Electrochemical Reduction of Arylsulfonyl Indoles

Yimeng He

A Thesis Presented to The University of Guelph

In partial fulfillment of the requirements for the degree of Master of Science in Chemistry

Guelph, Ontario, Canada

Abstract

ELECTROCHEMICAL REDUCTION OF ARYLSULFONYL INDOLES

Yimeng (Jack) He Advisor University of Guelph, 2015 Professor Abdelaziz Houmam

The indole framework has been recognized as a biologically important pharmacophore with a vast array of pharmacological effects and therapeutic applications.

The N-arylsulfonyl indole derivatives, particularly the nitro-substituted arylsulfonyl indoles, are emerging as candidates as novel HIV-1 inhibitors. The electroactive nature of indole and its ability to generate radicals have been attributed to some of its observed pharmacological effects; in this regard the indolic radicals have received wide attention.

In this thesis, a series of arylsulfonyl indoles was successfully synthesized. These compounds were subjected to electrochemical studies in an attempt to investigate their susceptibilities to reduction, the nature of the initial electron transfer mechanism, the potential bond dissociation, as well as any potential dependence on the nature of the substituent. Many aspects of the thesis are built upon the foundation laid out by the past studies on the electrochemical reduction of arylsulfonyl chlorides and arylsulfonyl phthalimides, by previous members of the Houmam group. In this regard the study also served as a further investigation of the fundamental aspects of electron transfer to organic molecules in general and to arylsulfonyl derivatives in particular. Data was compared with previously-investigated and structurally-related compounds such as arylsulfonyl chlorides and arylsulfonyl phthalimides.

Acknowledgements

My most sincere gratitude would go to my supervisor, Dr. Aziz Houmam, who not only

took me under his wings and provided me with a meaningful Master’s thesis, but was in fact the

professor who inspired me to delve into the intriguing and magnificent realm of organic chemistry during my undergraduate career. Dr. Houmam presented me with a magnificent overview of various topics in organic chemistry through his masterful and engaging teaching, which made attending his course an enjoyable and mind opening endeavor. My university career would never be nearly as meaningful and rewarding had it not been for Dr. Houmam’s unstinting guidance and continuous support. For that, I would forever be in debt to his kindness.

I would like to thank my advisory and examination committee, Dr. Adrian Schwan, Dr.

Dan Thomas, and Dr. Wojciech Gabryelski, our graduate secretary, Ms. Karen Ferraro, as well as the past and present members of the Houmam group, along with our wonderful and helpful friends and colleagues from our neighboring research groups, whose handholding and patience were largely responsible for my progress in some of the most delicate techniques that I have encountered thus far. To Emad, Kallum, Serhat, Hamida, and Ryan, and all the other unsung heroes of my graduate career – thank you for being there when I needed you, and most importantly, thank you for your forbearance. I would like to give special thanks to Dr. Emad

Hamed for his kindness in sharing his research findings on the electrochemical reduction of phthalimides. I would like to extend my gratitude to Dr. Robert Reed, whom I appreciate beyond my ability for all the technical support that he provided me for the synthesis, as well as for granting my teaching assistantship for organic chemistry – something that I had always dreamed of doing since the early stage of my undergraduate career.

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I would also wish to extend my appreciation to my past employers and coworkers whom

I met during my undergraduate co-op employment. Especially, to Dr. Satya Kadali, Dr. Vimal

Balakrishan, Dr. Kirsten Exall, and Ms. Arun Malaviyia. Though not directly involved in any

part of the thesis, their projection of professionalism and dedication, coupled with their masterful

guidance, have not only facilitated the smooth transition of my academic knowledge into

professional applications, but ascertained my desire to pursue the graduate study in chemistry as

well.

Finally this degree would not have been possible had it not been for the wholehearted support of my parents Jack Sr. and Joyce, who were always there to support me no matter how tough the goal got, and always stood by me during even the darkest hours. Thank you, mom and dad, for everything you have done for me.

List of Abbreviations

≠ ΔGο Standard activation free energy or intrinsic barrier ΔGο Standard free energy or driving force or reaction free energy ΔG ≠ Activation free energy α Transfer coefficient λ Reorganization energy

λi Internal reorganization energy

λS Solvent reorganization energy AIDS Acquired immunodeficiency syndrome BDE Bond dissociation energy CV Cyclic voltammetry DET Dissociative electron transfer DR Bond dissociation energy of the reactant DP Bond dissociation energy of the product Ep Peak potential Ep1/2 Half peak potential Ep-Ep1/2 Half peak width ET Electron transfer e- Electron E0 Standard potential Ep Peak potential EP/2 Half peak potential F Faraday’s constant HIV Human immunodeficiency virus HTS High-throughput screening K Equilibrium constant LUMO Lowest unoccupied molecular orbital n Number of electrons RX Alkyl halide ROS Reactive oxygen species SOMO Singly occupied molecular orbital SCE Saturated calomel electrode T Temperature TBAHF Tetrabutylammonium hexafluorophosphate TBATFB Tetrabutylammonium tetrafluoroborate υ Scan rate

Table of Contents Abstract ...... ii Acknowledgements ...... iii List of Abbreviations ...... v Chapter 1 – Background Information ...... 1 Preamble ...... 1 I. Electron Transfer and Bond Cleavage ...... 4 I.1 Hush-Marcus Model - Outer Sphere Electron Transfer Theory ...... 5 I.2 Savéant’s Model - Dissociative Electron Transfer Theory ...... 10 I.3 Stepwise and Concerted Electron Transfer ...... 13 I.4 Concerted - Stepwise ET Mechanism Transition ...... 17 I.5 Extensions of the Dissociative Electron Transfer Theory ...... 19 II. Indoles in Medicinal Chemistry ...... 23 II.1 Indoles as Anti-HIV-1 Inhibitors ...... 24 II.2 Arylsulfonyl Indoles in Modern Drug Disocvery ...... 25 II.3 Nitro Radical Anions and Electrochemical Behavior of Indoles ...... 27 III. Electrochemical Techniques ...... 29 III.1 The Electrochemical Cell ...... 30 III.2 Cyclic Voltammetry ...... 32 IV. Aim of the Thesis...... 36 Chapter 2 – Experimental Section ...... 37 I. Cyclic Voltammetry ...... 37 II. Theoretical Calculations ...... 37 III. Chemicals ...... 38 III. 1 Commercially Available Chemicals ...... 38 III.2 Synthesis of N-Arylsulfonyl Indoles ...... 38 Chapter 3 – Electrochemical Reduction of Arylsulfonyl Indoles ...... 41 I. Overview ...... 41 II. Results and Discussion ...... 44 II.1. Voltammetric Behavior ...... 44 II.2. Theoretical Calculation Results ...... 63 III. Deduced Electron Transfer Mechanism ...... 68 III.1. Deduced Electron Transfer Mechanism for compounds 1a – e ...... 68 III.2 - Deduced Electron Transfer Mechanism for Compounds 1f and 1g ...... 71

III.3. Comparison with Other Arylsulfonyl Compounds ...... 73 III.4. Reduction of Nitroaromatics and the Futile Cycle ...... 75 Chapter 4 – Results Pertaining to the Synthesis of Arylsulfonyl Indoles ...... 77 I.1 – Phenylsulfonyl Indole Yields ...... 77 I.2 – Yields Pertaining to the Synthesis of 1b-g ...... 78 II. 1H and 13C NMR Experiment and Data ...... 79 Chapter 5 – Conclusion and Future Work ...... 80 I.1 - Conclusion ...... 80 I.2 - Electrochemical Techniques and Drug Discovery ...... 82 II – Future Work ...... 84 II.1 – Electrolysis to Provide Further Confirmation of the N-S Bond Dissociation ...... 84 II.2 – Expansion of the Indole Library ...... 84 II.3 Surface Modification by 1-(4-Nitrophenylsulfonyl)indole ...... 85 Chapter 6 - Reference List ...... 87 Appendix ...... 93 1 – Total Energies and Coordinates ...... 93

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List of Figures

Figure 1.1 - Morse curves for an outer-sphere electron transfer at zero driving force. Adapted with permission. Copyright 2008 American Chemical Society...... 6 Figure 1.2 - Variation of the intramolecular ET rate of a series of acceptor-spacer-donor systems as a function of the driving force. Adapted with permission. Copyright 1984 American Chemical Society...... 9 Figure 1.3 - Morse curves for a concerted DET at zero driving force. Adapted with permission. Copyright 2008 American Chemical Society...... 11 Figure 1.4 - Electron transfer mechanism dependence on driving force. Adapted with permission. Copyright 2008 American Chemical Society...... 18 Figure 1.5 - Variation of α app with E for (a) 1 (0.85 mM) and (b) 2 (0.69 mM) at scan rates of 7.2, 10, 20, 30, 40, 60 and 80 Vs-1. Adapted with permission. Copyright 2008 American Chemical Society...... 18 Figure 1.6 - The bicyclic structure of indole ...... 23 Figure 1.7 - Tryptophan (a), serotonin (b) and melatonin (c) ...... 23 Figure 1.8 - Three-electrode electrochemical cell employed for the study ...... 31 Figure 1.9 - Sample CV plot for the cathodic peak of an irreversible ET ...... 34 Figure 1.10 - Sample CV plot for the anodic and cathodic peaks of a reversible ET ...... 34 Figure 3.1 - Cyclic voltammetry pertaining to the electrochemical reduction of 1.94 mM 1- (phenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile with 0.1 M Bu4NBF4 at 0.2 Vs-1 at ambient temperature...... 45 Figure 3.2 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 1.94 mM 1-(phenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1). All scans were carried out on a glassy carbon working electrode in acetonitrile at ambient temperature...... 46 Figure 3.3 - Slope of Ep vs log (v) for obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 1.94 mM 1-(phenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1)...... 46 Figure 3.4 - Cyclic voltammetry pertaining to electrochemical reduction of 1.99 mM of 1-(4- methylphenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile with 0.1 M -1 Bu4NBF4 at 0.2 Vs at ambient temperature...... 48 Figure 3.5- Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 1.99 mM of 1-(4-methylphenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1). All scans were carried out on a glassy carbon working electrode in acetonitrile at ambient temperature...... 48 Figure 3.6 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 1.99 mM 1-(4-methylphenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1)...... 49 Figure 3.7 - Cyclic voltammetry pertaining to the electrochemical reduction of 1.95 mM 1-(4- methoxyphenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile with 0.1 M -1 Bu4NBF4 at 0.2 Vs at ambient temperature...... 50 Figure 3.8 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 1.95 mM 1-(4-methoxyphenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, and 10 Vs-1)...... 51

