Dependence of mechanism to thermodynamics in electrochemical oxidation of acetaminophen in the presence of different nucleophiles

Accepted Manuscript Dependence of mechanism to thermodynamics in electrochemical oxidation of acetaminophen in the presence of different nucleophiles

Hadi Beiginejad PII: DOI: Reference:

S1572-6657(18)30534-4 doi:10.1016/j.jelechem.2018.08.004 JEAC 12543

To appear in:

Journal of Electroanalytical Chemistry

Received date: Revised date: Accepted date:

13 June 2018 25 July 2018 5 August 2018

Please cite this article as: Hadi Beiginejad , Dependence of mechanism to thermodynamics in electrochemical oxidation of acetaminophen in the presence of different nucleophiles. Jeac (2018), doi:10.1016/j.jelechem.2018.08.004

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ACCEPTED MANUSCRIPT Dependence of mechanism to thermodynamics in electrochemical oxidation of acetaminophen in the presence of different nucleophiles

Hadi Beiginejad*a Faculty of science, Malayer University, 65719, Malayer, Iran.

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Tel.: +988512355404 Fax: +988512355404. E-mail:

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[email protected]

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ACCEPTED MANUSCRIPT Abstract In this work, electrochemical oxidations of three aminophenol species (4-aminophenol, N-methyl 4-aminophenol and acetaminophen) have been investigated both computationally and experimentally. The computational data were obtained using DFT (B3LYP) level of theory and

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6–311G (p,d) basis set. Also, cyclic voltammetry and controlled potential coulometry were used

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to obtain the experimental results. The results indicate that the electrochemical oxidation

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potential of studied species (EpA) is dependence on ∆Gtot , and it increases upon increasing ∆Gtot .

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The ∆Gtot of studied species, calculated by the use of a general thermodynamic cycle, were used to mechanistic study of the electrochemical oxidation of acetaminophen in the presence of

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various nucleophiles. The results show that mechanisms of the electrochemical oxidation of acetaminophen in the presence of different nucleophiles are not the same, and the mechanisms

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are dependent on the ∆Gtot species which are produced during electrolysis. It was found that the

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mechanism of the electrochemical oxidation of acetaminophen in the presence of 2-thiobarbituric

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acid in phosphate buffer solution is ECEC and in a buffer solution/acetonitrile mixture is ECECE. Finally, the calculated results were used to predict the electrochemical oxidation

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as nucleophiles.

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mechanisms of acetaminophen in the presence of 4-mercaptocoumarin, pyridine and cyanide ion

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ACCEPTED MANUSCRIPT Introduction Acetaminophen or paracetamol is a popular medicine and widely used to treat pain and fever [1-3]. According to the importance of acetaminophen, a lot of researches were reported about a chemical and biochemical reaction of acetaminophen [4-7]. Electrochemical oxidation of

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acetaminophen has been studied at various conditions such as aqueous solution with different

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pHs and non-aqueous solvents [8-14]. And numerous modified electrodes were performed for

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determination of acetaminophen in biological fluids using electrochemical methods [15-17]. The reported results indicate that acetaminophen oxidized to its p-benzoquinoneimine via two

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electron process [18-20]. The produced p-benzoquinoneimine is unstable and participates in

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different type reactions based on nucleophile which is present in the solution [21-24]. Also in the absence of the nucleophiles hydrolysis, dimerization and hydroxylation of acetaminophen were

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reported in various pHs [8,9]. According to the wide usage of acetaminophen and the importance

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of it, the electrochemical oxidation of acetaminophen in the presence of different nucleophiles has been investigated both experimentally and theoretically. In another word, the current study is

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tried to answer this question that: why the mechanism of the electrochemical oxidation of

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acetaminophen is dependent on nucleophile? To answer this question, firstly dependence of the electrochemical oxidation (EpA) of acetaminophen (1), 4-aminophenol (2) and N-methyl 4-

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aminophenol (3) to their total change of Gibbs free energy (∆Gtot ) was investigated. Secondly, the electrochemical oxidation of acetaminophen has been studied in the presence of, ptoluenesulfinic acid

(4),

4-hydroxy-1-methyl-2(1H)-quinolone (6), nitrite ion (5) and 2-

thiobarbituric acid (7) as the nucleophiles. Using dependence of the EpA to ∆Gtot [25-30], the effect of ∆G tot of the electrochemical oxidation of the species on the reaction mechanism was studied. The ∆Gtot of the oxidation of the aminophenols, intermediates and products were

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ACCEPTED MANUSCRIPT calculated at DFT (B3LYP) level of theory and 6–311G (p,d) basis set, with considering a general thermodynamic cycle (Born- Haber cycle). The results of this work indicate that thermodynamic study can be used to predict the mechanisms of the electrochemical oxidation of acetaminophen in the presence of some nucleophiles.

