 LPA-IPQ r=0.96 LPA-BQ r=0.99

ð4Þ

where F0 is the initial fluorescence intensity measured in the absence of quencher and F is that in the presence of quencher concentration [Q]. The Stern–Volmer constant KSV is obtained by plotting F0/F against [Q]. In all the cases, the S  V plot showed deviation at higher [Q] (Fig. 11) indicating the fluorescence quenching may occur via both static and dynamic mechanisms (Park et al., 2006; Zhou and Swager, 1995). The relationship between the fluorescence quenching intensity and the concentration of quenchers can be described by the following equation.

4.5

0.6

ð3Þ

log (Fo-F/F)

1=ð1  hÞKf ¼ ½AT =h  n½DT 

0.8

LPA-MQ r=0.90 LPA-EQ r=0.96 LPA-IPQ r=0.95 LPA-BQ r=0.97

3.0

3.6. Theoretical calculations 1.5

0.0 0.00000

0.00001

0.00002

0.00003

0.00004

0.00005

0.00006

[Q]

Figure 11 Stern–Volmer plots for the fluorescence quenching of LPA with the acceptors MQ, EQ, IPQ and BQ in water at 298 K.

To understand the foregoing experimental observations on the CT complex formed between LPA and acceptors, we have performed the optimization of LPA, MQ, EQ, IPQ and BQ using Density Functional Theory with the Backle3LYP hybrid functional, by using a basis set of 6-31G. Computations have been performed using the Gaussian 03 Revision D.01 program package (Frisch et al., 2004). The optimized geometry of the donor along with HOMO and acceptors along with LUMO are depicted in Fig. 13. In the case of LPA, the HOMO is concentrated on the ANH2 group and in the case of acceptors the

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10

K. Ganesh et al.

MQ LUMO (-4.4017 eV)

LPA HOMO (-6.3481eV)

EQ LUMO (-4.3522 eV)

IPQ LUMO (-4.3370 eV)

The optimized structure for LPA with HOMO and acceptors with LUMO.

Figure 13

LUMO resides on the carbonyl group of the quinone ring. The energies of the frontier orbitals of the donors and acceptors along with the energy corresponding to the CT transition, DE = (HOMOLPA  LUMOacceptor) (Ganesh et al., doi 10.1016/j.molstruc.2012.09.062; Cho et al., 2012; Tejerina et al., 2012), for all the systems are shown in Fig. 14. It is evident from the figure that the DE depends on the nature of the substituent present in the quinone and the order of the strength of acceptors is similar to that observed in the spectral studies.

EQ

IPQ

BQ

ΔΕ = 1.9464

Energy (eV)

ΔΕ = 2.0111

-5.0

ΔΕ = 1.9959

LUMO

ΔΕ = 2.0155

MQ

-5.5

As a representative case, the Mulliken charges of various atoms of MQ, LPA and LPA–MQ CT complex were calculated using DFT [B3LYP-631G++(d,p)] basis set in the gas phase. The electronic charges thus computed, for selected atoms are given in Table 9. It is interesting to compare the charge distribution in MQ with that reported in chloranil (Shukla et al., 2012). In the case of chloranil the four carbon atoms attached to Cl-atom (CACl) are similar and likewise the two carbonyl carbon atoms (C‚O) possess exactly similar

Table 9 Mulliken electronic charge (a.u) on various atoms of MQ, LPA and LPA–MQ complex using DFT B3LYP (631G++(d,p) basis set calculation.

-4.0

-4.5

BQ LUMO (-4.3326 eV)

-6.0

HOMO of LPA -6.5

Figure 14 Relationship between energies of HOMOLPA and LUMOAcceptor.