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Figure 3.9 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to the electrochemical reduction of 1.95 mM 1-(4-methoxyphenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, and 10 Vs-1)...... 51 Figure 3.10 - Cyclic voltammetry pertaining to the electrochemical reduction of 2.13 mM 1-(4- chlorophenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile at 0.2 Vs-1 with 0.1 M Bu4NBF4 at ambient temperature...... 53 Figure 3.11 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 2.13 mM 1-(4-chlorophenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 2.0 Vs-1, 5.0 Vs-1, and 10 Vs-1)...... 53 Figure 3.12 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to the electrochemical reduction of 2.13 mM 1-(4-chlorophenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 2.0 Vs-1, 5.0 Vs-1, and 10 Vs-1)...... 54 Figure 3.13 - Cyclic voltammetry pertaining to the electrochemical reduction of 2.14 mM 1-(4- fluorophenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile at 0.2 Vs-1 with 0.1 M Bu4NBF4 at ambient temperature...... 55 Figure 3.14 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 2.14 mM 1-(4-fluorophenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, and 10 Vs-1)...... 56 Figure 3.15 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 2.14 mM 1-(4-fluorophenylsulfonyl)indole at varying scan rates (0.1Vs-1, 0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, and 10 Vs-1)...... 56 Figure 3.16 - Cyclic voltammetry pertaining to the electrochemical reduction of 2.08 mM 1-(3- nitrophenylsulfonyl)indole indole on a glassy carbon working electrode in acetonitrile at 0.2 Vs-1 with 0.1 M Bu4NBF4 at ambient temperature...... 58 Figure 3.17 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 2.08 mM 1-(3-nitrophenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1)...... 59 Figure 3.18 - Slope of Ep1 vs log (v) obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 2.08 mM 1-(3-nitrophenylsulfonyl)indole at varying scan rates from (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1)...... 59 Figure 3.19 - Cyclic voltammetry pertaining to the electrochemical reduction of 1.98 mM 1-(4- nitrophenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile at 0.2 Vs-1 with 0.1M Bu4NBF4 at ambient temperature...... 61 Figure 3.20 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 1.98 mM 1-(4-nitrophenylsulfonyl)indole at varying scan rates from (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1)...... 62 Figure 3.21 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 1.98 mM 1-(4-nitrophenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1)...... 62 Figure 3.22 - Molecular structure and calculated LUMOs for 1a-e ...... 64 Figure 3.23 - Molecular structure and calculated LUMOs and SOMOs for 1f-g ...... 65 Figure 3.24 – LUMO structures of (a) 1-(4-methylphenylsulfonyl)phthalimide and (b) 1-(4- nitrophenylsulfonyl)phthalimide...... 75 Figure 5.1 – Electrode modification of 1g: (a): first scan at the second reversible peak; (b, c and d): subsequent scan without polishing the electrode at the second reversible peak ...... 86

List of Charts

Chart 1.1 - Structures of the investigated substituted arylsulfonyl indoles for this thesis ...... 2 Chart 1.2 – Structures of the substituted arylsulfonyl chlorides previously investigated by the Houmam group ...... 2 Chart 1.3 – Structures of the arylsulfonyl phthalimides previously investigated by the Houmam group ...... 2 Chart 3.1 - Arylsulfonyl indoles subjected to the investigation of their electrochemical behaviors. X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e); X = NO2, Y = H (1f); X = H, Y = NO2 (1g) ...... 42

List of Schemes

Scheme 1.1 – Stepwise and concerted DET mechanisms ...... 5 Scheme 1.2 - Electrochemical reduction mechanism of 1,3-dihaloadamantanes. Adapted with permission. Copyright 2008 American Chemical Society...... 12 Scheme 1.3 - Decomposition of the radical anion ...... 19 Scheme 1.4 - Homolytic and heterolytic modes for the dissociation of a radical anion ...... 19 Scheme 1.5 - Products of the electrochemical reduction of substituted benzyl thiocyanates. Adapted with permission. Copyright 2008 American Chemical Society...... 22 Scheme 1.6 – 1-(4-nitrophenylsulfonyl)indole (a), 4-methyl-1-(4-nitrophenylsulfonyl)indole (b), and 6-methyl-1-(4-nitrophenylsulfonyl)indole (c) ...... 26 Scheme 2.1 – Overall scheme for the synthesis of arylsulfonyl indoles ...... 39 Scheme 3.1 - Dissociative electron transfer mechanism pertaining to arylsulfonyl indoles upon injection of one electron. X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e); X = NO2, Y = H (1f); X = H, Y = NO2 (1g) ...... 43 Scheme 3.2 - Potential radical and anion pairs as result of the stepwise dissociative mechanisms of arylsulfonyl indoles upon injection of one electron. X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e); X = NO2, Y = H (1f); X = H, Y = NO2 (1g)...... 43 Scheme 3.3 - Dissociation mechanisms for 1a-e ...... 68 Scheme 3.4 - Possible DET pathways for compounds 1a-e upon taking into account the cyclic voltammetry ...... 69 Scheme 3.5 - Deduced concerted electrochemical reduction mechanism of compounds 1a-e .... 70 Scheme 3.6 - Possible dissociative mechanisms for 1f (X=NO2, Y=H) and 1g (X=H, Y= NO2) 72 Scheme 3.7 - possible dissociative mechanisms of compounds for 1f (X=NO2, Y=H) and 1g (X=H, Y= NO2) ...... 73 Scheme 3.8 - Reduction mechanism of arylsulfonyl chlorides...... 74 Scheme 3.9 - One- and two-electron reduction of nitro-aromatics ...... 76

List of Tables

Table 3.1 - Electrochemical characteristics for 1-(phenylsulfonyl)indole ...... 45 Table 3.2 - Electrochemical characteristics for 1-(4-methylphenylsulfonyl)indole...... 47 Table 3.3 - Electrochemical characteristics for 1-(4-methoxyphenylsulfonyl)indole ...... 50 Table 3.4 - Electrochemical characteristics for 1-(4-chlorophenylsulfonyl)indole ...... 52 Table 3.5 - Electrochemical characteristics for 1-(4-fluorophenylsulfonyl)indole ...... 55 Table 3.6 - Electrochemical characteristics for 1-(3-nitrophenylsulfonyl)indole ...... 58 Table 3.7 - Electrochemical characteristics for 1-(4-nitrophenylsulfonyl)indole ...... 61 Table 3.8 - S-N and S-C bond lengths for 1f and 1g before and after reduction ...... 66 Table 3.9 - N-S bond dissociation energies for 1a-g ...... 67 Table 4.1 - Molar ratios and yields pertaining to the synthesis of 1-(phenylsulfonyl)indole ...... 77 Table 4.2 – Molar ratios and yields pertaining to the synthesis of 1b-g ...... 78

Chapter 1 – Background Information

Preamble

Electron transfer is a rudimentary process of all chemical reactions. Its far-reaching

importance extents to a vast array of research areas encompassing organic synthesis,1 biological

processes,2,3 and novel energy sources.4,5 In organic chemistry, electron transfer initiated

reactions and particularly electro-synthesis are well-established methodologies for the synthesis

of a wide range of valuable chemicals.6-9 In biological systems, photosynthesis10 and oxidative

phosphorylation,11 are some of the well-known electron transfer reactions amongst countless

other processes that are essential to the sustenance of life. Many useful devices such as solar

energy systems12,13 and biosensors12,14-16 are based on the electron transfer to organic or

bioorganic structures. Understanding the electron transfer reactions to organic and bioorganic molecules may thus provide valuable information to a broad range of science17-19 and engineering20-22 disciplines.

Our research group has been intensely involved in the electrochemical investigation of

many organic and bioorganic series. Examples of these series include aromatic and benzyl

thiocyanates,23-25 sulfenyl chlorides,26 sulfonyl chlorides,18 and sulfonyl phthalimides.19

Reduction mechanisms, kinetic and thermodynamic aspects, and factors controlling them such as substituents, solvent and driving force have been elucidated.17 While investigation of these

compounds provided important information regarding their electrochemical behavior, of equal

importance is the translation of various electron transfer theories in to applications through

experimentation. These include the stepwise and concerted electron transfer mechanism

transition,27 the occurrence of the so-called “sticky dissociative electron transfer”,12,18 and the

extension of the dissociative electron transfer theory to the case of formation and dissociation of

radical ions.18,19,23

In the present thesis the investigation of a series of substituted arylsulfonyl indoles (Chart

1.1) is reported. The compounds chosen for the study exhibit biological importance and

relevance, and represent an extension to the previous sulfonyl chlorides26 (Chart 1.2) and sulfonyl phthalimides19 (Chart 1.3) series investigated by our group. Their electrochemical

reduction is investigated and the results are rationalized though application of the adequate

electron transfer theories and use of theoretical calculations.

X Y

N S O O X = H, Y = H; X = H, Y = Me; X = H, Y = OMe; X = H, Y = Cl; X = H, Y = F; X = NO2, Y = H; X = H, Y = NO2

Chart 1.1 - Structures of the investigated substituted arylsulfonyl indoles for this thesis

X S Cl O X = CH3O, CH3, H, Cl, F and NO2

Chart 1.2 – Structures of the substituted arylsulfonyl chlorides previously investigated by the Houmam group

O O N S X O O X = CH3, NO2

Chart 1.3 – Structures of the arylsulfonyl phthalimides previously investigated by the Houmam group

In part one of the first chapter, a brief overview of the main electron transfer theories will be presented. The relevance of the investigated compounds (substituted arylsulfonyl indoles) will be discussed in part two of this chapter. The objectives of this thesis will be presented at the end of this chapter. The second chapter outlines the techniques methodologies employed for the study. The findings are presented and discussed in chapter three. Finally, the concluding remarks and recommendations for future work will be conveyed in chapter four.