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Experimental

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Apparatus and reagents

An Ivium potentiostat/galvanostat (model vertex) was used to voltammetric study. A glassy

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carbon disc (1.8mm diameter) and a platinum wire were used as working electrode and counter electrode used in the voltammetry experiments respectively. The working electrode used in

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controlled-potential coulometry was an assembly of four carbon rods (31 cm2 ), and a large

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platinum gauze constituted the counter electrode. The potential of the working electrode was

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measured versus standard SCE (all electrodes from AZAR Electrode). All chemicals were prepared from Aldrich and were used without further purification. All experiments were carried

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out at room temperature. More details are described in our previous paper [30].

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Computational study

Using Gaussian 03 [31] and the B3LYP level of theory and 6-311G (p,d) basis set, the optimized structures of all studied species in the gas phase were obtained. Vibrational frequency analysis was calculated at the mentioned method, and the results indicate that there is no negative frequency. Conductor-like Polarizable Continuum Model (CPCM) with the setting ICOMP = 0, at the same level of the theory, was used to calculate solvation energies [32]. The optimized atomic radii were invoked via the solvent keyword RADII = UAHF, and then solvation free

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ACCEPTED MANUSCRIPT energies were obtained using the SCFVAC keyword. To obtain ΔGtot , the values of -6.28 kcal/mol for Gibbs free energy of H+ at gas phase [33] (ΔG 0 (g,H+)) and -262.54 kcal/mol for solvation energy (ΔG 0 (s,H+ )) in solution [34] were used. Also for a free electron at 298 K in these calculations the value of -0.86 kcal/mol was used [35].

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Result and discussion

Cyclic voltammogram (CV) of 1.0 mM of acetaminophen (1) in aqueous solution

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containing 0.2 M acetate buffer (pH = 5) is shown in Fig.1, curve-a. There are an anodic peak

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(A1 ) in 0.3 V and a cathodic peak (C1 ) in 0.25 V vs. Saturated calomel electrode (SCE). The A1 peak corresponds to the oxidation of acetaminophen (1) to its p-quinoneimine (1ox), and the C1

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peak corresponds to the reduction of 1ox to 1 within a two-electron process (Fig. 1, curve-a).

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Nearly unity of a peak current ratio (IpC1 /IpA1 ) indicates that under the experimental conditions the produced 1ox is stable at the surface of the glassy carbon electrode (GCE). Fig.1 curves b

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and c show CVs of 1.0 mM of 4-aminophenol (2) and 4-methylaminophenol (3) respectively at

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the mentioned conditions. The anodic peaks (A2 and A3 ) are corresponding to the electrochemical oxidation of 4-aminophenol (2) and 4-methylaminophenol (3) to their p-

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quinoneimines (2ox and 3ox). Comparing these CVs indicates that electrochemical oxidation

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potential varies in the order 1> 2>3. [Figure 1]

It was reported that the oxidation potentials of some amines and their substituted species depend on the total change in Gibbs free energy (∆Gtot ) of the electrochemical oxidation [27, 28]. Also, the results indicate that species with larger ∆Gtot value have more positive oxidation potential. The dependence of oxidation potential of species to their ∆Gtot is given by:

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ACCEPTED MANUSCRIPT ∆Gtot = -nF (EC-EA)

(Eq.1)

In equation 1, the EA is the oxidation potential of species. By considering the reduction of water as the cathodic reaction, ∆Gtot is calculated by Eq. 2. ∆Gtot = K + nFEA

(Eq.2)

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Where K is constant, and ∆Gtot is the total change of Gibbs free energy. The ∆G tot was calculated

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using 6–311+G (p,d) basis set, and DFT(B3LYP) level of the theory according to the Born-

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Haber cycle. Because the dependence of EA and ∆Gtot was described in previously reported articles [25, 30], it seems that the repetition of the details of the calculation of ∆G tot is not

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necessary for this work. A linear relationship between ∆Gtot and EA is shown in Eq. 2, and

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according to this equation it could be concluded that the value of oxidation potential (EA) increases upon increasing ∆Gtot . As presented in scheme 1, the calculated ∆Gtot of the

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electrochemical oxidation of species (1-3) varies in the order ∆G1 > ∆G2 > ∆G 3 . The calculated

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results indicate that electrochemical oxidation of 1 is harder than 2 and 1, and the electrochemical oxidation of 2 is harder than 3. The obtained ∆G are agreed with the

[Scheme 1]

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electrochemical oxidation potentials of species (1-3) which are mentioned above (Ep1 >Ep2 >Ep3 ).

