Driving Forces for the Mutual Conversions ... - ACS Publications

11694

J. Phys. Chem. B 2008, 112, 11694–11707

Driving Forces for the Mutual Conversions between Phenothiazines and Their Various Reaction Intermediates in Acetonitrile Xiao-Qing Zhu,* Zhi Dai, Ao Yu, Shuai Wu, and Jin-Pei Cheng Department of Chemistry, the State Key Laboratory of Elemento-Organic Chemistry, Nankai UniVersity, Tianjin 300071, P. R. China ReceiVed: May 9, 2008; ReVised Manuscript ReceiVed: June 18, 2008

The thermodynamic driving forces (defined as the enthalpy changes or redox potentials in this work) of the 18 phenothiazines and their analogues, phenoxazine, N-methyl-dihydrophenazine, 9H-thioxanthene, 9Hxanthene and 9,10-dihydro-N-methylacridine, to release hydride, hydrogen atom, proton, and electron in acetonitrile, the thermodynamic driving forces of the radical cations of the phenothiazines and the analogues to release hydrogen atom, proton, and electron in acetonitrile, and the thermodynamic driving forces of the cations of the phenothiazines with two positive charges and their analogues to release proton in acetonitrile were estimated by using experimental methods. The effect of the remote substituents on the 11 determined thermodynamic driving forces were examined according to Brown’s substituent parameters; the results show that the values of the 11 thermodynamic driving forces all are linearly dependent on the sum of Brown substituent parameters (σ+) with very good correlation coefficients, which indicates that for any one- or multisubstituted at para- and/or meta-position phenothiazines and their various reaction intermediates, the 11 thermodynamic driving forces all can be easily and safely estimated from the corresponding Brown substituent parameters (σ+). The relative effective charges on the center nitrogen atom in phenothiazines and their various reaction intermediates were estimated from the related Hammett-type linear free-energy relationships, which can be used to efficiently measure the electrophilicity, nucleophilicity, and dimerizing ability of the corresponding reaction intermediates of phenothiazines and their analogues. All the information disclosed in this work could not only supply a gap of the chemical thermodynamics on the mutual conversions between phenothiazines and their various reaction intermediates in solution but also strongly promote the fast development of the chemistry and application of phenothiazines and their analogues. Introduction Phenothiazines are one class of very important organic molecules, which have a variety of important applications. In the field of medicinal chemistry, the molecules bearing the phenothiazine nucleus, such as chlorpromazine, triflupromazine, and promethazine, are widely represented in pharmaceutics of current use.1 Many recent publications in this area have adequately demonstrated their significance as antiviral, antifungal, antibacterial, antihypertensive, and anti-AIDS.2-5 At the same time, phenothiazines can be used as antioxidants for a wide variety of easily oxidizable substrates including lubricants, rubber, polymers, and some biological materials.6-8 Moreover, phenothiazines and their related analogues have been regarded as polymerization inhibitors to stop the reactions of radical polymerization which may take place during the preparation and workup of acrylic monomers or during their storage.9 Another important application of phenothiazines concerns their use as an excellent probe to study the photoionization process in photobiology, photosynthesis in chloroplasts, and solar energy storage. There are many reports on photoionization behavior of phenothiazines in different organic and micellar solutions.10-14 Another area of growing application of phenothiazine and phenoxazine compounds is as light-emitting and charge-transport materials in solid-state organic electronic devices, such as lightemitting diodes, thin-film transistors, and photovoltaic cells.15 The salts of phenothiazines are also immensely important * Corresponding author. E-mail: [email protected].

compounds and are extensively employed in dye industry and medical chemistry.16-21 As a typical example, methylene blue (MB+) not only is an important member of the thiazine dye family but also can be used as photosensitizer to produce singlet oxygen in photodynamic therapy for the treatment of cancer.22-26 The neutral and charged radicals of phenothiazines as important reaction intermediates of phenothiazines not only are quite stable but also have many special chemical properties and important roles which are evidently different from their corresponding parent compounds.27-31 Because of having many important roles in medicine, bioantioxidation and dye, phenothiazines and their various reaction intermediates have been very interesting chemical species in medicinal chemistry, antioxidant chemistry, and dye chemistry. Many famous chemists have devoted most of their time to the study on the chemistry of phenothiazines. But by systematically examining the publication on the chemistry of phenothiazines, it is clear that although the preparation, structure characterization, reaction, and applications of phenothiazines and their various reaction intermediates have been well documented, the most fundamental thermodynamic questions on the driving forces to make the mutual conversions between phenothiazines and their various reaction intermediates are not still resolved; that is, the thermodynamic driving forces of phenothiazines and their various reaction intermediates to release hydride, hydrogen atom, proton, and electron, especially in solution, are not available so far, except for some redox potentials and the homolytic bond dissociation energies of the N-H bonds in phenothiazines.32-37 Because the mutual conver-

10.1021/jp8041268 CCC: $40.75  2008 American Chemical Society Published on Web 08/26/2008

Conversions between Phenothiazines and Intermediates

J. Phys. Chem. B, Vol. 112, No. 37, 2008 11695

SCHEME 1: Mutual Conversions between Various Relative Stable Forms of Phenothiazines

sion between phenothiazines (XH) and their various reaction intermediates (XH+•, XH+2, X•, X+, and X-) directly involves the transfer of hydride, hydrogen atom, proton, and electron from XH, the transfer of hydrogen atom, proton, and electron from XH+•, the transfer of proton from XH+2, and the transfer of electron from X• and X- (Scheme 1), it is evident that the thermodynamic driving forces of XH, XH+•, and XH+2 to release hydride, hydrogen atom, and proton and the thermodynamic driving forces of XH, XH+•, X•, and X- to release electron in solution should be very important and urgently required for chemists and biochemists not only to thoroughly elucidate the detailed mechanism of the hydride and hydrogen atom transfers from phenothiazines and predict the thermodynamic stability and redox activity of phenothiazines and their various reaction intermediates in solution but also to further scientifically design and synthesize new desired phenothiazine analogues as the more efficient drugs, antioxidants, and dyes. In fact, the terrible lack of knowledge about the thermodynamic driving forces for the mutual conversions between phenothiazines (XH) and its various reaction intermediates (XH+•, XH+2, X•, X+, and X-) has seriously restricted the application of phenothiazines and the development of phenothiazines chemistry. In this paper, five main contributions can be provided. (1) The thermodynamic driving forces of the phenothiazines (XH) to release hydride anion, neutral hydrogen atom, proton, and electron in acetonitrile were determined by using experimental methods. (2) The thermodynamic driving forces of XH+• to release proton, neutral hydrogen atom, and electron were quantitatively estimated or determined. (3) The thermodynamic driving forces of XH+2 to release proton in acetonitrile were quantitatively estimated. (4) The effects of substituents at the two side rings of phenothiazine on the 11 thermodynamic driving forces were examined. (5) Distributions of effective charge at the heteroatoms in phenothiazines and their various reaction intermediates were evaluated by using Hammett-type linear free energy analyses. Beside phenothiazines (1H-3H), phenoxazine (4H), Nmethyldihydrophenazine (5H), 9H-thioxanthene (6H), 9Hthioxanthene (7H), and 9,10-dihydro-N-methylacridine (AcrH2) as their two types of analogues (4H and 5H carrying two heteroatoms and 6H, 7H, and AcrH2 carrying one heteroatom)