I. Electron Transfer and Bond Cleavage

Amongst the numerous electron transfer-initiated reactions, oxidative and reductive bond

cleavages are arguably the most common occurrence and result in bond dissociation.17,28,29 This

process is referred to as Dissociative Electron Transfer (DET) and is very common in the

reduction and oxidation of organic and bioorganic molecules. The study of the DET processes

has attracted considerable attention owing to its ubiquity in bio-organic process as well as its

broad range of applications.17 Many valuable publications have reported the theoretical and

experimental aspects of the DET.17,28-51 It is worth noting that an electron transfer may also lead

to the formation of a chemical bond, a phenomenon called the Associative Electron Transfer.

Furthermore, chemical bond breakage and formation as a result of electron transfer often occurs

concomitantly.17,49,51 However, since the aim of the thesis is to study the bond dissociation for

our compounds of interest, the discussion hereafter concerns primarily the dissociative aspect of the electron transfer.

Most pioneering experimental studies and breakthroughs in electron transfer stem from the study of the reductive cleavage of alkyl halides,52-57 hence the notation RX (Scheme 1.1).

Over the course of the past few decades, incredible pioneering feats and breakthroughs

eventually afford us the knowledge that a reductive DET in a chemical reaction may follow a

stepwise or concerted mechanism, as depicted in Scheme 1.1.17 In the stepwise mechanism, the

initial electron transfer leads to the intermediate formation of a radical anion (considering the

reduced molecule is neutral), which then dissociates to a radical and an anion. In a concerted

process, however, both electron transfer and bond cleavage are simultaneous without the

formation of radical anion intermediate.17 The fundamental aspects of electron transfer reactions

have been widely investigated.17,28,29 When no bond cleavage is observed upon an initial electron

transfer, or when the intermediate radical anion has a long life expectancy, the electron transfer process can successfully be described by the Hush-Marcus theory of electron transfer.17,58,59 This theory is not applicable when the intermediate has a very short lifetime or when the electron transfer mechanism is concerted. In this case, Savéant’s dissociative electron transfer theory is used.17,58,59 In some cases a radical/ion pair is formed, instead of or subsequent to a radical anion.17,60,61 Such a mechanism is known as the “sticky” dissociative electron transfer and

Savéant successively extended his theory to take in consideration such a phenomenon.17 He also extended his theory to the case of formation and dissociation of radical ions. These processes do indeed involve an electron along with the formation or cleavage of a chemical bond. concerted - RX + e- R + X

st ep w i se - RX

Scheme 1.1 – Stepwise and concerted DET mechanisms

I.1 Hush-Marcus Model - Outer Sphere Electron Transfer Theory

In a stepwise DET mechanism, the bond dissociation occurs subsequent to the initial electron transfer process, in which case the Hush-Marcus theory can be applied to the electron transfer step.17 In a stepwise mechanism an intermediate radical anion is formed and subsequently fragmented (Scheme 1.1). Marcus formulated a theory to address the outer sphere electron transfer reactions. The theory postulates that the electron transfer takes place at the outer-sphere between the species in the solution and the electrode.17,32-34,37,38 Noel Hush subsequently extended Marcus’ theory to incorporate the inner sphere electron transfer

reactions.17,28,29,40,41 The resultant Marcus-Hush theory is applied to the electron transfer step

involving a stepwise DET.17,17,28,29,40,41 After several iterations of breakthroughs carried out by

Marcus and Hush, the current model considers the solvent and the reactant molecules in terms of a general charge distribution system, which permitted the depiction of the reaction through free energy plots as a function of a global reaction coordinate (Figure 1.1).17,36,39

According to Hush-Marcus model, such a mechanism is influenced by thermodynamic

and kinetic factors.17,28,29 The thermodynamic parameter, ΔG°, is described as the driving force and is determined from the experimental standard potential (Equation 1.1).

ΔGο = F(E − Eο ) (1.1)

Where F is the Faraday constant. E and E° are the electrode potential and the standard

potential of the reactant, respectively.

The kinetic parameter, λ, describes the reorganization energy, is estimated from expressions based on the dielectric continuum model assuming the molecules involved in the

electron transfer are solid spheres.17 The reorganization energy consists of the outer

reorganization energy, λo, and the inner reorganization energy, λi. λo represents the energy

required to reorient the solvent molecules around any charged species due to an electron transfer.

λi describes the changes in bond lengths and angles in the reactant that accompanies the electron

transfer process (Equation 1.2).17,28,29

λ = λo + λi (1.2)

The Hush-Marcus model assumes a quadratic activation free energy relationship

≠ ≠ (Equation 1.3), where ΔG and ΔGο are the activation free energy and the intrinsic barrier,

respectively.17

2 ⎛ ΔGο ⎞ ΔG ≠ = ΔG ≠ ⎜1 + ⎟ (1.3) 0 ⎜ ≠ ⎟ ⎝ 4ΔG0 ⎠

≠ ≠ The intrinsic barrier ( ΔGο ) is the activation energy at zero driving force. ΔGο involves only the outer sphere or solvent reorganization energy (λo) and inner (λi) reorganization energy

in the electron transfer (Equation 1.4). Hush-Marcus theory assumes that the electron transfer

will only result in structural reorganization of the molecule and no bond disruption.19

λ + λ ΔG ≠ = o i (1.4) ο 4

An important aspect of Hush-Marcus’s outer-sphere electron transfer theory is its

capability in predicting the rate of a chemical reaction on the basis of reorganization energies and

driving force.17

The outer-sphere electron transfer theory has been subjected to various experiments aimed and succeeded at verifying the many aspects and predication of the theory.17 Since its inception, many compounds have been rationalized using the out-sphere theory. Among the initial studies was the reduction of aryl and anthracenyl substituted chlorides and bromides conducted by Marcus.17,28,29,39-41 The study verified the formation of the aryl radical and the

halide anion are due to the cleavage of the carbon-halide bond.33

The kinetic aspects of the theory have undergone extensive verification. The internal and

external reorganization energies are attributed to rate constants.17,29,34,35,37,40,41 Kinetic electron

transfer studies have proven that the internal reorganization accompanies the energy the electron

transfer and causes an increase of the intrinsic barrier and hence decreasing the rate constant of

the reaction.

An important experiment was carried out by Miller et al. who designed a pulse radiolysis-initiated intramolecular electron transfer experiment62 that verified the existence of the

“inverted region”. The inverted region is the resulted of the initial decree of ΔG ≠ as the standard

free energy, Δ G°, value varies from 0 to −λ, and the subsequent increase of ΔG ≠ as Δ G°

becomes more negative values. Due to the quadratic relationship (Equation 1.3) imposed by

Hush-Marcus’s model, the model predicts that a reaction would be subject to deceleration as the

reaction becomes increasingly exergonic (ΔG°<<0).17,62 Miller’s study employed biphenyl as the

electron donor. The use of various aromatic compounds with different standard reduction

potentials provided the means of varying the driving force of electron transfer. The predicted

normal and inverted regions are readily observable based on the plot of variation of the

intramolecular electron transfer rate constant of the acceptor-space-donor system as a function of

the driving force (Figure 1.2).17,62 Building onto Miller et al.’s success, many other research

groups were successful at further verifying the inverted region.17,63-72

Marcus’ outer sphere electron transfer theory laid the foundation for rationalizing the stepwise electron transfer mechanism involving the intermediacy of the radical anion, regardless of the fate of the intermediate. The theory only involves structural changes where the intrinsic barrier associated with such an electron transfer is low.

While Hush-Marcus’s outer-sphere electron transfer theory provides description for the stepwise DET, the theory cannot adequately account for the concerted mechanism. The concerted DET involves the concomitant electron transfer and bond breaking, and has been the subject of intensive research. Over the course of several decades, another model developed by

Savéant that can account for concerted DET eventually emerges.17,49

I.2 Savéant’s Model - Dissociative Electron Transfer Theory

The Savéant model not only provides description for the concerted DETs, but also establishes ways to distinguish the concerted DET from its stepwise counterpart.17 The model leads to a quadratic free energy relationship (Equation 1.5) that mirrors the Marcus equation. The

≠ Savéant model differs in the intrinsic barrier ( ΔGο ), which in this case is the contribution of both the solvent reorganization free energy (λo) and bond breaking. The solvent reorganization free energy is the same as that described in the Marcus-Hush model of the outer sphere electron transfer. The contribution of the bond breaking is one fourth of the bond dissociation energy

17,44,49-51 (DR). The extra reorganization energy associated with the bond breaking causes the intrinsic barrier of the concerted DETs to be much larger than that of outer-sphere DET. As

Savéant put it, "the kinetic price to pay for the thermodynamic advantage offered by the breaking of the bond".47

2 ⎛ ΔGο ⎞ ΔG ≠ = ΔG ≠ ⎜1+ ⎟ (1.5) ο ⎜ ≠ ⎟ ⎝ 4ΔGο ⎠

λ + D ΔG ≠ = o R (1.6) ο 4

The extra reorganization energy also renders the concerted DETs to be much slower than its stepwise counterpart. In this regard, these two mechanisms are readily distinguishable in terms of reaction kinetics.

Savéant’s model is based on the Morse curve approximation of the energy of the cleaving bond in the reactant. The model describes the energy of the dissociating bond in the reactant in terms of a Morse potential curve and is based on the assumption that the repulsive interaction of the products of DET is the same as the Morse curve of the dissociative component of the

reactant17 (Figure 1.3). The approximation was validated by ab initio calculations, as well as numerous subsequent studies.17,48,73

Figure 1.3 - Morse curves for a concerted DET at zero driving force. Adapted with permission. Copyright 2008 American Chemical Society. Savéant’s model has been extensively studied and tested. Numerous studies are concerned with experimentally confirming the theoretical predications under homogeneous and heterogeneous electron transfer conditions.17,47,48,61 Savéant et al. have demonstrated agreement between the theoretical and experimental intrinsic barrier values through the electrochemical reduction of organic halides.48,49 Through the use of voltammetric technique they observed that alkyl halides exhibited broad and irreversible waves, an indication of large intrinsic barrier contributed by the bond dissociation energy.17,42,45 The electrochemical reducation of alkyl and benzyl halides provided the early examples of successful application of the DET theory in estimating the bond dissociation energies.44,47 The study of bicyclic dihalides further

demonstrated the applicability of the DET theory as a tool to rationalize the effect the presence

of nearby halogen atoms.43,45,46 For the reduction of dihalo bicyclic compounds such as 1,3-

dihaloadamantanes (Scheme 1.2), the study showed that the selective ring closure takes place at

the level of the carbanion produced by reduction of the one-electron reductive cleavage radical.50

It was found that the effect of changing the remaining halogen from I to Br, to Cl, and to F reduced the amount of ring closure. The finding was rationalized using the DET theory and attributed to the variations of the bond dissociation energy of the first carbon-halogen bond to be cleaved in the radical mainly produced by one-electron reductive cleavage.43,45,50,51

An important aspect of the DET theory is that it can successfully be used to predict the

mechanism of the initial electronic process. Determining whether an initial ET intermediate is

produced, through a stepwise ET mechanism, and decomposes very fast, or whether a concerted

mechanism prevails is not experimentally possible. Application of the DET theory using

parameters easily accessible experimentally provides the tools to distinguish between the two

processes. This will be reviewed in part 3.