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Fig.1, curve-a shows the CV 1.0 mM of acetaminophen (1) in an aqueous solution containing acetate buffer (pH=5.0, c=0.2 M). Also recorded CV 1.0 mM of acetaminophen in the presence of 0.25 mM p-toluenesulfinic acid (p-TSA) was shown in Fig.1, curve-b. As shown in the presence of p-TSA (2) the cathodic peak (C 1 ) decreased while the current of A1 peak remains constant. This electrochemical behavior is related to the reaction of produced 1ox and 4 at the surface of GCE. Varying the potential scan rate and concentration of p-TSA (4) indicates that in

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ACCEPTED MANUSCRIPT parallel with increasing potential scan rate or decreasing concentration of p-TSA, the peak current ratio (IpC1 /IpA1 ) increases [21]. Electrolysis a solution containing acetaminophen and pTSA (4) was performed at the potential of the A1 peak (0.49 V) using controlled potential coulometry (CPC). The results indicate that after consumption of two electrons per molecule of

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acetaminophen (1) the electrolysis was terminated. According to these data and reported results

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[21], scheme 2 is proposed for the electrochemical oxidation of acetaminophen (1) in the

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presence of p-TSA (4). In another word, the electrochemically generated 1ox reacts with 4 as a nucleophile and converts to 1a as a final product (EC mechanism). The oxidation potential of 1a

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is positive than that of 1 and the electrolysis terminated after producing 1a. The electrochemical

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oxidation of acetaminophen in the presence of nitrite ion (5) was studied, and the reported results indicate that via an EC mechanism 5a is produced as a final product (Scheme 2).

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[Figure 2]

Mechanistic studies of different species in the presence of different nucleophiles [25-30]

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indicate that when ∆Gtot of a product is less than the initial molecule, it oxidizes at the CPC

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conditions, and if ∆G tot of a product is more than starting molecule, the electrolysis is terminated because the species is not electroactive in the CPC. The calculated ∆Gtot of the electrochemical

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oxidation of 1, 4a and 5a indicate that the ∆G tot of 4a and 5a is more positive than 1. This led to the increase of the electrochemical oxidation potential of 4a and 5a. So, the oxidation of 4a and 5a are harder than the oxidation of 1 and consequently via an EC mechanism the final products (4a and 5a) are produced. [Scheme 2]

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ACCEPTED MANUSCRIPT Cyclic

voltammetry

and

controlled

potential

coulometry

were

used

to

study

electrochemical oxidation of acetaminophen (1) in the presence of 4-hydroxy-1-methyl-2(1H)quinolone (6). Fig.3, curve-b shows obtained CV of acetaminophen (1) in the presence of 6 in a mixture of phosphate buffer (pH = 2.5, c = 0.2 M) and acetonitrile (70/30, v/v). Decreasing the

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peak current ratio (IpC1 /IpA1 ) in the presence of 6 is related to the following chemical reaction

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[Figure 3]

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between produced 1ox and 6 [22].

The electrolysis a solution containing acetaminophen (1) and 6 was performed at the A1

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peak potential (0.61 V vs. SCE). The reported results indicate that after consumption 6e − per

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molecule of acetaminophen (1) the electrolysis terminated and a final product (6e) was produced via an ECECEC mechanism (Scheme 3) [22]. According to the scheme 3, the electrochemically

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generated 1ox reacts with 6 as the nucleophile and leads to 6a. Because the oxidation of 6a is

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easier than the oxidation of 1, under experimental conditions the produced 6a oxidized to 6b. The 6b converts into 6c, via another Michael type addition reaction. Also, the electrochemical

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oxidation of 6c is easier than that of 1, and it converts to 6d. Because at experimental conditions

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6d is unstable, it hydrolyzed to 6e as the final product. Scheme 3 shows the calculated ∆Gtot of the electrochemical oxidation of 1, 6a and 6c. As shown, the ∆Gtot varies in the order ∆G1 >

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∆G6a > ∆G6c. The calculated results indicate that intermediates 6a and 6c oxidize during CPC, and 6e was produced via an ECECEC mechanism at the applied potential (Scheme 3).