Atom number

MQ

C10 C11 C12 C13 C14 C15 Cl1 Cl2 Cl3 O3 O4 O5 C7 C8 C9 N1 O1 O2

0.459 0.166 0.200 0.133 0.093 0.197 0.319 0.304 0.267 0.423 0.404 0.174

LPA

LPA–MQ

0.252 0.831 0.327 0.374 0.421 0.402

0.200 0.364 0.226 0.521 0.154 0.457 0.363 0.288 0.267 0.387 0.402 0.327 0.328 0.826 0.355 0.328 0.418 0.441

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Formation of charge transfer complexes of L-phenylalanine electronic charges. However in the case of MQ the charges on all the atoms are found to be different. The electronic charges on the carbonyl atom are relatively less (0.200, 0.197 a.u)

O

Cl

Cl

Cl

> O

MQ

O

Cl

Cl

Cl

O

O

Cl

Cl

Cl O

Cl

Cl O

IPQ

4. Conclusions The charge transfer properties of 1,4-benzoquinones possessing varying alkoxy substituents with LPA were investigated. Various spectral techniques have been employed to characterize the CT complex of these interactions that indicated that the amino group of the amino acid acts as a donating site and the carbonyl group of the quinones behaves as a accepting/recepting site. In all the cases, the stoichiometry of the CT interaction was found to be 1:1. The trends in the pseudo first order rate constants and formation constants showed that the strength of the complex formation is in the order of LPA–MQ > LPA–EQ > LPA–BQ > LPA–IPQ. The observed equilibrium and kinetic properties of these acceptors were found to be well supported by the theoretical calculations.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.arabjc.2014.10.020. References

A preliminary attempt has been made to correlate the results (i.e., formation constant Kf) with Taft’s polar and steric constants (Shorter, 1982). The results of the correlation analysis are shown below:

Kf ¼ 3835 Es þ 3606 ðr ¼ 0:87; n ¼ 4Þ

O

>

BQ

EQ

3.7. Correlation analysis

ðr ¼ 0:99; n ¼ 4Þ

O Cl

>

when compared to those of chloranil (0.734 a.u). These observations may be due to the presence of an electron donating methoxy substituent in the case of MQ. On complexation with LPA charges of LPA were found to vary from atom to atom as shown in Table 9. The results of spectral and MO studies indicated that the ANH2 group of LPA acts as the donor in the CT complexation with MQ. The results depicted in Table 9 indicated the charge of N-atom of LPA decreased drastically from 0.374 to 0.328 a.u. on complexation with MQ. Consequently the charges on the carbonyl atoms of MQ were found to increase from 0.200 to 0.226 and 0.197 to 0.457 a.u. This clearly indicated that an appreciable amount of electronic charge has been transferred from the ANH2 group of LPA to MQ through CT complex formation. This result is also well supported by the calculated dipole moments of the donor and acceptor. Dipole moments of MQ, LPA and LPA–MQ CT complex were calculated to be 3.1450, 1.7609 and 1.5922 D respectively. The dipole moment of the chloranil is zero. The higher dipole moment of MQ suggested that the electronic charge distribution in this molecule is highly asymmetric. A decrease in dipole moment of both donor and acceptor, observed on complexation is a clear indication of charge transfer from LPA to MQ.

Kf ¼ 12656r þ 4043

The above observations indicated that the strength of the acceptor decreases in the order: O

O

O

11

ð6Þ

ð7Þ

The good correlation obtained, between the association constant of the CT complexes and Taft’s polar constant, indicated that the electronic effects of the substituents play a significant role in governing the reactivity of the quinones when compared to steric factors which showed a poor correlation. The positive correlation observed between Kf and r* (Eq. (6)) indicated that with an increase in electron releasing power of the alkoxy substituent, the quinone becomes a weaker acceptor. Hence, isopropoxy substituted quinone is the weakest among the chosen acceptors as the i-Pr group is the strongest electron releasing when compared to other substituents.

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Please cite this article in press as: Ganesh, K. et al., Spectroscopic studies on the formation of charge transfer complexes of L-phenylalanine with 2,3,5-trichloro-6alkoxy-1,4-benzoquinones in aqueous medium. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.10.020