TABLE 1: Reaction Enthalpy Changes of the X+ with BNAH in Acetonitrile at 25 °C (kcal/mol) and Standard Redox Potentials of the Relevant Species in Acetonitrile at 25 °C (V vs Fc+/0) XH

E0 ∆Hra (XH+/0)b

Eo (X+/0)b

Eo Eo E0 (X0/-)b (X+1/-1)c (XH+2/+1)d

N(CH3)2 CH3O CH3 H Cl Br

30.9 40.3 43.1 45.5 47.1 47.7

-0.192 0.066 0.150 0.218 0.275 0.282

1H(G) -0.430 -1.205 -0.090 -1.035 0.010 -0.982 0.098 -0.954 0.159 -0.913 0.179 -0.902

-0.817 -0.563 -0.486 -0.428 -0.377 -0.362

0.371 0.550 0.616 0.673 0.690 0.699

CH3O CH3 Cl

42.9 44.0 47.2

0.141 0.180 0.276

2H(G) 0.005 -0.971 0.038 -0.966 0.157 -0.909

-0.483 -0.464 -0.376

0.595 0.631 0.692

N(CH3)2 CH3O CH3 Cl Br 4H 5H 6H 7H AcrH2f

20.2 35.3 40.9 49.2 50.0 44.1 26.9 29.9 32.2

-0.453 -0.040 0.088 0.310 0.320 0.250 -0.285 0.962e 1.146e 0.460

3H(G) -0.765 -1.412 -0.230 -1.145 -0.075 -1.010 0.230 -0.870 0.240 -0.862 0.135 -0.980 -0.468 -1.419 -0.227e -0.278e -0.787

-1.089 -0.695 -0.543 -0.320 -0.311 -0.398 -0.944

0.151 0.408 0.579 0.739 0.743 0.695 0.274

a ∆Hrxn obtained by titration calorimetry in dry acetonitrile and expressed in kcal/mol were average values of at least two independent runs, each of which was an average value of eight consecutive titrations, except the first. The reproducible is (0.5 kcal/mol. b Measure by CV in acetonitrile solution at 25 °C; V vs Fc+/0; and reproducible to 5 mV or better. c Derived from calculation according to the equation of Eo(X+1/-1) ) 1/2[Eo(X+/0) + Eo(X0/-)]. d Derived from the left wave in the CV of XH, see Figure 1a. e Derived from OSWV, because OSWV has been verified to be more exact for evaluating the standard one-electron redox potentials of analyte with irreversible electrochemical processes than CV.43 f From the literature.43

were also investigated in this work for comparison (Scheme 2) in order to dig out the structural origins of phenothiazines

11696 J. Phys. Chem. B, Vol. 112, No. 37, 2008

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SCHEME 2: Structures of Phenothiazines (1H-3H), phenoxazine (4H), N-methyl dihydrophenazine (5H), 9H-thioxanthene (6H), 9H-xanthene (7H), and N-methyl-9,10-dihydroacridine (AcrH2)

TABLE 2: Enthalpy Changes of XH to Release Hydride Anion, Proton, and Hydrogen Atom as well as the Enthalpy Changes of XH+• to Release Proton and Hydrogen Atom in Acetonitrile (kcal mol-1)a XH

∆HH(XH)

∆Hp (XH)

∆HH (XH)

N(CH3)2 CH3O CH3 H Cl Br

95.1 104.5 107.3 109.7 111.3 111.9

53.4 51.1 50.3 50.0 49.3 49.2

CH3O CH3 Cl

107.1 108.3 111.4

50.2 50.1 49.3

N(CH3)2 CH3O CH3 Cl Br 4H 5H 6H 7H AcrH2b

84.4 99.5 105.1 113.4 114.2 108.3 91.1 94.1 96.2 81.1

54.2 51.8 50.7 48.8 48.9 48.4 55.2

∆Hp (XH+•)

∆HH (XH+•)

∆Hp (XH+2)

1H(G) 78.8 80.4 80.9 81.2 81.4 81.6

30.1 25.7 24.2 23.0 21.9 21.9

73.3 76.8 77.6 78.4 78.7 79.2

11.6 10.9 10.2 9.8 9.7 9.9

2H(G) 81.0 81.1 81.5

24.5 23.7 22.0

77.6 77.9 78.8

10.9 10.0 9.7

3H(G) 75.8 78.9 80.6 81.9 82.4 79.0 75.7 73.1 76.6 73.0

33.1 27.2 25.4 21.6 21.4 20.0 29.1 -2.2 -3.0 9.2

68.6 75.1 76.9 80.0 80.4 76.3 71.4 43.8 45.7 44.2

12.0 11.3 10.3 9.8 10.0 7.1 12.2

a ∆HH-(XH), ∆Hp(XH), ∆HH(XH), ∆Hp(XH+•), ∆HH(XH+•), and ∆Hp(XH+2) are estimated according to eqs 4-9, by taking E1/2(H+/0) ) -2.307 (V vs Fc+/0), E1/2(H0/-) ) -1.137 (V vs Fc+/0).45 b From the literature.43

resulting in the special chemical activities, important biological functions, and extensive applications.

azine, 3,7-dibromophenothiazine, 3-methylphenothiazine, 3,7dimethylphenothiazine, 3-methoxyphenothiazine, and 3,7dimethoxy-phenothiazine were prepared according to literature procedures.39 All the cation salts of phenothiazines (1+-3+) were prepared from the corresponding parent phenothiazines (1H-3H) by using similar method according to the literature.40 The N-(sustitututed benzyl)-phenazonium cation salts were prepared from phenazine and methyliodide.41 Titrated Calibration Experiments. Titrated calibration experiments were performed in acetonitrile solution at 298 K on a CSC4200 isothermal titration calorimeter. Prior to use, the instrument was calibrated against an internal heat pulse. Data points were collected every 2 s. The reaction heats of BNAH with the cations of the phenothiazines and their analogues were determined by following nine automatic injections from a 250 µL injection syringe containing 2 mM of the cations of the phenothiazines and their analogues into the reaction cell (1.00 mL, containing 8 mM BNAH). Injection volumes (10 µL) were delivered at 0.5 s intervals with 300 s between every two injections. The reaction heats were obtained by area integration of each peak except the first one. Measurement of Redox Potentials. The electrochemical experiments were carried out by cyclic voltammetry (CV) by using a BAS-100B electrochemical apparatus in deaerated acetonitrile under an argon atmosphere at 298 K as described previously.42a n-Bu4NPF6 (0.1 M) was employed as the supporting electrolyte. A standard three-electrode cell consisting of a glassy carbon disk was used as working electrode, a platinum wire was used as counter electrode, and 0.1 M AgNO3/ Ag (in 0.1 M Bu4NPF6-CH3CN) was used as reference electrode. All sample solutions were about 1.5 mM. The ferrocenium/ferrocene redox couple (Fc+/0) was taken as the internal standard. Results