[Scheme 3]

The

voltammetric

investigation was performed

on the electrochemical study of

acetaminophen (1) in the presence of 2-thiobarbituric acid (7) as a nucleophile. Figure 4-I shows 8

ACCEPTED MANUSCRIPT CVs of acetaminophen (1) in the presence of various concentrations of 7. As shown, in parallel with increasing of thiobarbituric acid’s concentration, the current of the cathodic peak (IpC1 ) decreases. Recorded CVs by changing the scan rate indicates that with decreasing the potential scan rate the peak current ratio (IpC1 /IpA1 ) decreases. Figure 4-II shows normalized CVs of 1.0

–1/2

). These behaviors are related to the

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current by the square root of the potential scan rate (I/v

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mM solution of 1 at two potential scan rates. The normalized CVs are obtained by dividing the

increasing concentration of 7.

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[Figure 4]

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increase of reaction rate between produced 1ox and 7 upon decreasing potential scan rates or

A solution (0.2 M phosphate buffer, pH 7.0) containing 1.0 mmol of 1 and 1.0 mmol of

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2-thiobarbituric acid (7) was electrolyzed by the use of CPC at 0.52 V vs. SCE. Recorded CVs in

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parallel with electrolysis progress indicates that after consumption of about 3e− per molecule of 1 the anodic peak A1 disappeared [23]. Using these data, reported results of the electrochemical

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oxidation of acetaminophen (1) in the presence of 2-thiobarbituric acid [23] and spectroscopic

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results of 7c [23], scheme 4 is proposed for the electrochemical oxidation of 1 in the presence of 2-thiobarbituric acid (7). According to this scheme, 7 reacts with the produced 1ox leading to 7a.

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Because the oxidation of 7a is easier than the oxidation of 1, it oxidized to 7b. Another produced 1ox reacts with 7b, and 7c produced as a final product via an ECEC (Scheme 4) [23]. [Scheme 4]

Calculated ∆G tot of 1 and its substituted species (7a and 7c) indicates that ∆Gtot varies in the order ∆G 1 > ∆G7c> ∆G7a >. In another word, because ∆G1 is positive than ∆G7a , the oxidation

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ACCEPTED MANUSCRIPT of 7a is easier than 1, and the produced 7a oxidized to 7b during controlled potential coulometry. As shown ∆G7c is lower than ∆G 1 therefore, it should oxidize under experimental conditions. It seems precipitation of 7c during CPC prevents the oxidation of it. Therefore using CPC, the electrolysis

of

a

buffer

solution/acetonitrile

mixture

(50:50)

containing

1.0

mmol of

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acetaminophen (1) and 1.0 mmol of 7 was performed at 0.5 V vs. SCE. The obtained CVs during

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the coulometry indicate that the anodic peak A1 disappeared when the consumed charge becomes

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about 4e− per molecule of 1 (Fig. 5). Using coulometric data and calculated ∆Gtot , it can be

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concluded that 7d is produced as a final product via an ECECE mechanism (scheme5).

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[Figure 5]

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As mentioned, the results indicate that oxidation potential of substituted acetaminophen

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species is dependence to their ΔG tot . In another word, because ΔGtot of 1a is positive than that of 1, 1a cannot oxidize in CPC, and because ΔG tot of 6a and 7a are negative than that of 1, both the

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species can oxidize in CPC. The previous experiences in the relation between ΔGtot and

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oxidation potential [25-30] and good dependence of EpA to ΔGtot for substituted acetaminophen species in this research, the mechanism of the electrochemical oxidation of acetaminophen in the

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presence of some nucleophiles (8-10) were estimated without having experimental results. According to scheme 5, the electrochemically generated 1ox reacts with nucleophiles (8-10) and converts to substituted acetaminophens (8a-10a) as final products. ΔG tot of 8a-10a were calculated and it was found that for the all three species calculated ΔGtot are positive than ΔGtot of 1, therefore it seems that the electrochemical oxidation of acetaminophen (1) in the presence

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ACCEPTED MANUSCRIPT of 4-mercaptocoumarin (8), pyridine (9) and cyanide ion (10) as nucleophiles are EC and CPC terminated after consumption two electrons per molecule of acetaminophen (1) (Scheme 5). [Scheme 5]