Savéant’s model, sometimes referred to as the “classical” DET model, has been successful in describing concerted and fast cleaving stepwise mechanisms.17,18 The theory has

since been extended to provide explanation to formation and dissociation reactions of radical

ions. A brief review of this extension of the DET will be presented in part 4.

I.3 Stepwise and Concerted Electron Transfer

Ascertaining the electron transfer mechanism is essential for gaining the full

understanding of the reaction mechanism.17,47-49 In this regard, several studies74-80 have focused

on understanding the differences in terms of theromdynamics and kinetics between concerted

and stepwise electron transfer mechanisms.

The presence of the electron transfer intermediate is the hallmark of a stepwise

mechanism. Hence, the ability to accurately ascertain a stepwise mechanism hinges on the

detection of such an intermediate. When a parent substrate (RX) is subject to an electron

transfer, the life expectancy of the resulting radical anion (RX●-) can vary markedly. Radical anions that exhibit long life expectancies can be easily detected by electrochemical kinetic techniques such as cyclic voltammetry, thus, a stepwise mechanism can be identified rather easily in the presence of long-lasting radical anions. As the radical anion becomes less stable, discrimination between stepwise and concerted mechanisms becomes increasingly difficult. High scan rate cyclic voltammetry (up to a few million V/s) can be used to detect electron transfer intermediate with lifetimes up to the microsecond. Use of homogeneous catalysis can increase the detection limit up to a nanosecond which cannot be detected using direct electrochemistry.80-

82 In homogeneous catalysis, the electron transfer to the substrate is not achieved directly at the

electrode. A catalyst, which is a stable molecule that can easily take an electron and exchange it,

is used to transfer the electron between the electrode and the substrate. Homogeneous catalysis

has been widely used to investigate mechanisms and kinetics of electron transfer initiated

reactions to organic and bioorganic compounds.83-85 When the electron transfer intermediate has

an even lower lifetime and cannot be detected by cyclic voltammetry and homogeneous

catalysis, application of the DET can successfully allow distinction between the two

mechanisms.

The difference in the reaction free energy between stepwise and concerted mechanisms

can be expressed by the corresponding standard potentials in equation 1.12. As seen, the electron

transfer is more thermodynamically favourable for the system with a weaker bond.17

Furthermore, for a stepwise mechanism, the activation barrier involves the solvent and the inner reorganization energies (Equation 1.4). For a concerted mechanism, however, the bond dissociation energy (DR-X) of the fragmented bond contributes to the activation barrier (Equation

1.6).

0 0 0 0 E •− − E • − = E •− + D − E • − − TΔS • • (1.7) RX / RX RX / R + X RX / RX R−X X / X RX / R + X

Knowing the exact mechanism pertaining to an electron transfer reaction is important to

understanding the reaction mechanism. However, ascertaining the mechanism is not always a straightforward task since some electron transfer intermediates can have very short lifetimes and are not possible to detect experimentally as previously explained. Under these circumstances the transfer coefficient (α) can be used to probe the mechanistic nature of the DET process.

The transfer coefficient is directly related to the intrinsic barrier and is described as a function of the change in the activation energy with respect to the driving force (equation 1.8).

The important features of the transfer coefficient are that it can be easily determined from the electrochemical peak characteristics.

∂ΔG≠ 1 ⎛ ΔGο ⎞ α = = ⎜1+ ⎟ (1.8) ∂ΔGο 2 ⎜ 4ΔG≠ ⎟ ⎝ ⎠

Equation 1.8 provides a numerical means of probing the mechanistic nature of the first

ET in dissociative process. α values for a concerted mechanism is expected to be significantly

lower than 0.5 while that for the stepwise mechanism is expected be close to or higher than 0.5.17

The rationale to the aforementioned expected α values is that for a concerted process, the large

ΔGο negative driving force compensates for the high intrinsic barrier, in turn becomes a small 4ΔG ≠ negative number, resulting in an α value that is significantly lower than 0.5. For the stepwise

mechanism, the smaller driving force leads to an α value close to or higher than 0.5. Such aspect

of the transfer coefficient has underwent extensive investigation especially for heterogeneous ET

reactions at electrodes owing to the ease of controlling the driving force through varying the

potential, as well as to the fact that the transfer coefficient can be easily determined from the

peak characteristics.

The transfer coefficient can readily be determined for a chemical compound through use

of cyclic voltammetry. This can be achieved either from the cyclic voltammetric peak width (eq.

1.9) or from the plot of the variation of the peak potential (Ep) as a function of the logarithm of

the scan rate, log(v) (eq. 1.10).

RT 1.85 α = (1.9) F E − E P / 2 P

−1 RT ⎛ ∂E ⎞ α = − ⎜ P ⎟ (1.10) 2F ⎜ ∂ log()υ ⎟ ⎝ ⎠

Transfer coefficient values have been determined for a large number of organic and

bioorganic compounds. The obtained values are consistent with the electron transfer

mechanisms. Values much lower than 0.5, most of the time in the range of 0.3 to 0.4, have been

found for the reduction of compounds such as alkyl halide,85-88 which all follow a concerted

electron process. On the other hand, values equal or greater than 0.5 have been found for compounds following a stepwise mechanism. Examples include the nitro-substitued sulfonyl chlorides17,18,88 and the nitro-substituted benzyl thiocyanates.24,25

For an ET reaction governed by a single mechanism, the transfer coefficient is linearly proportional to the driving force. Savéant and Tessier were among the first to demonstrate the linear relationship between the transfer coefficient and the driving force for a series of organic compounds in aprotic solvents. Antonello et al.89 later on presented a more concrete evidence of the expected linearity based on the electrochemical reduction of a series of dialkyl peroxides, as seen in the typical example provided in Scheme 1.2. The importance of this aspect of the transfer coefficient is that the observed linearity is indicative of an ET reaction governed by a single mechanism, especially since there are cases where an ET is not ruled by a single mechanism. As well, a transition of one mechanism to the other has been observed.27 In these instances, a nonlinear relation-ship is usually observed for the variation of the transfer-coefficient with the driving force.

I.4 Concerted - Stepwise ET Mechanism Transition

Transitioning of one electron transfer mechanism to another, as well as the coexistence of

both mechanisms, have been encountered for certain compounds.89,96-98 The phenomenon

demonstrates that the nature of the electron transfer process is dictated by the energetic

feasibility of one pathway over another. As illustrated in Figure 1.4, the mechanism of an

electron transfer process may change from concerted to stepwise as a result of the change in the

driving force and activation free energy of the reaction.

The driving force of an ET reaction can be controlled through varying the electrode

potential, or the electron donor in homogeneous thermal and photochemical initiations.

Electrochemical techniques such as cyclic voltammetry are widely used in studying the

mechanism transition owing to the ease in controlling the driving force through variation of the

electrode potential.17

As previously mentioned, the non-linear variation for the transfer coefficient with the

driving force indicates a transition between concerted and stepwise mechanism as a function of

the driving force. Only a handful of compounds, namely the triphenylmethyl phenyl sulfide, 4-

nitrocumyl chloride, iodobenzenes, peroxides, arylthiocyanates, and sulfonium salts, have been

experimentally proven to exhibit such non-linearity.17

The reduction of triphenylmethyl phenyl sulfide using homogenous catalysis provided an

early evidence of the mechanistic transition.90,91 The study employed a series of stable electrochemically-generated radical anions to provide a wide range of variation of driving force.

Increasing the driving force led to a transition of mechanism as evidenced by the rate constants of the homogeneous electron transfer and investigation of the variation of the activation energy as a function of the driving force.17

The study of sulfonium salts, specifically the benzylmethylphenyl sulfonium salt,

provided a classical example of using electrochemical techniques in studying the mechanistic transition.83,92 The variation of the peak width (E p − E p / 2) and the transfer coefficient (α) with

the scan rate (Figure 1.5) revealed a nonlinear dependence of the peak width and α with the

driving force, an indication of a transition between a concerted and a stepwise mechanism.

I.5 Extensions of the Dissociative Electron Transfer Theory

As an extension of the classical DET, the intramolecular DET describes the dissociation

of radical ions into a radical ( R• ) and a nucleophile ( X − ) (Scheme 1.3).50 The dissociation of

the radical anion is the result of an intramolecular concerted electron-initiated bond breaking,

where an electron residing in the LUMO is ejected into the σ* orbital of the weakend bond

coupled with the simultaneous dissociation of the radical anion. In general, addition of an

electron to form a radical anion results in an elongation of the R-X bond, thereby weakening it.

As a result, the reorganization energy increases which facilitates the electron transfer.17,93-97

R X R + X

Scheme 1.3 - Decomposition of the radical anion

In a stepwise DET mechanism the radical anion intermediate is generated and

subsequently undergoes a σ bond cleavage resulting in either a homolytic cleavage or heterolytic

cleavage (Scheme 1.4).17

RX R + X

R X

Scheme 1.4 - Homolytic and heterolytic modes for the dissociation of a radical anion

The activation energy of the radical anion decomposition (equation 1.11) is same as the equation that describes the activation energy for concerted DET. In the case of heterolytic

cleavage, the equation takes into account the contribution of the bond breaking ( D •− ) to the RX intrinsic barrier at the radical anion level (equation 1.12).