Experimental Section Materials. Reagent grade acetonitrile was refluxed over KMnO4 and K2CO3 for several hours and distilled over P2O5 under argon before use. 1-Benzyl-1,4-dihydronicotinamide (BNAH) was prepared according to the literature method.38 Phenothiazine, phenazine, and methylene blue (MB+Cl-) were purchased from Aldrich and were used as received. 3-Chlorophenothiazine, 3-bromophenothiazine, 3,7-dichlorophenothi-

Phenothiazines (1H-3H) and their close analogues, phenoxazine (4H), N-methyldihydrophenazine (5H), 9H-thioxanthene (6H), and 9H-xanthene (7H) as well as their corresponding salts (X+) were prepared according to conventional and convenient synthetic strategies, and the structural characterization was performed by using 1H NMR, UV-vis, and MS. The detailed synthetic routes and the representative spectral data of the target compounds are provided in Supporting Information.



Figure 2. Isothermal titration calorimetry (ITC) for the reaction heat of 3+ (G ) CH3O) with N-benzyl-1,4- dihydronicotinamide (BNAH) in acetonitrile at 298 K. Titration was conduced by adding 10 µL of 3+ (G ) MeO), 2.02 mM, every 300s into the acetonitrile solution containing BNAH (8.56 mM).

determined by titration calorimetry on a CSC 4200 isothermal titration calorimeter (Figure 2). The detailed results are also listed in Table 1. The thermodynamic driving force of the phenothiazines and their analogues (XH) to release hydride anion in acetonitrile was defined in this work as the enthalpy changes of XH to release a hydride anion (eqs 1 and 2), which can be obtained from the reaction enthalpy change of the hydride transfer to the corresponding cations (X+) from a well-known hydride donor (BNAH) in acetonitrile (eqs 3 and 4). In eq 4, ∆Hr is the enthalpy change of the reaction in eq 3, which can be determined by using titration calorimetry (Figure 2); ∆HH-(BNAH) is the enthalpy change of BNAH to release a hydride in acetonitrile, which is available from our previous work.43 The detailed enthalpy changes of the 18 XH to release hydride are summarized in Table 2.

∆HH-(XH) ) Hf(X+) + Hf(H-) - Hf(XH)

(2)

∆HH-(XH) ) ∆HH-(BNAH) + ∆Hr

(4)

Figure 1. (a) Cyclic voltammogram of 3H (G ) CH3O) (XH), (b) Cyclic voltammogram of 3- (G ) CH3O), and (c) Cyclic voltammogram of 3+ (G ) CH3O) in acetonitrile containing 0.1 M n-Bu4NPF6 as supporting electrolyte, sweep rate at 100 mV s-1.

The standard one-electron oxidation potentials of the phenothiazines and their analogues (XH, X ) 1-7) as well as the corresponding anions (X-) and the standard one-electron reduction potentials of the cations of phenothiazines and their analogues (X+) in acetonitrile all can be directly determined by using CV, because the CV spectra of the related species all show quite well reversible waves (see Figure 1). The standard two-electron reduction potentials of X+ Eo(X+1/-1) can be obtained by calculation from the corresponding one-electron redox potentials of X- and X+ according to the equation of Eo(X+1/-1) ) 1/2[Eo(X+/0) + Eo(X0/-)].42b The detailed results are summarized in Table 1. The molar enthalpy changes (∆Hr) of hydride transfer to the cations of phenothiazines and their analogues (X+) from a well-known hydride donor BNAH were

The thermodynamic driving forces of XH to release hydrogen atom and proton, XH+• to release proton and hydrogen atom, and XH+2 to release proton in this work are also defined as the enthalpy changes of the corresponding N-H bond dissociation processes in acetonitrile, which can be quantitatively estimated from eqs 5-9. The five eqs 5-9 were derived from the related thermodynamic cycles shown in Scheme 3 according to Hess’s law, which states that the heat evolved or absorbed in a chemical process is the same whether the process takes place in one or in several steps, respectively.44 In eqs 5-9, ∆HH-(XH), ∆HP(XH), and ∆HH(XH) are the enthalpy changes of XH to


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SCHEME 3: Related Thermodynamic Cycles for the Constructions of eqs 5-9

SCHEME 4: Comparison of Electron-Donating Ability of Phenothiazine and Their Analogues in Acetonitrile

release hydride, proton, and neutral hydrogen atom, respectively; ∆HP(XH+•) and ∆HH(XH+•) are the enthalpy changes of XH+• to release proton and neutral hydrogen atom, respectively; ∆HP(XH+2) is the enthalpy change of XH+2 to release proton; Eo(X+/0), Eo(XH+/0), Eo(XH+2/+1), Eo(X0/-), Eo(H0/-), and Eo(H+/0) are the standard redox potentials of X+, XH, XH+•, X-, H+, and H-, respectively. Evidently, it is not difficult to obtain ∆HP(XH), ∆HH(XH), ∆HP(XH+•), ∆HH(XH+•), and ∆HP(XH+2) in acetonitrile, if only ∆HH-(XH), Eo(X+/0), Eo(XH+/0), Eo(XH+2/+1), Eo(X0/-), Eo(H0/-), and Eo(H+/0) are available. In fact, ∆HH-(XH) can be available from the enthalpy changes of the corresponding reaction of eq 3 (Table 1), Eo(H0/-) and Eo(H+/0) can be obtained from the literature,45 Eo(X+/0), Eo(XH+/0), Eo(XH+2/+1), and Eo(X0/-) can be directly measured by using experimental methods (Table 1). The detailed values of ∆HH(XH), ∆HP(XH), ∆HP(XH+•), ∆HH(XH+•), and ∆HP(XH+2) for the 18 XH in acetonitrile are also summarized in Table 2.