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Conclusion

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In this work electrochemical oxidation of 4-aminophenol, N-methyl 4-aminophenol and

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acetaminophen has been investigated and dependence of electrochemical oxidation potential to ∆Gtot was studied. The results indicate that the electrochemical oxidation potential of studied

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species (EpA) is dependence on ∆Gtot , and it increases upon increasing ∆Gtot . The calculated

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∆Gtot were used to the study of mechanisms of the electrochemical oxidation of acetaminophen in the presence of different nucleophiles. The results show the EC mechanism for the

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electrochemical oxidation of acetaminophen (1) in the presence of p-toluenesulfinic acid (4) and

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nitrite ion (5), but the mechanism for the electrochemical oxidation of acetaminophen in the presence of 4-hydroxy-1-methyl-2(1H)-quinolone (6) and 2-thiobarbituric acid (7) are ECECEC

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and ECECE respectively. The ∆Gtot of studied species were calculated by the use of a general

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thermodynamic cycle. It was found that the mechanism of the electrochemical oxidation of acetaminophen is dependent on the ∆Gtot of the species produced during electrolysis. The results

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of this work indicate that the mechanism of the electrochemical oxidation of acetaminophen in the presence of 2-thiobarbituric acid (7) in aqueous solution is ECEC, but the mechanism in a buffer/acetonitrile (50/50) solution is ECECE, and this mechanism agrees with the obtained thermodynamic data. Also using calculated ΔGtot of 8a-10a, it is estimated that the electrochemical oxidation of acetaminophen (1) in the presence of 4-mercaptocoumarin (8),

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ACCEPTED MANUSCRIPT pyridine (9) and cyanide ion (10) as nucleophiles are EC and CPC terminated after consumption two electrons per molecule of acetaminophen (1). Acknowledgments I acknowledge the Malayer University Research Council and my Partners of Analytical

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Chemistry Laboratory in Malayer University for their support of this work.

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Figure Captions

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Figure 1. Cyclic voltammograms 1.0 mM of: a) acetaminophen (1), b) 4-aminophenol (2) and c) 4-methylaminophenol (3) in acetate buffer solution (c = 0.2 M, pH = 5.0); scan rate: 100 mV s-1 ,

CR

t = 25 ± 1 o C.

US

Figure 2. Cyclic voltammograms 1.0 mM of acetaminophen (1): a) in the absence and b) in the presence 0.25 mM of TSA (5) in acetate buffer solution (c = 0.2 M, pH = 5.0) at a glassy carbon

AN

electrode, scan rate = 100 mV s−1 ; t = 25 ±1 °C.

Figure 3. CVs 1.0 mM of 1: a) in the absence, b) in the presence 1.0 mM of 6, at a glassy carbon

M

electrode in water/acetonitrile (70/30, v/v) solution containing phosphate buffer (c = 0.2 M, pH

ED

2.5), scan rate = 100 mV s−1 ; t = 25 ±1 °C.

Figure 4. (I) CVs 1.0 mM of acetaminophen (1) in the presence: a) 0 , b) 1.0 and c) 5.0 mM of

PT

2-thiobarbituric acid (7) at glassy carbon electrode in phosphate buffer solution (c = 0.2 M, pH = 7.2), scan rate=50 mV/s, (II) Normalized CVs of acetaminophen (1) at scan rate a) 10 mV/s and

CE

b) 25 mV/s, t = 25 ± 1 o C.

AC

Figure 5. CVs 1.0 mmol of acetaminophen (1) in the present 1.0 mmol of 2-thiobarbituric acid (7) during CPC at 0.5 V versus Ag/AgCl in aqueous solution containing phosphate buffer (pH = 7.0, c = 0.2 M), after the consumption of: (a) 0 C, (b) 51 C, (c) 91 C, (d) 191 C, (e) 332 C, and (f) 480 C. Scan rate: 100 mV s-1 ; t = 25±1 ◦ C.

17

ACCEPTED MANUSCRIPT Scheme captions Scheme 1. Proposed mechanism for the electrochemical oxidation of acetaminophen (1), 4aminophenol (2) and 4-methylaminophenol. Scheme 2. Proposed mechanism for the electrochemical oxidation of acetaminophen (1) in the

IP

T

presence of p-TSA (4) and nitrite ion (5).

CR

Scheme 3. Proposed mechanism for the electrochemical oxidation of acetaminophen (1) in the

US

presence of 6.