2 ο ⎛ ΔG RX •− →R• +X − ⎞ ≠ •− • − ≠ ΔG RX →R +X = ΔG •− • − ⎜1+ ⎟ (1.11) ο RX →R +X ⎜ ≠ ⎟ 4ΔG •− • − ⎝ ο RX →R +X ⎠

D •− + λ ≠ RX o ΔG •− • − = (1.12) ο RX →R +X 4

The bond dissociation energy is provided by equation 1.13, where DRX is the bond

•− dissociation of the cleaved bond R-X in the neutral molecule (RX), E°RX/RX is the standard

reduction potential of RX, S is the partial molar entropy, and (R•)•− corresponds to an excited

state of the carbanion (R−) resulting from the injection of one electron into the LUMO of the

radical R•:17

0 0 D •− = D + E •− − E • − + T (S − S •− + S • •− − S • ) (1.13) RX RX RX / RX RX / R + X RX RX (R ) R

The equation can be simplified by neglecting the entropic term since it is effectively self-

canceling. The result is that the intrinsic barrier is expressed as a function of the bond

dissociation energy (equation 1.14).

≠ 1 0 0 λo ΔG •− • − = ()D + E •− − E • − + (1.14) ο RX →R +X 4 RX RX / RX RX / R +X 4

The standard free energy of the cleavage reaction can be written as:

ο •− • − 0 0 ΔG RX →R +X = D − E •− + E • − − TΔS • − (1.15) RX X / X RX / R +X RX / R +X

Several experiments have proven the applicability of this extension of the DET in the

case of heterolytic cleavage of radical ions.46-48 Initial studies revolved around the reductive

cleavage of aryl chlorides and bromides.98 It was demonstrated that aryl chlorides and bromides

exhibited a rough linear correlation between the log of the cleavage rate constant and the standard potential for the formation of the radical anion.98 The observed correlation is attributed

to the heterolytic cleavage of the radical anion, which is considered as an intramolecular DET.

In the vast majority of DET studies, the bond breaking takes place exclusively at the

same bond regardless of the driving force variation. Regioselective bond cleavage was only rarely observed and the factors controlling the regioselectivity are not always clear. In a recent study, Houmam et al provided an interesting example of regioselective reductive bond cleavge.

The extension of the DET to the dissociation of radical ions was successfully used to rationalize

the regioselectivity and to explain the factors controlling it. The study employed substituted

benzyl thiocyanates and revealed a change in the reductive cleavage mechanism and

regioselective bond cleavage as a function of the substituent on the aryl ring of the benzyl

thiocyanate (Scheme 1.5).18 It was demonstrated that the electrochemical reduction of nitro-

24,25 substituted phenyl thiocyanates favors the CH2–S bond cleavage (α-cleavage) while the

benzyl thiocyanates with electron-donating to weak electron-withdrawing substituents favored

the S–CN bond cleavage (β-cleavage). The extension of the DET theory provided

thermodynamic and kinetic rationales for the regioselectivity.24,25

X = CH3O, CH3, H, Cl, F, CN, and NO2

Scheme 1.5 - Products of the electrochemical reduction of substituted benzyl thiocyanates.

Our understanding of the various electron transfer mechanisms has reached a reasonable degree of comprehensiveness owing to the development and continued refinement of the electron transfer theories and the experimental facts that accompanied them. The fact that numerous chemical and biological reactions are triggered by an initial electron transfer highlights the importance in having these theories at our disposal as one chemical or biological behavior can be fully rationalized by one or a number of the theories.47,51

II. Indoles in Medicinal Chemistry

The indole is an aromatic heterocyclic compound which is defined by the fused benzene-

pyrrole bicyclic structure (Figure 1.6). The indole moiety, along with numerous other

heterocyclic molecules, possesses a wide range of biological activities and many of which

exhibit applications in human and animal therapeutics.99-103 In medicinal chemistry, indole has

been extensively utilized as a core scaffold for constructing libraries of molecules to be screened

for potential pharmacological values.104-106 The indole scaffold can be found in several important

bioactive compounds, such as tryptophan (Figure 1.7a), an indolic amino acid; and serotonin and

melatonin (Figure 1.7b and c, respectively), which are neurotransmitters.107-110

N H Figure 1.6 - The bicyclic structure of indole

a) H b)H c) H N N N

NH2

OH NH2 N H O O HO O

Figure 1.7 - Tryptophan (a), serotonin (b) and melatonin (c)

Tryptophan is an essential amino acid to humans. It plays an important role in protein

synthesis and acts as the biochemical precursor for several physiologically important molecules

such as melatonin and serotonin.101 Melatonin exhibits a vast array of functions such as

mediating the circannual reproductive rhythms and circadian cycles, stimulating immune system, anti-inflammatory and antioxidant properties.111 Serotonin is a neurotransmitter primarily found

in the gastrointestinal tract, platelets and in the central nervous system. It plays an important role in regulation of mood, appetite and sleep.112 The indole derivatives are widely used as the backbones for new drug molecule discovery.

Over the course of the past decades, the indole framework has been recognized as a

biologically important pharmacophore, due in large part to its antioxidant therapeutic

activities.101 For example, the indole scaffold has been attributed to the protection of both

proteins and lipids from oxidation.105 The indolic nitrogen plays a critical role in the reactive

oxygen species (ROS) scavenging activities of indole molecules, as confirmed by an abundance

of studies aimed at investigating the antioxidant activities of the compound.101,107-110,113

In addition to the antioxidant activities, many indole derivatives also exhibit important

pharmacological applications in anti-inflammatory, anti-cancer, and anti-HIV.105 In recent years,

studies aimed at evaluating the anti-HIV activities of indoles is emerging and have become

increasingly popular in drug discovery.103,114-116

II.1 Indoles as Anti-HIV-1 Inhibitors

Since the first emergence of acquired immunodeficiency syndrome (AIDS) was reported

in 1981, the search for the drug entities as efficacious AIDS inhibitors has become an on-going

global research initiative.101,117 Human immunodeficiency virus (HIV) infection, the causative

agent to AIDS, leads to the progressive deterioration of the immune system, eventually renders

the body unable to fend off infections and other diseases.101,115,117 According to World Health

Organization, as of today more than 35.3 million people are currently living with HIV and truly

efficacious treatment for HIV remains elusive.101,117

Today's commercially available anti-HIV1 drug molecule carries out its therapeutical

activity through a combination of the following antagonist action: viral nucleoside/nucleotide

reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitors,

integrase inhibitors or fusion inhibitors.109,113 The resultant antagonist action suppresses the

replication and proliferation of HIV-1 viremia, dramatically reduces HIV-1-associated morbidity and mortality, but the therapeutic effect is far from being curative. Furthermore, the incomplete suppression of HIV-1 replication may give rise to drug-resistant HIV-1 strains, further complicating the condition. Hence, there is still a compelling need for a curative, selective and patient compliant drug molecule for combating HIV.117

The indole derivatives have been explored as potential HIV-1 inhibitors.101,102,115,118

Among the first generation of drugs for HIV treatment was delavirdine, approved by the Food and Drug Administration (FDA)119 in 1997 for use in combination with other antiretrovirals in

adults with HIV infection.120,121 However, delavirdine, along with many of its successors, are plagued with low efficacy and inconvenient dosing schedule. In addition, severe side effects have rendered many existing anti-HIV drugs transient in clinical benefit.122-124 Hence the

screening of indole derivatives as suitable therapeutical agents for HIV suppression and cure is

still on-going.101

II.2 Arylsulfonyl Indoles in Modern Drug Disocvery

The advences in the human genome project and bioinformatics have enabled the

identification and isolation of genomic and proteomic targets as critical intervention points in a

disease process. The high-throughput screening (HTS) is an emerging method for drug discovery

that harness the power of computers and robotics to identify pharmacologically active molecules.

In the race to obtain new drug molecules, the N-arylsulfonyl indole derivatives have been

identified and screened as promising drug candidates. The interest in the screening of the N-

arylsulfonyl indole derivatives stems from their selectivity as ligands for certain human receptors

125,126 such as the serotonin 5-HT6 receptor. As a result, numerous N-arylsulfonyl indole

126-131 derivatives have been identified as novel ligands for the 5-HT6 receptor. Recently the N-

arylsulfonyl indole derivatives have been identified to exhibit anti-HIV1 activity, thus prompting

the screening of N-arylsulfonyl indole derivatives as novel HIV-1 inhibitor candidates.103,114-116

Fan et al. were among the first group to evaluate the applicability of N- arylsulfonylindoles as novel HIV-1 inhibitors.115 Their preliminary results suggested the N-

arylsulfonylindoles could lead to significant HIV-1 suppression, depending on the nature of the

substituents on the indole and the sulfonyl moieties, as evidenced by the in vitro testing.115

Amongst a variety of N-arylsulfonylindoles subject to their study stands out a group of compounds, the nitrophenylsulfonyl indoles (Scheme 1.6), which provided the highest anti-HIV-

1 activities.115 Building on the successful of their preliminary findings, additional in vitro anti-

HIV-1 screenings soon followed suit, incorporating an ever-expanding array of N- arylsulfonylindoles.103,110,114,115,132 An interesting aspect of these studies is the commonality in

that the derivatives with nitro substituents are found to provide the highest anti-HIV-1 activities among the numerous N-arylsulfonylindole derivatives tested.103,110,114,115 These findings warrant

a more in-depth look at the nitro-substitued N-arylsulfonylindoles.

a) b) c)

NO NO2 NO 2 2

N N N S S S O O O O O O Scheme 1.6 – 1-(4-nitrophenylsulfonyl indole) (a), 4-methyl-1-(4-nitrophenylsulfonyl)indole (b), and 6-methyl-1-(4-nitrophenylsulfonyl)indole (c)

II.3 Nitro Radical Anions and Electrochemical Behavior of Indoles

The therapeutic value of the nitro aryl compounds have been well recognized over the

course of the past three decades. The interest in nitro drugs has spurred numerous studies aimed

at rationalizing their biological and pharmacological properties.133-136 As a general consensus, the

radical actions of the nitro functionality are attributed to the activities of nitro drugs.133,137