∆HH(XH) ) ∆HH-(XH) + F[Eo(H0⁄-) - Eo(X+⁄0)] +⁄0)

∆Hp(XH) ) ∆HH(XH) + F[E H o(

+⁄-)

-E X o(

]

(5) (6)

∆HH(XH+•) ) ∆HH-(XH) + F[Eo(H0⁄-) - Eo(XH+⁄0)]

(7)

∆Hp(XH+•) ) ∆HH(XH) + F[Eo(H+⁄0) - Eo(XH+⁄0)]

(8)

∆HP(XH+2) ) ∆HP(XH+•) - F[Eo(XH+2⁄+1) - Eo(X0⁄-)] (9) Discussion Driving Forces of Phenothiazines to Release Electron in Acetonitrile. As it is well-known, the standard oxidation potential of XH is a very important electrochemical parameter of XH, which can be used as an indicator of the electrondonating ability of XH in thermodynamics. From the third column in Table 1, it is clear that the one-electron oxidation potentials of phenothiazines (1H-3H) [Eo(XH+/0)] range from -0.453 to 0.320 (V vs Fc+/0). Because the one-electron

oxidation potentials of phenothiazines are negative values or small positive values relative to ferrocene, phenothiazines especially attached by electron-donating groups should belong to strong one-electron donors, which means that it is easy, in general, to convert phenothiazines into the corresponding radical cations by electron transfer. In order to more intuitively compare the electron-donating abilities of phenothiazines and the five analogues (4H, 5H, 6H, 7H, and AcrH2), the six tricyclic aromatic amines were ranked in a row according to their oneelectron oxidation potentials from negative to positive (Scheme 4). From Scheme 4, it is clear that the one-electron oxidation potential of phenothiazine 1H (G ) H, 0.218 V vs Fc+/0) is larger than that of 5H (-0.285 V vs Fc+/0) but smaller than those of 4H (0.250 V vs Fc+/0), AcrH2 (0.460 V vs Fc+/0), 6H (0.962 V vs Fc+/0), and 7H (1.146 V vs Fc+/0), which indicates that the electron-donating ability of phenothiazine is smaller than that of 5H but larger than that of 4H, AcrH2, 6H, and 7H. If the six tricyclic aromatic amines may be grouped into two categories according to the number of the heteroatoms on the in-between ring, it is found that the one-electron oxidation potentials of the tricyclic aromatic amines with one heteroatom (6H, 7H, and AcrH2) are larger than those of the corresponding tricyclic aromatic amines with two heteroatoms (1H-5H) by 0.744-0.896 V. This result shows that the second heteroatom in the middle ring makes great contributions to the electrondonating ability of the tricyclic aromatic amines. The main reason could be that relative to the electron-donating force of the carbon atom group of CH2C6H5 (F ) 0.17),46 the heteroatom group of NHC6H5 in the tricyclic aromatic amines has a much greater electron-donating force (F ) -0.35 for NHC6H5).46 Because the one-electron oxidation potential of the unsubstituted phenothiazine in acetonitrile (0.218 V vs Fc+/0) is very close to that of the NADH model BNAH in acetonitrile (0.219 V vs Fc+/0),43 an important inference can be made that in vivo, the electron-donating ability of phenothiazine as a drug should be close to that of NADH coenzyme, which indicates that the



SCHEME 5: Comparison of Hydride-Donating Ability of Phenothiazine and Their Analogues in Acetonitrile

SCHEME 6: Comparison of Hydrogen Atom-Donating Ability of Phenothiazine and Their Analogues in Acetonitrile

neutral phenothiazine like NADH should be a good electron donor in vivo. Driving Forces of Phenothiazines to Release Hydride Anion in Acetonitrile. It is well-known that the standard state enthalpy change of XH to release hydride anion is a very important thermodynamic parameter of XH, which can be used as an indicator of the hydride-donating ability of XH. From the second column in Table 2, it is clear that the enthalpy changes of phenothiazines (1H-3H) to release hydride anion [∆HH-(XH)] in acetonitrile range from 114.2 to 84.4 kcal/mol. Because the enthalpy changes of phenothiazines (1H-3H) all are quite large, the phenothiazines (1H-3H) especially with strongly electron-withdrawing groups should belong to very weak hydride donors. By simply comparing phenothiazine 1H (G ) H) and its analogues, 4H, 5H, 6H, 7H, and AcrH2 (Scheme 5), it is found that the enthalpy changes of the six important tricyclic aromatic amines increase in the following order: AcrH2 (81.1 kcal/mol) < 5H (91.1 kcal/mol) < 6H (94.1 kcal/mol) < 7H (96.2 kcal/mol) < 4H (108.3 kcal/mol) < 1H (G ) H, 109.7 kcal/mol), which indicates that hydride-donating abilities of the phenothiazine is the weakest one among the six aromatic tricyclic amines. This result suggests that although phenothiazines are very good one-electron donors, they are not good hydride donors, the conversion of phenothiazines (XH) into the corresponding cations (X+) is difficult to accomplish by hydride transfer in one step. In fact, methylene blue (MB+) as a typical salt of phenothiazines can easily capture a hydride anion from many organic compounds related to our daily life. Driving Forces of Phenothiazines to Release Hydrogen Atom. From the fourth column in Table 2, it is clear that the enthalpy changes of phenothiazines (1H-3H) to release hydrogen atom range from 75.8 to 82.4 kcal/mol. By comparing the enthalpy change of phenothiazine 1H (G ) H, 81.2 kcal/ mol) and its five analogues, 4H (79.0 kcal/mol), 5H (75.7 kcal/ mol), 6H (73.1 kcal/mol), 7H (76.6 kcal/mol), and AcrH2 (73.0 kcal/mol), Scheme 6, it is found that the hydrogen atom-donating ability of the phenothiazine 1H (G ) H) is not only smaller than that of AcrH2, 5H, 6H, and 7H but also smaller than that

of 4H, which indicates that phenothiazines should not belong to good hydrogen-atom donors. The bioantioxidations of phenothiazines and their analogues could be due to their electrondonating ability rather than their hydrogen atom-donating ability. But because the enthalpy changes of the phenothiazines to release hydrogen atom in acetonitrile (75.8-82.4 kcal/mol) are much smaller than those to release hydride anion (84.4-114.2 kcal/mol), the abilities of the phenothiazines to donate hydrogen atom are quite larger than those to donate hydride anion. If the phenothiazines, especially the one with strong electron-donating group, met an oxidant which has larger affinity of hydrogen atom, such as phenolic radicals,47 it should be likely that the hydrogen atom transfers from phenothiazines to the oxidant in one step. If the comparison of enthalpy changes of phenothiazine and phenoxazine to release hydrogen atom in acetonitrile and in DMSO36b is made, it is found that the enthalpy changes of phenothiazine (81.2 kcal/mol) and phenoxazine (79.0 kcal/mol) in acetonitrile are quite close to the enthalpy changes of phenothiazine (82.2 kcal/mol)36b and phenoxazine (79.8 kcal/ mol)36b in DMSO, respectively, which indicates that the effect of the nature of solvents on the enthalpy changes of XH to release neutral hydrogen atom is quite small. Driving Forces of Phenothiazines to Release Proton. As it is well-known, the enthalpy change of phenothiazines in acetonitrile to release proton is a very important thermodynamic parameter for the measurement of the acidity of phenothiazines in acetonitrile, but no data are available from the literature so far. Table 2 shows the enthalpy changes of phenothiazines (1H-3H) to release proton in acetonitrile (48.8-54.2 kcal/mol). Because the enthalpy change values are all quite large, even though some of them carry strong electron-withdrawing groups, it can be suggested that the Brønsted acidities of phenothiazines should be very weak in acetonitrile, which indicates that it is difficult for phenothiazines to convert into the corresponding nitranions, except to meet very strong bases, such as KH. If the enthalpy changes of phenothiazine 1H (G ) H) and its analogues: phenoxazine (4H) and N-methyldihydrophenazine