Scheme 4. Proposed mechanism for the electrochemical oxidation of acetaminophen (1) in the

M

AN

presence of 2-thiobarbituric acid (7).

Scheme 5. Proposed mechanism for the electrochemical oxidation of acetaminophen (1) in the

AC

CE

PT

ED

presence of 4-mercaptocoumarin (8), pyridine (9) and cyanide ion (10).

18

Figure 1

AC

CE

PT

ED

M

AN

US

CR

IP

T

ACCEPTED MANUSCRIPT

19

Figure 2

AC

CE

PT

ED

M

AN

US

CR

IP

T

ACCEPTED MANUSCRIPT

20

M

AN

US

CR

IP

T

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

Figure 3

21

AC

CE

PT

ED

M

AN

US

CR

IP

T

ACCEPTED MANUSCRIPT

Figure 4

22

Figure 5

AC

CE

PT

ED

M

AN

US

CR

IP

T

ACCEPTED MANUSCRIPT

23

ACCEPTED MANUSCRIPT OH

O

-2H+, -2eHN

O

∆G tot=245.91 kcal/mol N

O

1ox

OH

US

-2H+, -2e∆Gtot=233.55 kcal/mol

AN

NH2

M

2

CE

∆G tot=232.89 kcal/mol

NH

2ox

O

N

3ox

3

AC

O

-2H+, -2e-

PT

ED

OH

HN

CR

IP

T

1

Scheme 1

24

ACCEPTED MANUSCRIPT OH

O

-2H+, -2eHN

O

∆Gtot=245.91 kcal/mol N

O

1ox

IP

T

1

CR

O

O

Nu

HN

O

AN

N

US

Nu (4,5)

OH

4a, 5a

OH Nu

ED

M

1ox

O Nu

AC

4a, 5a

O

CE

HN

PT

-2H+, -2e-

∆G 4a =247.47 kcal/mol ∆G 5a =254.18 kcal/mol

O

4b, 5b

O SH O

Nu 4 =

N

Nu 5 = NO2(Ref.20)

(Ref.17)

Scheme 2

25

ACCEPTED MANUSCRIPT O

OH

-2H+, -2e-

HN

O

∆Gtot=245.91 kcal/mol

N

O

1

1ox OH

N

N

O

O

-2H+, -2eOH

∆G 6a =242.64 kcal/mol

O

O

O

N

6b

O

N

N

O HO

M

O

N

OH

AN

HN

6a

CR

N

US

O OH

O

HN

O

IP

OH

(6) N

T

O OH

O

OH

Nu(6)

ED

OH

HO

O

OH

O

HN

O

6c

O

O

N

O

OH +

-2H , -2e

-

OH N

∆G 6c=241.72 kcal/mol

6c

O

N

O

AC

N

HN

O

N

CE

OH

N

PT

O

N

OH

Hydrolysis

O

O

N

OH OH N

Scheme 3 26

O

O

6e

6d

ACCEPTED MANUSCRIPT OH

O

-2H+, -2e-

1

HN

1ox

∆G 1 =245.91 kcal/mol

O

N

O

S O HN

H N

O OH

NH

S NH

T

O

O

O

O

HN

O

OH

US

HN

NH

O

O

7b

+ N

HN O

NH

O

O

OH

7c

O

PT

O

S

ED

NH O

N

AN

S

M

H N

O

S

O

∆G7a =241.87 kcal/mol

O

HN

7a

N

H N

O

-2H+, -2eO

O

7a

O

CR

H N

S

O

IP

(7) N

O

HN

O

CE

N

AC

S

HN

O

O

S

NH

HN

O OH

+

-

-2H , -2e

O

NH

O

O

O

∆G7c=245.28 cal/mol N

O

HN

O

N

7c

O

N

7d Scheme 4 27

O

ACCEPTED MANUSCRIPT OH

1

O

HN

IP

T

∆G1 =245.28 kcal/mol

1ox

SH O

(8)

O

N

AN

CN- (10)

OH

OH S O

8a

O

HN

∆G10a =252.06 kcal/mol ∆G9a =250.54 kcal/mol

CE

∆G8a =246.55 kcal/mol

O

AC

O

HN O

PT

HN

N

9a

ED

O

OH

CN

M

10a

(9) N

US

O

CR

O

O

O

S

N

CN

O

8b

O

9b

10b N

O

N

O

Scheme 5

28

N

O