Electrochemical Investigation of Some Pharmaceutical Compounds at Mercury Electrode

Introduction

The biological activity of aryl azomethine derivatives is well known and established in the literature.¹ It has been used as antitumor,² anticancer,³ antidiabatic,⁴ antiviral agents.⁵ Substituted aryl azomethine triazole have important applications in microbiology as bactericidal,⁶ and fungicidal effects⁷ and pharmacological activities^8,9 in addition to their uses in ulcer treatment and prevention.¹⁰ and antihypertensive agents to lower blood pressure.¹¹ Triazoles  studies are also interested in many subjects because of their synthetic characteristics and other theoretical aspects.¹² Azomethine prodrugs of (R) α- methylhistamine are potent histamine H₃ receptors.¹³ Azomethines not only serve as a valuable tool for pharmacological studies related to histamine H₃ receptors but also represent a promising approach to achieve therapeutic applications  of histamine H₃ receptors against (R) α – methylhistamines. Several Schiff base complexes of transition metals have been synthesized and studied at different electrodes.^14-16 Azomethines have found additional uses as polymer organic frameworks (POFs) for H₂ and CO₂ sequestering.^17,18 This is a result of their large surface area.^19,20 They have further been used as epoxy-derivatives for the preparation of thermostable and thermoconductive polymers.^21-23 The thermal stability of the azomethines is courtesy of the rigid imine bond. Their thermal stability and thermal conductivity have been exploited for use as electrical isolators and adhesives in motors, transformers and integrated circuits.

Azomethines have been used in plastic electronics such as organic field-effect transistors, photovoltaic devices, and electrochromic devices. For example, Sek et al. synthesized a series of triphenylamine (TPA) oligomers that are normally used as hole-transporting materials in organic light emitting diodes.²⁴

Convolution transforms have been used in this work to assess the electrochemical data^25-29 of 3- arylazomethine-1,2,4-triazole derivatives. The main advantage of this technique is the possibility of using all the data obtained from cyclic voltammetric experiment instead of only involving the data concerned with the peak magnitude. Convolutive transforms were found to provide high accuracy in mechanism diagnosis and rate constant determination. The inverse square root of time convolution or semi integral of the current is evaluated via the history dependent integral.²⁶

The aim of the described work here is to reports the electrochemical behaviour of some 3- arylazomethine-1,2,4-triazole derivatives, which have a biological activity, at mercury electrode in universal buffer solution via various voltammetric methods in order to give some light on the elucidation of the mechanistic pathway and determination of the heterogeneous and homogeneous parameters of the investigated compounds.

Experimental

Chemicals

The compounds were prepared according to the procedure reported in literature.³⁰ A stock solution of 2.5 x 10^-3 M of each arylazomethine triazole compound was prepared in ethanol. Britton–Robinson³¹ buffers in the pH range 2 – 12 were prepared. The nomenclature and structure of the investigated compounds are indicated in scheme 1.

Scheme 1 Click here to View scheme

 

Apparatus and Techniques

Cyclic voltammetric studies were carried out using the polarographic Analyzer (from EG & G) model 264 A and HMDE (hanging mercury drop electrode) with a surface area 2.6×10^-4 m², model 303A, as working electrode, Ag/AgCl as a reference electrode and Pt wire as a counter electrode. Data processing and digital simulations were performed using a software package (EG & G) Condecon-Condesim (EG & G). Coulometric measurements for calculation the number of electrons was performed using digital coulometer model 179 (from EG & G).

Controlled Potential Coulometry (CPC) Measurements

The charge accumulated during the electrolysis of the compounds is given by the relation:

Q = nFW/M                                            (1)

Where F is the Faraday constant (96485 Coulombs/ equivalent) and the other symbols have their usual meaning.

In CPC measurements, firstly the condenser current of the inert electrolyte was measured after application of a stream of N₂ gas to the working electrode (mercury pool) then the measurements continued until the background current exhibits a constant value of charge. Then 0.5 ml of the aryl azomethine derivatives solution (1×10^-3 M) was introduced to the coulometry cell, the potential was selected at the top of the voltammetric peak current, and the electrolysis process was run until constancy the current. The amount of consumed charge (Q) was recorded directly from coulometer and the obtained data were given in Table 1 indicate that the cathodic reduction process consumed two electrons /depolarizer molecule.

Table 1: Indicates the values of the number of electrons involved in mechanistic pathway via CPC.

Compound	Substituent	pH	wt x 104, g	-E,V	Q x 102, C	n
I	m-OH-naphthol	3.1	1.58	1.1	12.68	1.98
		8.4	1.75	1.5	13.83	1.95
II	m-OH-phenol	3.0	1.19	1.2	20.58	2.1
		8.2	1.87	1.62	19.09	1.99
III	o-OH-phenol	3.1	1.32	1.28	12.80	1.89
		8.4	1.67	1.61	16.45	1.92

 

Where wx10⁴ is the weight of aryl azomethine triazole compound, Qx10² is the number of charge in coulomb and n is the number of electrons involved in the reaction.