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SCHEME 7: Comparison of Some Thermodynamic Parameters for Phenothiazine and Their Analogues to Release Proton in Acetonitrile

SCHEME 8: Comparison of Proton-Donating Ability of the Radical Cations of Phenothiazine and Their Analogues in Acetonitrile

(5H), to release proton are compared, it is found that the enthalpy changes of the three compounds to release proton increase in the order of 4H (48.4 kcal/mol) < phenothiazine (50.0 kcal/mol) < 5H (55.2 kcal/mol), see Scheme 7; that is, the abilities of XH to donate proton decrease in the order of phenoxazine > phenothiazine> N-methyldihydrophenazines. Because the electronegativities of the three heteroatoms O, S, and N increase in the order of O (3.5) > N (3.0)> S (2.5),48 it is evident that the magnitude of acidities of the three types of organic heterocyclic compounds is not completely controlled by the electronegativity of the three heteroatoms. In order to determine whether the value of entropy changes of phenothiazine and its analogues to release proton in solution [∆SP(XH)] is positive or negative, which has been a dispute in academe for a long time, the entropy changes of phenothiazine and its analogues to release proton in acetonitrile were estimated in this work. From the pKa values of phenothiazine and phenoxazine in DMSO, which are available from the literature,49 and the previously confirmed equations pKa(XH)MeCN ) 0.982pKa(XH)DMSO + 9.94 and ∆GP(XH) ) 1.37pKa(XH)MeCN,50 it is easy to estimate the free energy changes of phenothiazine and phenoxazine to release proton in acetonitrile; the results are 44.2 kcal/mol for phenothiazine and 42.7 kcal/mol for phenoxazine. The entropy changes of phenothiazine and phenoxazine to release proton in acetonitrile are 19.4 and 19.1 cal/mol K, respectively. Because the free energy changes of phenothiazine and phenoxazine (XH) to release proton are all smaller than the corresponding enthalpy changes, it is evident that the entropy changes of phenothiazine and phenoxazine to release proton in acetonitrile are positive rather than negative, even though the solvation of the negatively charged nitranions (X-) in polar solvents is quite larger than that of the corresponding neutral parent species (XH), which could result in the entropy decrease of the related system. This, to our best knowledge, could be the first example to estimate the entropy change of the N-H bond heterolytic dissociation in solution. Because

the entropy changes of phenothiazine (19.4 cal/mol K) and phenoxazine (19.1 cal/mol K) to release proton in acetonitrile are very close to each other, it is reasonable to suggest that the entropy change of N-methyldihydrophenazine (5H) to release proton in acetonitrile should be close to 19.4 or 19.1 cal/mol K, because N-methyldihydrophenazine is similar to phenothiazine and phenoxazine in structure. If the entropy changes of N-methyldihydrophenazine in acetonitrile is 19.4 cal/mol K, the pKa of N-methyldihydrophenazine in DMSO should be 26.6. If the entropy change of N-methyldihydrophenazine in acetonitrile is 19.1 cal/mol K, the pKa of N-methyldihydrophenazine in DMSO should be 26.7. Driving Forces of Cation Radicals of Phenothiazines (XH+•) to Release Proton and to Release Hydrogen Atom. As it is well-known, the radical cations of phenothiazine are one of the very important and familiar reaction intermediates of phenothiazines and have many important chemical properties. Because the enthalpy changes of the radical cations of phenothiazines to release proton and to release hydrogen atom both are very important thermodynamic parameters to diagnose their chemical activities, it is necessary to examine and compare the enthalpy changes of the radicals cations (1H+•-3H+•) to release proton and hydrogen atom. From Table 2, we found that enthalpy changes of the radical cations of phenothiazines (1H+•-3H+•) to release proton in acetonitrile range from 21.4 kcal/mol for 3H+• (G ) Br) to 33.1 kcal/mol for 3H+• (G ) NMe2). Because the enthalpy changes of 1H+•-3H+• to release proton in acetonitrile are not small, it is evident that 1H+•-3H+• do not belong to very strong Brønsted acids, even though they carry one positive charge. If the enthalpy changes of 1H+• (G ) H) and its analogues (4H+•, 5H+•, 6H+•, 7H+•, and AcrH2+•) to release proton are compared (Scheme 8), it is found that although the acidity of 5H+• (29.1 kcal/mol) is smaller than that of 1H+• (G ) H, 23.0 kcal/mol), the acidities of the other, especially 6H+• (-2.2 kcal/mol) and 7H+• (-3.0 kcal/mol), are much larger than that of 1H+• (G ) H). When Scheme 8 is carefully examined, it is interesting to find that the enthalpy



SCHEME 9: Comparison of Hydrogen Atom-Donating Abilities of the Radical Cations of Phenothiazine and Its Analogues in Acetonitrile