The free-radical intermediates of several classes of therapeutically important compounds have gained widespread interest in drug discovery for over three decades.108,134,135,138 In

particular, the nitro aryl compounds used in medicine and cancer therapy relies upon the free radical mechanism. While the exact mode of their radical-elicited therapeutic action remains elusive, the nitro drugs have nevertheless provided direct proof of radical production.133,137 The use of electron spin resonance (ESR) and spectrophotometric monitoring studies have provided concrete evidence attributing the free radical reaction to the therapeutic activities.133-135 There is considerable evidence that the free-radicals are largely responsible for the biological and medicinal applications of nitro-aromatic compounds.133 While the presence of radicals in

biological systems and the consequential oxidative stress are largely responsible for a variety of

pathologies, resulting in disturbances as well as damages to biological molecules139, the use of

radicals in medical treatment has become increasingly common in cancer radiotherapy where

oxidative stress is used to carry out localized cellular destruction thereby eliminating cancerous

cells in the process133,140-145. In the context of anti-HIV1 activity, although most drugs employ suitable active pharmaceutical ingredient to suppress the viral replication, it is possible that the radicals may play an influential rule.133-135

The use of electrochemistry has become increasingly common in drug discovery, as

redox reactions play an integral part in many physiological processes.108,134,135,138

Electrochemistry is the standard method for studying redox reactions and can be utilized as preliminary means of studying drug reaction mechanisms and their correlation with biological activity.146 The electrochemical data may provide important kinetic and thermodynamic

information regarding the mechanisms of biological electron-transfer processes.146 In this regard,

our research ties in with the on-going N-arylsulfonyl indole screening studies by providing the

mechanistic overview of the nitro drugs which are known to be activated by the biological redox

environment.133

III. Electrochemical Techniques

Electrochemistry is the core discipline amongst all of the research efforts in studying the

electrochemical behaviors. In electrochemistry, electrical stimulation is used to induce reduction

(gain of electrons) or oxidation (loss of electrons).29,50 The collective reduction and oxidation

reactions are known as redox reactions, which provide the backbone of electrochemistry.

Electrochemical analysis of redox reaction can provide valuable information about the important

thermodynamic, kinetic, and mechanistic information regarding an electron transfer reaction.

An electrochemical analysis revolves around the measurement of the four parameters –

potential (E), current (i), charge (Q) and time (t). Potential is the amount of electrical energy in a

system, measured in units of volt (V). Current is the magnitude of the electron flow in a system,

measured in units of amperes (A). Charge is a measure of the number of electrons, measured in

units of coulombs (C). In the context of electrochemical analysis, time is usually a measure of

duration, oftentimes measured in seconds. The current-potential relationship is an important

aspect of electrochemical techniques in that varying one of the parameters, either the current or

the potential, would allow the measurement of the other parameter.17 Furthermore, electron transfer can be induced in an experimentally controlled setting through application of a specific potential or current to the electrode.17

In this thesis, cyclic voltammetry will be employed for the investigation of the

electrochemical properties of the various arylsulfonyl indoles.

III.1 The Electrochemical Cell

The typical CV experiment employs an electrochemical cell designed to work as a closed system. As depicted in Figure 1.8, the main components of the cell consist of a working electrode, a counter electrode and a reference electrode.

The working electrode is an inert electrode where the electrochemical reaction takes place. The working electrode can be composed of platinum, gold, graphite or glassy carbon. The cleanliness and the smoothness of the electrode surface may strongly affect the accuracy of the

CV scan, which can be greatly improved through subjecting the electrode to special treatment such as polishing with alumina paste and sonication prior to each scan. The counter electrode is used to balance the faradaic process at the working electrode. It is usually composed of platinum or carbon, which does not produce products that can interfere with the reaction taking place at the working electrode. The counter electrode is used in conjunction with the reference electrode,

where the pair maintains a constant potential while passing current to counter redox events at the

working electrode.

The potential at the working electrode is monitored and precisely controlled with respect

to the reference electrode via the potentiostat, which is controlled via interfacing with a

computer. The desired waveform is imposed on the potential at the working electrode by a

waveform generator; the current flowing between the working electrode and working electrode is

usually measured as the potential drop V across a resistor, R (from which i=V/R), the resistor is

connected in series with the two electrodes. The resulting i/V trace is plotted in a computer to

allow any desired data analysis.17

An inlet and outlet for a purging gas such as nitrogen or argon are included in the cell as

removing of oxygen with a purging gas is usually necessary to prevent currents due to the

reduction of oxygen interfering with the response from the system under study. All electrodes are

immersed in the solution composed of the electroactive species dissolved in the solvent with a

supporting electrolyte. Supporting electrolytes are chemical species that are electrochemically

inert. The purpose of including supporting electrolytes in the solution is to minimize solution

resistance thereby improving the signal of the results. Conductivity, solubility of the supporting

electrolyte and the electroactive species, as well as the stability of the electrolytic products, are important factors for consideration when selecting the suitable solvent for electrochemical experiments such as CV.

Figure 1.8 - Three-electrode electrochemical cell employed for the study

III.2 Cyclic Voltammetry

The electrochemical reduction of the compounds was studied by cyclic voltammetry

(CV), an electrochemical technique that measures the current as a result of the cycling of the

potential of the working electrode. First reported in 1938 by Randles and Sevcik, CV is a widely

employed electrochemical characterization technique with a vast array of applications in

analytical and electrochemistry and is often the first experiment performed by the electrochemist,

yielding useful information regarding the presence of electroactive species in solution or at the electrode surface, as well as the dynamics and mechanism of an electron transfer reaction.48,59,83,84,147-150

CV is a simple electrochemical technique that functions based on the aforementioned

current-potential relationship, in which the current migrates in the presence of the electric field

of the potential, a process known as the electrode reaction. The electrode reaction provides

important information about the mechanism, energetic and kinetic of the electron transfer. The

electrode reaction is controlled by various factors: the mass transport of the electroactive species

at the electrode surface, the electron transfer, as well as the ensuing chemical reactions.

The important advantages of CV include the ability to vary the working electrode

potential linearly with time, and the wide range of scan rates available.17 The technique imposes

a periodic potential change on the system in which the potential is swept back and forth between

the two chosen vortexes (i.e forward and reverse scans), at a fixed scan rate with respect to time.

The current changes as result of the scan and the result is plotted as a current-potential curve

(cyclic voltammogram). During the CV scan, reduction or oxidation of the electroactive species

occurs, and the generated electroactive intermediates and products are detected and reflected on

the CV plot. Varying the scan rate controls the time scale of the CV experiment: a high scan rate

of up 1 × 106 Vs-1 could sometimes detect short-lived reaction intermediates that are otherwise

undetectable at slower scan rates.17,82,151-155 CV can provide important information about the

electrochemical characteristics, the number of electron exchanged in the overall reaction, as well

as the mechanistic, kinetic, and thermodynamic data. CV experiments can involve a single or

multiple scans. In a single scan CV experiment, the resultant voltammogram is useful in

determining many parameters including the reduction or oxidation potential, the number of

electrons transferred as result of the redox reaction, and the transfer coefficient. The presence of

multiple peaks also provides an initial information about the potential occurrence of chemical

reactions leading to new products. Multiple CV scans are useful in observing the chemical

changes occurring at the surface of an electrode. The cyclic voltammogram holds the keys to

gaining insight about the electrochemical behavior and reaction mechanism of a system.

The cyclic voltammogram can generally be categorized as irreversible (Figure 1.9), or

reversible (Figure 1.10). An irreversible reaction occurs when the rate constant of the

heterogeneous electron transfer is less than the rate constant of the chemical reaction that can

consume the product of the electron transfer.17 On the other hand, a reaction is considered

electrochemically reversible if its electron-transfer kinetics is fast enough to maintain the

concentration of both reactant and product at the electrode surface. The reversibility is an

indication of the presence of the radical ion within the time scale of the experiment.17 The Nerst equation (Equation 1.16) describes the relationship between the actual potential of the electrode

(E), and standard potential of the electrode couple (E°) and the number of electrons (n). Where

CO and CR are the concentrations of oxidized and reduced species, respectively.

RT C E = Eο + ln( o ) (1.16) nF CR

Figure 1.9 - Sample CV plot for the cathodic peak of an irreversible ET

Figure 1.10 - Sample CV plot for the anodic and cathodic peaks of a reversible ET

The cyclic voltammogram contains several important parameters about the

electrochemical characteristics, the number of electrons exchanged in the overall reaction, as

well as the mechanistic, kinetic, and thermodynamic data.

Epc and Epa are the cathodic and anodic peak potentials, respectively. Ep/2 is the half-peak

potential. Depending on whether the peak of interest is the result of the cathodic or anodic

reaction. The peak potentials allow for the determination of transfer coefficient, which provides

important information about the mechanistic nature of the first electron transfer in DET. The

transfer coefficient can be determined from either the electrochemical peak characteristics

(Equation 1.17), or the variation of the peak potential with respect to scan rate (ν) (Equation

1.18). In addition, for a stepwise electron transfer reaction exhibiting reversibility, the peak

potentials can be used to determine the standard reduction potential (E°) using Equation 1.19.

RT 1.85 α = (1.17) F (EP / 2 − EP ) RT ⎛ ∂(lnν ) ⎞ α = ⎜− ⎟ (1.18) 2F ⎝ (∂EP ) ⎠ E + E E o = pc pa (1.19) 2

ipc and ipa are the cathodic and anodic peak currents, respectively. The peak current for a

reversible system at 298K is described by the Randles-Sevcik equation (Equation 1.20). Where n

is the number of electrons, A is the electrode area in cm2, D is the diffusion coefficient in cm2 s-1,

ν is the scan rate in Vs-1 and C is the concentration. Equation 1.21 describes the peak current for an irreversible processes. As seen, the current is proportional to the concentration as well as to the transfer coefficient (α) and the number of electrons involved in the charge-transfer step (na).

5 3 / 2 1/ 2 1/ 2 ip = 2.69 ×10 n AD ν C (1.20) 5 1/ 2 3/ 2 1/ 2 ip = 2.99 ×10 (αna ) n AD C (1.21)

IV. Aim of the Thesis

The aim of this study is the investigation of the electrochemical reduction of substituted arylsulfonyl indoles. The substituents will include electron donating and electron withdrawing groups. The 4-nitrophenylsulfonyl indole, which showed high NHV-1 inhibition activity will be studied along with other derivatives which showed low activity and their electrochemical behaviors will be compared.