Results and Discussion

Cyclic Voltammetry and Convolutive Voltammetry

Figure 1 indicates an example of cyclic voltammograms of the investigated aryl azomethine triazole compounds in universal B.R. buffer solution at pH 3.1 and at scan rates 200, 500 and 1000 mV.s^-1. It was found that the compounds under consideration exhibit one well-defined cathodic peak at scan rates ≤ 500 mV.s^-1, while at scan rates more than 500 mV.s^-1 the voltammograms exhibit a small anodic peak in the reverse scan confirming a fast chemical reaction follow and coupled with electron transfer. Also, the shift of  E_p to more negative potential and increasing the difference between E_p and E_p/2 (E_p –E_p/2) values with scan rate confirm the sluggish of charge transfer.³²

Figure 1: Cyclic voltammograms of the investigated aryl azomethine triazole compounds (I), (II) and (III) in B.R. buffer solution at pH 3.1 and at various scan rates. Click here to View figure

 

It was observed  that the potential of the cathodic peak  (E_p) varies with the logarithmic   of scan rate according to the eq.(2).³³

E_p = -1.14(RT/αn_aF) + (RT/αn_aF) ln (k_f,_h/D^1/2) – (RT/2αn_aF) ln (αn_av)                (2)

Linear correlations were obtained on plotting of E_p vs. log v, and the cathodic symmetry coefficients (α) were calculated  from the slopes of these plots at the selected pH values.  Also, the symmetry coefficients (α) were calculated from the following equation³⁴:

Ep – E_p/2 = 1.857 (RT/α_naF)                                                 (3)

and were found to be less than 0.5 when n_a = 1 (Table 2), confirming the sluggish nature of the reduction reaction.

Table 2: Values of half peak width (E_p-E_p/2) and transfer (α) of the aryl azomethine triazole compounds under investigation at pH’s 3.1 & 8.4, T = 25⁰C, and v = 0.5 V.s^-1.

Compound	pH	Mol. wt	Ep – Ep/2	α(na = 1)
I	3.1	238	123	0.39
	8.4		137	0.35
II	3.0	188	115	0.41
	8.2		127	0.37
III	3.1	188	111	0.43
	8.4		123	0.39

 

For irreversible charge transfer,³⁵ the peak current (i_p) can be related to the square root and the concentration of the depolarizers (1.25 x 10^-4 M) via the following equation:

i_p = 2.99 x 10⁵ n (αn_a)^1/2 AD^1/2Cv^1/2                               (4)

At different pH values, it was noted that the investigated compounds exhibit diffusion character of the current with some adsorption contribution due to a slight deviation from the origin of i_p vs. v^1/2 plot.³⁶ At scan rate ≥ 1000 mV.s^-1 the heterogeneous rate constant (k_s) was computed from the voltammograms using the peak potential separation, ΔEp, versus dimensionless parameters constants ψ.^37,38 (Table 3).

Table 3: Values of k_s determined experimentally and theoretically of aryl azomethine triazole compounds under consideration at 25^oC.

Compound	pH	ks x104 (cm.s-1)
		Ref.39	Ref.40	Simulated method
I	3.1	6.2	5.8	6.4
	8.4	4.8	4.6	4.1
II	3	5.7	5.5	5.4
	8.2	3.1	2.9	2.8
III	3.1	5.9	6.1	6
	8.4	4.1	4.2	4.4

 

I₁ convolution^39-41 was used for determination of mass transfer coefficient of the electroactive aryl azomethine triazole compounds from Eq. (5)⁴²:

I_lim = nFAC/√ (D)^1/2                            (5)

where I_lim is the value of I₁ transforms at extreme  potential  past the peak,  the other symbols  have their known definition. The mass transfer coefficients (D) of the investigated aryl azomethine triazole compounds were computed via Eq. (5) and cited in Tables 4. The I₁ vs. E plot which shown in Fig. 2 exhibits a large distance between the reductive and oxidative sweep which confirms the sluggish kinetics of the two electrons transferred. Also, the reverse sweep does not return to initial current (i = 0) due to a fast chemical process following the electron transfer.

Table 4: Mass transfer coefficient (D) of the aryl azomethine triazole compounds computed via different methods at 25^oC.