changes of the three aromatic tricyclic amines with two heteroatoms are greater than those of the corresponding analogues with mere one heteroatom by 19.9–25.2 kcal/mol, which means that the second heteroatom in the tricyclic compounds can greatly reduce the acidities of the radical cations. The main reason could be that the valence shell lone electron pair on the heteroatoms (S, N, and O) can deconcentrate the positive charge of the radical cations so as to make the acidities of the radical cations become weaker. From Table 2, we also found that that enthalpy changes of the radical cations of phenothiazines (1H+•-3H+•) to release hydrogen atom in acetonitrile range from 68.6 kcal/mol for 3H+• (G ) NMe2) to 80.4 kcal/mol for 3H+• (G ) Br). Because the enthalpy changes of 1H+•-3H+• to release hydrogen atom (68.6-80.4 kcal/mol) are much greater than those to release proton (21.4-33.1 kcal/mol), the abilities of the radical cations to release hydrogen atom in acetonitrile are much smaller than those to release proton in the same solvent. If the enthalpy changes of 1H+• (G ) H) and its analogues (4H+•, 5H+•, 6H+•, 7H+•, and AcrH2+•) to release hydrogen atom are compared (Scheme 9), it is found that the enthalpy change of 1H+• (G ) H) to release hydrogen atom (78.4 kcal/mol) is the greatest one among those of the six tricyclic compounds, which means that 1H+• (G ) H) is the weakest hydrogen-atom donor among the six radical cations with similar structures. If the enthalpy changes of the radical cations with two heteroatoms and the corresponding analogues with one heteroatoms are compared, it is clear that the hydrogen atom-donating abilities of the radical cations with two heteroatoms are much smaller than those of the analogues with one heteroatom, which indicates that the second heteroatom in the tricyclic compounds also greatly reduce the hydrogen atom-donating ability of the radical cations. Because the enthalpy changes of the radical cations of the tricyclic compounds with two heteroatoms to release proton and to release hydrogen atom are quite large, it is not difficult to understand why the radical cations of tricyclic compounds with two heteroatoms in acetonitrile are easy to be detected and characterized by EPR spectroscopy at room temperature. Driving Forces of Cations of Phenothiazines Carrying Two Positive Charges (XH+2) to Release Proton. From the last column in Table 2, we find that the enthalpy changes of cations of phenothiazines carrying two positive charges (XH+2) to release proton range from 9.7 kcal/mol for 1H+2 (G ) Cl) or 2H+2 (G ) Cl) to 12.0 kcal/mol for 3H+2 (G ) NMe2). Because the enthalpy changes of XH+2 are quite small, it is conceivable that these cations should have large acidity and could be quite unstable in the most organic or inorganic solvents. By comparing the enthalpy changes of XH, XH+•, and XH+2 to release proton, it is found that the more positive charge the species carry, the stronger acid is the species, but they do not

change according to the positive proportion linear relationship (Figure 3); the effect of the first electron releasing is markedly larger than that of the second electron releasing on the enthalpy changes (Scheme 10). Effect of Substituent on the Driving Forces of Phenothiazines and Their Reaction Intermediates. From Tables 1 and 2, it is clear that the enthalpy changes and the redox potentials of phenothiazines and their analogues are not only strongly dependent on the nature of the heteroatoms on the aromatic ring but also largely dependent on the nature of the substituents at the two side-benzene rings. In order to elucidate the effect of the remote substituents on the enthalpy changes and the redox potentials, the dependences of the remote substituents were examined on ∆HH-(XH), ∆HP(XH), and ∆HH(XH) of phenothiazines (1H-3H), on ∆HP(XH+•) and ∆HH(XH+•) of 1H+•-3H+•, and on ∆HP(XH+2) of XH+2, as well as on Eo(XH+/0) and Eo(XH+2/+1) of XH, Eo(X+/0), Eo(X0/-), and Eo(X+1/-1) of X (see Figures 4-5); the results show that the ∆HH-(XH), ∆HP(XH), ∆HH(XH), ∆HP(XH+•), ∆HH(XH+•), ∆HP(XH+2), Eo(XH+/0), Eo(X0/-), Eo(X+1/-1), Eo(X+/0) and Eo(X+2/+1) of the 11 chemical and electrochemical processes are all linearly dependent on the sum of Brown substituent parameters σ+ with very good correlation coefficients, which indicates not only that the Brown linear free energy relationship holds in the 11 chemical and electrochemical processes but also that the concerted effects of multiple substituents at the two positions vis-a`-vis the position of the ring nitrogen atom have good linear additivity on the enthalpy changes and the redox potentials. From the slopes and the intercepts of the 11 straight lines, the corresponding 11 mathematical formula (eqs 10-20)

Figure 3. Dependences of enthalpy changes of phenothiazine (b), phenoxazine (4H) (2), and N-methyldihydrophenazine (5H) (9) on the carried positive charge.


Zhu et al.

SCHEME 10: Effect of Charge on the Proton-donating Abilities of Phenothiazine and Its Analogues

can be easily derived. Evidently, for any phenothiazine (XH) and the corresponding radical cation (XH+•) with one- or multisubstituents at the para and/or meta position, it is not difficult to safely estimate the values of the corresponding ∆HH-(XH), ∆HP(XH), ∆HH(XH), ∆HP(XH+•), and ∆HH(XH+•) according to eqs 10-15, if only the corresponding Brown substituent parameters (σ+) are available, and the standard deviation of the estimations is not larger than (0.25

kcal/mol. In the same way, for any one- or multisubstituted at para- and/or meta-position phenothiazines (XH), any of the corresponding salts X+, and any of the corresponding negative anions (X-), the values of the corresponding redox potentials can also be reliably estimated from eqs 16-20, if only the corresponding Brown substituent parameters (σ+) are available, and the standard deviation of the estimations is not larger than 25 mV. Because the family of phenothiazines is very large and most of Brown substituent parameters of various substituents located at the para and meta position are easily obtained from the literature, it is evident that the 11 formula should have very extensive application in the prediction of the related thermodynamic driving forces of the various phenothiazines and their reaction intermediates to provide or capture hydride, hydrogen atom, proton, and electron.

∆HH-(XH) ) 7.56Σσ+ + 109.8

(10)

∆HP(XH) ) –1.47Σσ+ + 49.8

(11)

∆HH(XH) ) 1.57Σσ+ + 81.3

(12)

∆HP(XH+•) ) –3.15Σσ+ + 23.1

(13)

+•)

∆HH(XH Figure 4. Dependences of ∆HH-(XH) (full square), ∆HH(XH) (upward triangle), ∆HP(XH) (full circle), ∆HP(XH+•) (downward triangle), ∆HH(XH+•) (open square), and ∆HP(XH+2) (left triangle) as well as of the hydride affinities of some para-substituted benzyl cations in acetonitrile51 (right triangle) on the sum of the Brown substituent constants (Σσ+).

+2)

∆HP(XH

) 2.83Σσ + 78.5 +

) –0.65Σσ + 10.1

Eo(XH+⁄0) ) 0.202Σσ+ + 219 +⁄0)

E(X

0⁄-)

E(X

+

) 0.259Σσ + 0.099 +

) 0.141Σσ - 0.938

o(

+⁄-)

o(

+2⁄+1)

E X E X

Figure 5. Dependences of Eo(XH+/0) (9), Eo(X+/0) (b), Eo(X0/-) (2), Eo(X+1/-1) (1), and Eo(X+2/+1) ([) on the sum of the Brown substituent constants (Σσ+).

+

+

) 0.200Σσ - 0.420 +

) 0.154Σσ + 0.660

(14) (15) (16) (17) (18) (19) (20)

Evaluation of the Relative Effective Distribution in Phenothiazines and Their Reaction Intermediates. From the past chemical researches on phenothiazines, it is found that phenothiazines (XH) have many stable reaction intermediates, such as neutral and charged radicals (X•, XH+•), cation (X+), and anion (X-). These stable reaction intermediates all have many important and special chemical properties. In order to elucidate the special chemical behaviors of the reaction intermediates, the relative effective charge distributions in the various reaction intermediates of phenothiazines need to be examined quantitatively, because the effective charge density on the active center in the reaction intermediates can be used as an efficient measurement of the electrophilicity or nucleophilicity as well as the dimerizing ability of the reaction intermediates. First, we examine the position of the effective positive charge center of the cations of phenothiazines (X+). From the structure


Figure 6. Dependences of ∆HH-(XH) for 1H (9) and 2H (b) on the Brown substituent constants (σ+P).