Among the initial questions to answer will be whether these derivatives can accept extra electrons through electrochemical reduction, the ease of the reduction process and its dependence on the substituent. The mechanism of the initial electron transfer will be determined. It is well established that the reaction outcome may depend on the electron transfer mechanism to the initial molecule. Whether an initial radical anion is generated as an intermediate in the reduction process or whether dissociation takes place leading directly to a radical and an anion can affect both the chemical reactivity and the biological activity of the precursor. Cyclic voltammetry data, along with application of the electron transfer theories, will allow determination of the initial electron mechanism of the investigated compound. It would be important to find out whether this mechanism depends on the nature of the substituent on the aryl ring.

The potential dissociation of a chemical bond in the electrochemical reduction will be investigated. The dissociation will be rationalized through application of the DET with the help of theoretical calculations. The global mechanism or mechanisms of the electrochemical reduction of the investigated arylsulfonyl indoles will be determined. Finally comparisons with structurally related compounds such as arylsulfonyl chlorides and arylsulfonyl phthalimides will be performed. These series have already been studied by previous members of the Houmam group.

Chapter 2 – Experimental Section

I. Cyclic Voltammetry

All CV measurements were conducted in the closed electrochemical cell with and purging gas inlet. The solution was purged with nitrogen prior to each CV scan to ensure the oxygen-free state of the solution. An Ekochemie 2 mm diameter glassy carbon electrode was used as the working electrode and underwent thorough polishing and sonication in methanol prior to each scan. The reference electrode employed in this study was a strand of silver wire.

The counter electrode was a platinum wire. An Autolab PGSTAT30 was used to control the experimental parameters such as the voltage, scan rate, and the vortexes. A feedback correction was applied to minimize the Ohmic drop between the working and reference electrode. The working solution consisted of about 2 mM of a compound of interest, in the presence of 0.1M of the supporting electrolyte tetrabutylammonium hexafluorophosphate (TBAHF). The monoelectronic wave of ferrocene was used as the internal standard for correcting the electrode potentials with respect to the known reduction value for the ferrocene/ferricinium couple, as well as for determining the number of electrons comused per molecule.

II. Theoretical Calculations

The molecular orbitals for the arylsulfonyl indoles calculations are performed using

Gaussian 2003.156 The LUMO orbitals were calculated using the UHF and B3LYP methods with the 6-31G+(d,p) basis set. LUMO orbitals and radical structure minima were calculated after the optimization without imposing symmetry of the conformation. Minimum energy structures were fully optimized and the obtained conformations were checked by running frequency calculations.

III. Chemicals

III. 1 Commercially Available Chemicals

Acetonitrile (Caledon) dispensed from a solvent purification system was used as the

solvent for CV studies. Toluene dispensed from a solvent purification system was used as the

solvent for the synthesis. Tetrabutylammonium tetrafluoroborate (Bu4NBF4) (Fluka, 98%) and

tetrabutylammonium hexafluorophosphate (TBAHF) (Fluka, 98%) were used as the supporting

electrolytes. Potassium hydride (Aldrich, 95%), indole (Aldrich, 97%), phenylsulfonyl chloride

(Aldrich, 97%), 4-chlorophenylsulfonyl chloride (Aldrich, 97%), 4-fluorophenylsulfonyl

chloride (Aldrich, 97%), 4-methylphenylsulfonyl chloride (Aldrich, 98%), 4-

methoxyphenylsulfonyl chloride (Aldrich, 97%), 3-nitrophenylsulfonyl chloride (Aldrich, 97%)

and 4-nitrophenylsulfonyl chloride (Aldrich, 98%) were used for the synthesis of the respective

substituted arylsulfonyl indoles. Tetrabutylammonium hydrogensulfate (TBAHS) (Fluka, 98%)

was used as the phase transition catalyst.

III.2 Synthesis of N-Arylsulfonyl Indoles

There are a number of synthetic schemes for N-arylsulfonylindoles available in the

literature, due in large part to the importance of their medicinal applications as well as their use

as robust intermediates under harsh reaction conditions.99-101,103,110,114,115,157-159 However, the vast

array of the published pathways for the synthesis of N-arylsulfonylindoles require rather harsh

reaction conditions such as employing lithium diisopropylamide (LDA) and extremely low

temperature, or an excess amount of base and long periods of refluxing. Several recent

publication on this topic focused on a more energy-efficient and environmentally-friendly

approach, albeit the tradeoff in lower yields in some cases.132,160

We are primarily interested in employing a synthetic scheme that strikes an optimal balance between environmental sustainability and yield. Through our literature search, it became apparent that there are two major synthetic approaches that would fall under the aforementioned category of being environmentally friendly yet feasible. One of such approach employs the use of phase transfer catalyst132 while the other utilizes hydrides. The commonality between these pathways is the deprotonation of indole thereby allowing the subsequent attack from the arylsulfonyl cation (Scheme 2.1).

R R Base + Cl N N S S H O O O O

Scheme 2.1 – Overall scheme for the synthesis of arylsulfonyl indoles

III.2.1 Phase Transfer Catalyst Method

Moisture-free toluene dispensed from the solvent-purification system was used as the solvent for the synthesis. Indole and tetrabutylammonium hydrogen sulfate (TBAHS) were dissolved in 10 mL of toluene under argon, followed by the addition of aqueous sodium hydroxide with rapid stirring. A solution of the corresponding phenylsulfonyl chloride (1 equivalent) dissolved in toluene (10 mL) was added drop-wise to the solution and allowed to stir for over six hours. The organic layer was separated and washed with water (3x30 mL), dried over Mg2SO4 and evaporated. The resultant solid was recrystallized from ethanol to give a crystalline product. The product is characterized using 1H and 13C NMR. The spectra were recorded at 400 MHz using a Bruker Advance-400 NMR spectrometer.

III.2.2 Synthesis of Nitro-substituted Arylsulfonyl Indoles – Potassium Hydride

Method

1.2 to 2.5 equivalents of potassium hydride from 35 wt% suspension in mineral oil was washed three times with pentane and suspended in 20 mL of THF and cooled to 0 °C. 5 equivalent of indole was dissolved in 10 mL of THF and was added dropwise to the KH solution over 5 minutes. The mixture was stirred at 0 °C for 30 min. A solution of 1 equivalent substituted arylsulfonyl chloride in 10 mL of THF was then added dropwise over 2 minute, and with continuous stirring for 30 min at 0 °C. The reaction was quenched with saturated 15mL of

NH4Cl solution and poured into a separatory funnel containing 50 mL of H2O. The solution was

extracted with EtOAc (3X 50 mL), the combined organic phases were dried over MgSO4, filtered through a pad of silica, and concentrated to afford the final product. The product is characterized using 1H and 13C NMR. The spectra were recorded at 400 MHz using a Bruker Advance-400

NMR spectrometer.

Chapter 3 – Electrochemical Reduction of Arylsulfonyl Indoles

I. Overview

Electrochemical investigations of the redox behavior of biologically important

compounds have the potential to provide insights into the biological redox behavior of these

molecules. As a biologically important molecule, the indole serves as a framework for a large

number of naturally occurring compounds. Drug discovery studies focusing on the indole frame

have attracted a great deal of attention amongst research community owing to their therapeutic

uses. The electroactive nature of indole makes the indole derivatives great candidates for

electrochemical investigation.58,103,107,115

Recent studies on the electrochemical behavior of indoles aimed at drug discovery have

been focusing on the electrochemical oxidation of the compounds, due to the common

assumption that oxidation reactions take place for all nitrogen-containing compounds in the

biological system.58,161 The electroactive nature and its ability to generate radical cations with

low oxidation potentials have been attributed to some of the observed therapeutic activities of the

indoles, in this regard the indolic radicals have received wide attention.58,99,107,110,114,115,162-164

However, the efficacy of the indolic radical cations to carry out oxidative action has been shown to be elusive.58 As Greci et al. has demonstrated, the aromatic amines and indoles interact only

through coupling of their neutral radicals.161

Our study of electrochemical behavior of indoles focuses on the electrochemical

reduction of these compounds. Examining the reduction behavior of the indoles allows us to

study the electron transfer induced bond dissociation reactions of indoles. A series of the

arylsulfonyl indole derivatives are selected for the study. The phenyl sulfonyl indole (1a) can be

viewed as a reference to study the effect of the additional electron-donating (1b-c) and electron- withdrawing substituents (1d-g). The nitro-substituted arylsulfonyl indoles (1f and 1g) are given special interest owing to their increased therapeutic activities reported in several recent anti-

HIV1 studies.103,115 Comparing and contrasting the effect on the electrochemical behaviors due

to the electron-donating and electron-withdrawing substituents may help us rationalize the

increased therapeutic activities observed for some of these compounds.

In this chapter the investigation of the electrochemical reduction of a series of

arylsulfonyl indoles (Chart 3.1) will be presented. The electrochemical characteristics (peak

potential (Ep), peak width (Ep - Ep/2), Ep - log(v) plots and transfer coefficient (α) values are

determined. These electrochemical characteristics allow for the determination of the initial

electron transfer process (stepwise vs concerted) as well as the global reduction mechanism.

Certain associated kinetics and thermodynamics aspects are discussed and rationalized with the

help of theoretical calculations and application of the DET theory.

N S O O Chart 3.1 - Arylsulfonyl indoles subjected to the investigation of their electrochemical behaviors. X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e); X = NO2, Y = H (1f); X = H, Y = NO2 (1g) The first aspect to be investigated is whether these molecules would follow a stepwise or

concerted dissociative mechanism upon injection of an initial electron. Scheme 3.1 depicts the

possible pathways that the arylsulfonyl indole may take upon injection of one electron. It is

worth noting that this scheme highlights the bond dissociation taking place at the S-N bond,

which has been observed by a previous study of similar compounds – arylsulfonyl

phthalimides19. As depicted in scheme 3.2, injecting an electron to the arylsulfonyl indole may

lead to other possible pathways.