Compound	pH	Dx106 cm2.s-1
		A*	B	C
I	3.1	5.3	5.7	5.2
	8.4	4.6	4.3	4.8
II	3.0	6.8	6.7	6.9
	8.2	3.1	2.9	2.8
III	3.1	5.9	6.1	6.0
	8.4	4.1	4.2	4.4

 

*A Values determined from CV via Eq. (4), B From I_lim via eq. (5), and C via eq. (6).

Figure 2: The I1 convolution of aryl azomethine triazole compound (I) at a scan rate of 1000 mV.s-1. Click here to View figure

 

The Equation used to determine the mass transfer coefficient (D) of aryl azomethine triazole compounds is the following one^43,44:

I_lim = i_p/3.099(α n_a v)^1/2                       (6)

Chronoamperometry

Chronoamperometry experiments were carried out by stepping the potential from the initial potential (-0.6 V) to final potential till -1.20 V and the current was plotted versus time. The captured chronoamperograms of 2.5×10 ^-4 mol L^-1 solution of the aryl azomethine triazole compounds (I -III) were recorded at a glassy carbon electrode. Figure 3 shows the i – t plot of aryl azomethine triazole compound (I) which reveals that the current decreases with  increasing the time of the experiment.

Figure 3: Chronoamperogram of the investigated aryl azomethine triazole compound (I).Click here to View figure

 

As indicated the current was transited from initial potential to the steady-state reaction, controlled by the rate of mass transfer of the reduced aryl azomethine triazole compounds toward the surface of electrode according to Cottrell equation described by equation (7),⁴⁵

i = nFAC√D/√πt                                                          (7)

where; i, the current; n, the number of electrons involved; F, Faraday constant; D, mass transfer coefficient; C^bulk, concentration of the species in the bulk and t, time. The presentation of  i vs 1/√t exhibits linear plot and the mass transfer coefficient was determined from its slope (Table 5).

The k_f (forward rate constant), of the  investigated aryl azomethine triazole compounds was calculated from equation 8,⁴⁵

(t) = – βI₁ + u                              (8)

where u = nFSC^bulkk_f(D)^1/2 and β = k_f(D)^1/2. From the slope and the intercept of i_(t) vs. I₁ at I₁ = 0, the magnitude of  k_f can be obtained.

The variation of the heterogeneous rate constant with the electrode potential is presented using Butler-Volmer relationship.via equation (9)⁴⁶

The transfer coefficient, α, was calculated from the slope of ln k_f vs. (E_f – E^o) plot which derived from Butler-Volmer equation and found to be 0.31± 0.02, while k_s value (standard rate constant) was  6.3×10^–4  ± 0.1 cm s^-1 (Table 5).

Table 5: Values of  k_s, D and α of the compounds under consideration  determined from chronoamperometry  experiments  at 22^oC.

Compound	pH	ks x 104 (cm. s-1)	Dx106 (cm2.s-1)	α
I	3.1	6.3	5.6	0.32
	8.4	4.7	4.5	0.29
II	3.0	5.8	5.2	0.31
	8.2	3.6	4.1	0.27
III	3.1	6.5	5.9	0.30
	8.4	4.4	4.6	0.28

 

Digital Simulation

In this work, numerical simulation method was used for examining the values of the heterogeneous and homogeneous parameters determined experimentally via various electrochemical techniques as well as knowing the true nature of mechanistic pathway of the electrode reaction. In general the matching between the theoretical voltammograms with the captured one, confirm the accuracy of the determined parameters.^47,48 The generated cyclic voltammograms have been performed using Condesim software Package supplied from EG & G.

In this article, the mechanistic pathway of the compounds under consideration was determined from a digital simulation for the following models: i- E_revC_rer; ii- E_revC_irr; and iii- E_qC_irr (Figure 4). As shown the difference between the captured cyclic voltammograms (Figure 1) and the generated models of E_revE_rev & E_revC_irr (Figure 4) confirming the validity and accuracy of the proposed E_q C_irr mechanism.

Figure 4: Simulated cyclic voltammograms of ErevCrev, ErevCirr  & EqCirr. Click here to View figure

 

The following are the electrochemical parameters used in simulation process:

i- mass transfer coefficient of triazole compounds (D); ii- standard electrode  potential (E⁰); iii- initial concentration of the arylazomethine triazole compounds (C mol.l^-1); iv- standard heterogeneous rate constant (k_s, cm.s^-1); v- scan rate (V.s^-1); vi- temperature (K^-1); vii- homogeneous chemical rate constant (k_c s^-1); and  the cathodic symmetry coefficient (α_c).

Figure 5: Matching between experimental (- – -) and simulated (―) cyclic voltammograms  of compound (I) at pH 3.1 and sweep rate of 1000 mV.s-1. Click here to View figure

 

Figure 5 exhibits well matching between the experimental voltammograms and the theoretical voltammograms of E_qC_irr model of the aryl azomethine triazole compound (I) at pH 3.1 and a scan rate of 1000 mV.s^-1. Table 6 shows the measured values of the experimental and theoretical electrochemical parameters which indicate the validity and the accuracy of the electrochemical parameters calculated from the experimental techniques.