SCHEME 11

of X+, it is clear that the cations of phenothiazines have two heteroatoms, S and N, which rises an interesting question: is the positive charge center of X+ at the S atom or at the N atom? In fact, this question has been disputed for a long time in chemistry. In order to determine the position of the positive charge center of X+, the effects of the substituents at para and at meta position relative to S atom or to N atom on the enthalpy changes of the phenothiazines to release hydride anion are examined (Figure 6). The main reason for doing this is because the substituents at para positions in the cations of phenothiazines (X+) have direct-resonance effect on the positive charge center, but the substituents at meta positions do not, which naturally makes the substituents at para positions have larger effects on the stability of the cations than those at meta positions.52 From Figure 6, it is found that the effect of the substituents at para position relative to N atom (slope ) 8.73) is quite larger than that of the substituents at para position relative to S atom (slope ) 4.37), which indicates that the positive charge center in X+ should be mainly at N atom rather than at S atom (Scheme 11); that is, the N atom rather than the S atom should be the active center of X+ in the redox reactions and electrophilic reactions of the radical cations. Second, we estimate relative effective charges on the active center in XH, XH+•, X•, X+, and X-. The method applied herein is based on the dependencies of ∆HH-(XH), ∆HH(XH), and ∆HP(XH) as well as ∆HP(XH+•) and ∆HH(XH+•) on the Brown substituent constant (σ+) (Figures 5-6), because the Hammett-type linear free-energy relationship analysis can provide a very efficient access to estimate the effective charge distribution.53 From Figures 4, it is clear that the enthalpy changes of phenothiazines to release hydride anion, neutral hydrogen atom, and proton as well as the radical cations of phenothiazines to release proton and neutral hydrogen atom are all excellently linearly dependent on the sum of Brown substituent parameters ΣσP+ with the line slopes of 7.56, 1.57, and -1.47 for phenothiazines to release

J. Phys. Chem. B, Vol. 112, No. 37, 2008 11703 hydride, neutral hydrogen atom and proton, respectively, and with the line slopes of -3.15 and 2.83 for the radical cations of phenothiazines to release proton and neutral hydrogen atom, respectively, which means that the Hammett-type linear free-energy relationship holds in the five chemical processes. According to the root cause of the Brown substituent effect, it is conceived that the sign of the line slope values reflects an increase or decrease of the effective charge on the center N atom in the phenothiazine ring, and the magnitude of the line slope values is a measurement of the effective charge change on the center N atom during the corresponding five reaction processes. To quantitatively evaluate the relative effective charge changes on the N atom during the five different reaction processes, the Lewis electron structures of phenothiazines (XH) and the corresponding cations (X+) were examined. From the two Lewis electron structures of phenothiazines and the corresponding cations, it is found that phenothiazine is a neutral molecule and has no other more favorable resonance structure; the effective charge on the N atom in phenothiazines may be defined to be zero. But concerning the cations of phenothiazines, the effective charge on the N atom cannot be defined to be +1.000, even though the cations carry one unit of positive charge; the reason is that the positive charge on the cations can easily delocalize on the molecular plane. In order to examine the additional resonance effects in the phenothiazine system relative to the corresponding separated two benzene rings, the effective charge on the methyl carbon in benzyl cation (PhCH2+) may be defined to be +1.000 as a reference because two hydrogen atoms of the methyl group in PhCH2+ cannot make the positive charge on the methyl carbon to delocalize. This definition indicates that the line slope value of 14.7 for toluenes to release a hydride anion in acetonitrile is equivalent to positive effective charge increase of one unit on the methyl C atom in going from toluenes to the benzyl cation. According to this relationship, it is easy to deduce that the line slope of 7.56 for phenothiazines to release a hydride anion is equivalent to a positive effective charge increase of 0.514 on the center N atom in going from phenothiazines to the cations of phenothiazines, which indicates that the cations of phenothiazines have additional positive charge of 0.486 to delocalize from the center nitrogen atom into other place of the cations relative to the methyl carbon in benzyl cation. In a similar way, the line slope of 1.57 for phenothiazines to release neutral hydrogen atom is equivalent to positive effective charge increase of 0.107 on the center N atom in going from phenothiazines to the neutral radicals of phenothiazines. Because the effective charge on the nitrogen atom in phenothiazines has been defined as zero, the effective charge on the N atom in the neutral radicals of phenothiazines should be +0.107. According to this relationship, it is easy to deduce that the line slope of -1.47 for phenothiazines to release proton is equivalent to effective charge decrease of -0.100 on the N atom in going from phenothiazines to the nitranions of phenothiazines; therefore, the effective charge on the N atom in the nitranions of phenothiazines should be -0.100. In addition, because the line slopes of 2.83 for the radical cation of phenothiazines to release neutral hydrogen atom is equivalent to the positive effective charge increase of 0.193 on the N atom in going from the radical cations of phenothiazines to the cation of phenothiazines, the effective charge on the N atom in the radical cations of phenothiazines can be deduced to be +0.321 according to the effective charge of 0.514 on the nitrogen atom in the cations of


Zhu et al.

SCHEME 12: Relative Effective Charge on the Center Nitrogen Atom in the Phenothiazines and Their Various Reaction Intermediates

SCHEME 13: Three Most Reasonable Resonance Structures for the Four Reaction Intermediates of henothiazine

phenothiazines ascertained above. In fact, this result can also be estimated from the line slope of -3.15 for the radical cations of phenothiazines to release proton within experimental error according to the effective charge of 0.107 on the N atom in the neutral radicals of phenothiazines ascertained above. The details of the relative effective charge on the N atom in phenothiazines and their various reaction intermediates are shown in Scheme 12. From Scheme 12, it is clear that relative to the effective charge (+1.000) on the methyl C atom in benzyl cation, the effective charge on the center nitrogen atom in the cation of phenothiazine (X+) is +0.514, which means that the center nitrogen atom is of good electrophilicity. But according to reasonable resonance structures of the cation of phenothiazine (X+) (see Scheme 13), we found that the cation still has