Table 6: Values of peak characteristics, kc, α, and E0 determined via theoretical and experimental work at a sweep rate of 1000 mV.s-1.Click here to View table

 

The kinetic convolution I₂ was used for determination of homogeneous chemical rate constant (kc). This procedure was done via introducing different values of k_c until a value is obtained that returns I₂ to zero at the end of the return sweep. A diagrammatic examples of the function I₂ – E plot at the true value of kc is shown in Fig. 6. The true k_c valueof the chemical step is 4.5 s^-1  for the aryl azomethine triazole compound I at pH 3.1 (Table 6).

Figure 6: Kinetic convolution, I2, of aryl azomethine triazole (I) at pH 3.1 and sweep rate of 1000 mV.s-1. Click here to View figure

 

Differential Pulse Polarography

The differential pulse polarographic parameters of the aryl azomethine triazole compounds under investigation (E_p, w^1/2) are found to be pH – dependent, indicating that the H⁺ ions are participating in the electrochemical reaction³⁵ (Table 7). Figure 7 shows the dp-polarogram of the azomethine triazole compound (I) recorded at pH 3.1.  Experimental investigation of aryl azomethine triazole compounds under consideration  revealed that increased irreversibility of the electrode reaction  with increasing the half peak height (w^1/2), the pH of the medium and /or molecular weight of the investigated aryl azomethine triazole compounds³⁵ Table 7.

Table 7: Data obtained from dp polarography of the investigated aryl azomethine triazole compounds at 25^oC.

Compound	Mol. wt	pH	w1/2	-Ep, mV
I	238	3.1	122	1.23
		8.4	139	1.59
II	188	3.0	112	1.18
		8.2	129	1.49
III	188	3.1	109	1.17
		8.4	125	1.42

 

Figure 7: DP polarogram of aryl azomethine triazole compound I at pH 3.1. Click here to View figure

 

Mechanistic Pathway

Controlled potential coulometry experiments revealed that the electrolysis process of the aryl azomethine triazole compounds (I, II, and III) consumed 2 electrons / molecule  in acidic, neutral and alkaline solutions.

IR (KBr optics) spectrum of the products of electrode reaction due to saturation of the active group produce a broad band at ~ 3315 cm^-1 (stretching) confirming the  finger print of CH2-NH-) group in the products. All these experimental evidence indicate that the electrode reduction pathway consumes two-electron which convert the initial active aryl azomethine triazole species to an inactive aryl azomethine triazole compounds due to the secondary amine group (CH₂-NH-).

According to above, the reduction of the investigated compounds occurs on the – N = C- center in two irreversible consecutive one – electron transfer, the potential of which overlap i.e E⁰₁ = E⁰₂. It is assumed that the electron transfer is preceding by a fast proton addition then followed by another protonation i.e. H⁺, e^–, e^– , H⁺ which is confirmed from the shift of E⁰ with an increase in pH. Also from this behavior, it was concluded that the azomethine group is reduced in the protonated form to give anion radical in the first step and the second step is corresponding to the formation of secondary amine.

The obtained results indicated that the mechanism of the electrode pathway of some 3- arylazomethine-1,2,4-triazole derivatives  can be summarized  as follows.

Ar- N = CH – Ar’ – OH + H⁺ == Ar- ⁺N(H) – CH – Ar’ -OH             1

+ e^– == Ar- N(H)  – ^.CH – Ar’- OH                           2

+ e^–  + H⁺ == Ar-CH₂NHAr^‘ – OH                            3

Ar-CH₂NHAr^‘ – OH  === Ar-CH₂NHAr^‘ = O  + H⁺                           4

 

Ar = triazole ring and Ar’-OH = o-naphthalene, p-hydroxy phenol and o-hydroxy  phenol.

As shown the mechanistic pathway of electrode reaction proceeds in  the sequence H⁺, e^–, e^–_,H⁺, i.e EEC mechanism.

Conclusion

The electrochemical behavior of some pharmaceutical compounds was studied in universal aqueous buffer series at mercury electrode using cyclic voltammetry, chronoamperometry, convolution & deconvolution transforms, and dp polarography techniques. The number of electrons participating in electrode reaction was determined for elucidation of the mechanistic electrode pathway.  Digital simulation method was used to confirm the nature of electrode reaction and the accuracy of the  experimental chemical and electrochemical parameters  via matching between the experimental and  theoretical cyclic voltammograms.

Acknowledgements

This project was supported by King Saud University, Deanship of Scientific Research, College of Science, Research Center.

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