+0.486 positive charge to be scattered into the carbon atoms at positions 1 and 3 or 7 and 9, which indicates that the carbon atoms at the positions 1 and 3 or 7 and 9, as the center nitrogen atom, should also have good electrophilicity. But the electrophilicity of the carbon atoms should be smaller than that of the center nitrogen atom. Concerning the neutral radical of phenothiazine (X•), because of a +0.107 positive charge, the center radical nitrogen atom could have some resistance to dimerize, but the carbon atoms at the positions 1 and 3 or 7 and 9, especially at the position of 3 or 7, have favorable spin affinity to be dimerized for each other, which have been supported by experimental results.54 About the cation radical of phenothiazine (XH+•), because the center nitrogen atom carries +0.321 positive charge, the center nitrogen atom cannot dimerize for each other, but the carbon atoms at the positions 1 and 3 or 7



SCHEME 14: Most Likely Pathway for the Protonation of the Nitranion of Phenothiazine

and 9, especially at the position of 3 or 7, can be dimerized for each other because of good spin affinity.54 The hydrogen atom attached on the center nitrogen atom should be of good acidity. As to the nitranion phenothiazine (X-), because the negative charge that the center nitrogen atom carries is not too large (-0.100), the nucleophilicity of the center nitrogen atom should be quite weak, but the carbon atoms at the positions 1 and 3 or 7 and 9, especially the carbon atom at the position of 3 or 7, should have high nucleophilicity. The result indicates that if the nitranion is protonated with acid, the proton should first attack the carbon at the positions 3 or 7 to form an intermediate, 3H- or 7H-phenothiazine, and the formed intermediate then isomerizes to become a stable final product, 10H-phenothiazine (Scheme 14). Conclusions In this work, 14 substituted phenothiazines and their four important analogues were designed and synthesized. The thermodynamic driving forces of the phenothiazines and their analogues to release hydride anion, hydrogen atom, proton, and electron as well as the thermodynamic driving forces of the radical cations of the phenothiazines and their analogues to release hydrogen atom, proton, and electron were determined. After examining the experimental results, the following valuable conclusions and suggestions can be made. (1) Phenothiazines and their close analogues (4H and 5H) are very weak hydride donors, which means that the conversions of phenothiazines (XH) into the corresponding cation (X+) are generally difficult to take place by hydride transfer in one step, unless phenothiazines meet a very strong hydride donor. In fact, such strong hydride donors do not exist in vivo; that is, in vivo, the mutual conversion between phenothiazines and their cations is impossible. (2) The one-electron oxidation potentials of phenothiazines are generally quite small, even smaller than that of the redox coenzyme NADH close model BNAH (Eox ) 219 mV vs Fc+/0), which indicates that phenothiazines in vivo should be strong oneelectron donors. The bioactivities and biofunctions of phenothiazines in vivo could be related with their strong electrondonating ability. (3) Enthalpy changes of the phenothiazines to release proton in acetonitrile are not quite small (48.8-54.2 kcal/mol), which indicates that phenothiazines are not good Brønst acids, but they could be good Lewis bases. (4) Electron transfer from phenothiazines has a large effect on the proton-donating and hydride-donating abilities of phenothiazines; generally the first electron transfer has much larger effect than the second electron transfer. However, the electron transfer on the hydrogen atom-donating abilities of phenothiazines is small. (5) Because the enthalpy changes of the radical cations of phenothiazines to release proton and to release hydrogen atom are all quite large, generally much greater than 10 kcal/mol, the radical cations of phenothiazines in vivo could exist stably enough to be detected at room temperature by using EPR. (6) When the phenothiazines release proton in acetonitrile, the entropy of the reaction system is increased.

(7) For the cations of phenothiazines, although the center of the positive charge is on the N10, the carbon atoms at the positions 1, 3, 7, and 9 also have good electrophilicity, but the latter should be smaller than the former. (8) For the neutral radicals of the phenothiazines, the carbon atoms at the positions of 1, 3, 7, and 9, especially at the positions of 3 and 7, could have higher spin-activity than the center nitrogen atom. (9) For the positively charged radicals of the phenothiazines, the center nitrogen atom has no spin-activity, but the carbon atoms at the positions of 1, 3, 7, and 9, especially at the positions of 3 and 7, should have high spin-activity; the hydrogen atom attached on the center nitrogen atom has a good acidity. (10) For the nitranions of the phenothiazines, the nucleophilicity of the center nitrogen atom is not very strong, but the carbon atoms at the positions of 1, 3, 7, and 9, especially at the positions of 3 and 7, should have good nucleophilicity and can combine with some electrophilic agents. (11) The substituent effects hold excellent Hammett linear free-energy relationships on the enthalpy changes of XH to release hydride, to release hydrogen atom, and to release proton, and on the enthalpy changes of XH+• to release proton and to release hydrogen atom as well as on the redox potentials of XH, X-, and X+. Also, the substituent effects also have good additive properties for substituents at positions 3 and 7; the total effect of the substituents is equal to the sum of individual substituent effects. It is believed that the publication of this work will strongly promote the fast development of the chemistry and applications of phenothiazines and their analogues. Acknowledgment. Financial support from the Ministry of Science and Technology of China (Grant no. 2004CB719905), the National Natural Science Foundation of China (Grants no. 20332020, 20472038, 20421202, and 20672060) and the 111 Project (B06005) is gratefully acknowledged. Supporting Information Available: The detailed synthetic routes and general structure characterization of the phenothiazines and their analogues (XH) and their corresponding cations (X+), representative 1H NMR spectra of XH and X+, representative Esi-Ms spectrum of X+, representative UV spectra of X+, representative CV graphs of XH, X+ and X-. This materials is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Goodman Gilman, A.; Rall, T. W.; Nies, A. S.; Taylor, P. The Pharmacological Basis of Therapeutics, 8th ed.; Pergamon Press: New York, 1990. (2) (a) Chan, Y. Y.; Ong, Y. M.; Chua, K. L. Antimicrob. Agents Chemother. 2007, 51, 623. (b) Li, Y.; Niu, W.; Lu, J. Talanta 2007, 71, 1124. (c) Kitamura, K.; Omran, A. A.; Nagata, C.; Kamijima, Y.; Tanaka, R.; Takegami, S.; Kitad, T. Chem. Pharm. Bull. 2006, 54, 972. (d) Shirato, K.; Imaizumi, K.; Abe, A.; Tomoda, A. Biol. Pharm. Bull. 2007, 30, 331. (e) Hendrich, A. B.; Stanczak, K.; Komorowska, M.; Motohashi, N.; Kawased, M.; Michalak, K. Bioorg. Med. Chem. 2006, 14, 5948. (3) (a) Khan, M. O. F.; Austin, S. E.; Chan, C.; Yin, H.; Marks, D.; Vaghjiani, S. N.; Kendrick, H.; Yardley, V.; Croft, S. L.; Douglas, K. T. J. Med. Chem. 2000, 43, 3148. (b) Chan, C.; Yin, H.; Garforth, J.; McKie, J. H.; Jaouhari, R.; Speers, P.; Douglas, K. T.; Rock, P. J.; Yardley, V.;

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