X X Y concerted O + S Y N + e O S N O O ste pw ise X

N S O O Scheme 3.1 - Dissociative electron transfer mechanism pertaining to arylsulfonyl indoles upon injection of one electron. X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e); X = NO2, Y = H (1f); X = H, Y = NO2 (1g)

X X

Y Y + e N N S S O O O O C A X X

O O N + S Y S + Y N O O

B D

X X

O N O + S Y S + Y N O O Scheme 3.2 - Potential radical and anion pairs as result of the stepwise dissociative mechanisms of arylsulfonyl indoles upon injection of one electron. X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e); X = NO2, Y = H (1f); X = H, Y = NO2 (1g).

II. Results and Discussion

II.1. Voltammetric Behavior

The electrochemical reduction of the arylsulfonyl indole derivatives (1a-g) were studied by cyclic voltammetry in acetonitrile, in the presence of 0.1 M tetrabutylammonium tetrfluoroborate (Bu4NBF4) at a glassy carbon electrode. The ferrocene/ferrocenium couple was

used as the internal standard to determine the reduction potentials. The electrochemical behavior

are categorized according to the substituents (electron-donating vs. electron-withdrawing) on the

indole derivatives that the results are pertaining to. The peak characteristics (peak potential (Ep),

peak width (Ep-Ep/2)) were determined by cyclic voltammetry and used to calculate the transfer

coefficient (α) values. The ferrocene/ferrocenium couple is used to determine the number of

electrons involved in the electron transfer. The nitro-substituted indole derivatives are sub-

categorized from other derivatives with electron-withdrawing substituents owing to their distinct

electrochemical behavior.

II.1.1 - Electrochemical Reduction of 1-(Phenylsulfonyl)indole

Figure 3.1 shows the cyclic voltammogram corresponding to the reduction of 1.94 mM 1-

(phenylsulfonyl)indole (1a, PhSO2Ind). The electrochemical characteristics are summarized in

Table 3.1. A single cathodic peak is observed at a potential Ep = -1.68 V vs. SCE, measured at the scan rate of 0.2 Vs-1, and corresponds to the irreversible reduction of 1a. Its height, measured

by reference to the monoelectronic wave of the ferrocene internal standard, corresponds to the

consumption of two electrons per molecule. Figure 3.2 shows the overlay of the voltammograms

corresponding to the reduction of 1a obtained at scan rates varying from 0.2 Vs-1 up to 100 Vs-1.

As expected, increasing the scan rate resulted in a slight shift of the Ep towards the more negative potentials. The obtained Ep values at the varying scan rates enabled the determination

of the transfer coefficient using the Ep-log(v) plot (Figure 3.3), resulting in a value of 0.26. In

addition, the peak width (Ep-Ep/2) was also used to determine the transfer coefficient and a

value of 0.32 was obtained. In both cases the determined transfer coefficients are much lower

than 0.5, indicating a reaction kinetically controlled by the electron-transfer step.

Figure 3.1 - Cyclic voltammetry pertaining to the electrochemical reduction of 1.94 mM 1- (phenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile with 0.1 M Bu4NBF4 at 0.2 Vs-1 at ambient temperature.

Table 3.1 - Electrochemical characteristics for 1-(phenylsulfonyl)indole

Ep a Slopeb Compound α c Ep‐Ep/2 d α e n f (V/SCE) Ep‐log(v) 1a ‐1.68 ‐0.1086 0.27 ‐0.147 0.32 2 a: peak potential in V; b: from Ep vs. log(v) curve in V/log(v); c: transfer coefficient determined from Ep vs. log(v) curve; d: peak width from voltammogram, in V; e : transfer coefficient determined from peak width; f: number of electron(s) consumed per molecule

Figure 3.2 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 1.94 mM 1-(phenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1). All scans were carried out on a glassy carbon working electrode in acetonitrile at ambient temperature.

Figure 3.3 - Slope of Ep vs log (v) for obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 1.94 mM 1-(phenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1).

II.1.2 - Electrochemical Reduction of 1-(4-Methylphenylsulfonyl)indole

The electrochemical reduction of 1-(4-methylphenylsulfonyl)indole (1b, 4MePhSO2Ind)

exhibited similar voltammetric behavior as that of 1a. The introduction of the para-methyl group

resulted in a less negative potential when compared to 1a, as seen in Figure 3.4, corresponding to

the reduction of 1.99 mM of 1b. The electrochemical characteristics are summarized in Table

3.2. A single cathodic peak is observed at a potential Ep = -1.69 V vs. SCE, measured at the scan

rate of 0.2 Vs-1, corresponding to the irreversible reduction of 1b. Its height, measured with

respect to the monoelectronic wave of the ferrocene internal standard, corresponds to the

consumption of two electrons per molecule. Figure 3.5 shows the overlay of the cyclic

voltammograms corresponding to the reduction of 1b obtained at scan rates varying from 0.2 Vs-

1 up to 100 Vs-1. Once again, increasing the scan rate resulted in a slight shift of the Ep towards

the more negative potential, as seen previously for 1a. The obtained Ep values at the varying

scan rates enabled the determination of the transfer coefficient using the Ep-log(v) plot (Figure

3.6), resulting in a value of 0.31. In addition, the peak width (Ep-Ep/2) was also used to

determine the transfer coefficient and a value of 0.36 was obtained. Once again, the determined

transfer coefficients are much lower than 0.5, indicating a reaction kinetically controlled by the

electron-transfer step.

Table 3.2 - Electrochemical characteristics for 1-(4-methylphenylsulfonyl)indole.

Ep a Slopeb Compound α c Ep‐Ep/2 d α e n f (V/SCE) Ep‐log(v) 1b ‐1.69V ‐0.0952 0.31 ‐0.130 0.36 2

a: peak potential in V vs. SCE; b: from Ep vs. log(v) curve in V/log(v); c: transfer coefficient determined from Ep vs. log(v) curve; d: peak width from voltammogram, in V; e : transfer coefficient determined from peak width; f: number of electron(s) consumed per molecule.

Figure 3.4 - Cyclic voltammetry pertaining to electrochemical reduction of 1.99 mM of 1-(4- methylphenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile with 0.1 M -1 Bu4NBF4 at 0.2 Vs at ambient temperature.

Figure 3.5- Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 1.99 mM of 1-(4-methylphenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1). All scans were carried out on a glassy carbon working electrode in acetonitrile at ambient temperature.

Figure 3.6 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 1.99 mM 1-(4-methylphenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1).

II.1.3 Electrochemical Reduction of 1-(4-Methoxyphenylsulfonyl)indole

At the scan rate of 0.2 Vs-1, the reduction of 1.95 mM of 1-(4-

methoxyphenylsulfonyl)indole (1c, 4MeOPhSO2Ind) shows a single cathodic peak is observed

at a potential Ep = -1.69 V vs. SCE. The monoelectronic wave of the ferrocene internal standard

confirms the consumption of two electrons per molecule. The electrochemical characteristics are

summarized in Table 3.3. Figure 3.8 shows the overlay of the cyclic voltammograms

corresponding to the reduction of 1c obtained at scan rates varying from 0.1 Vs-1 up to 10 Vs-1.

Once again, increasing the scan rate resulted in a slight shift of the Ep towards the more negative potential, as seen previously for 1a and 1b. The obtained Ep values at the varying scan rates enabled the determination of the transfer coefficient using the Ep-log(v) plot (Figure 3.9), resulting in a value of 0.31. In addition, the peak width (Ep-Ep/2) was also used to determine the

transfer coefficient and a value of 0.38 was obtained. The voltammetric behavior of 1c indicates

a reaction kinetically controlled by the electron-transfer step due to the fact that transfer

coefficients are much lower than 0.5.

Figure 3.7 - Cyclic voltammetry pertaining to the electrochemical reduction of 1.95 mM 1-(4- methoxyphenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile with 0.1 M -1 Bu4NBF4 at 0.2 Vs at ambient temperature.

Table 3.3 - Electrochemical characteristics for 1-(4-methoxyphenylsulfonyl)indole

Ep a Slopeb Compound α c Ep‐Ep/2 d α e n f (V/SCE) Ep‐log(v) 1c ‐1.69V ‐0.0923 0.31 ‐0.12 0.38 2

Figure 3.8 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 1.95 mM 1-(4-methoxyphenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, and 10 Vs-1).

II.1.4 Electrochemical Reduction of 1-(4-Chlorophenylsulfonyl)indole

The 1-(4-chlorophenylsulfonyl)indole (1d, 4ClPhSO2Ind) affords the means of studying

the effect of introducing an electron-withdrawing group on the voltammetric behavior of the arylsulfonyl indoles. At the scan rate of 0.2 Vs-1, the reduction of 2.13 mM of 1d resulted in a

single cathodic peak at a peak potential Ep = -1.66 V vs SCE. Its height, measured with respect

to the monoelectronic wave of the ferrocene internal standard, corresponds to the consumption of

two electrons per molecule (Figure 3.10). The electrochemical characteristics are summarized in

Table 3.4. Figure 3.11 shows the overlay of the cyclic voltammograms corresponding to the

reduction of 1d obtained at scan rates varying from 0.1 Vs-1 up to 10 Vs-1. Once again, increasing

the scan rate resulted in a slight shift of the Ep towards the more negative potential, as seen

previously for 1a-c. The obtained Ep values at the varying scan rates enabled the determination

of the transfer coefficient using the Ep-log(v) plot (Figure 3.12), resulting in a value of 0.33. In

addition, the peak width (Ep-Ep/2) was also used to determine the transfer coefficient and a

value of 0.35 was obtained. Since the determined transfer coefficients are much lower than 0.5,

the voltammetric behavior of 1d indicates the reaction is kinetically controlled by the electron- transfer step.

Table 3.4 - Electrochemical characteristics for 1-(4-chlorophenylsulfonyl)indole

Ep a Slopeb Compound α c Ep‐Ep/2 d α e n f (V/SCE) Ep‐log(v) 1d ‐1.66 ‐00874 0.33 ‐0.13 0.35 2 a: peak potential in V vs. SCE; b: from Ep vs. log(v) curve in V/log(v); c: transfer coefficient determined from Ep vs. log(v) curve; d: peak width from voltammogram, in V; e : transfer coefficient determined from peak width; f: number of electron(s) consumed per molecule.

Figure 3.10 - Cyclic voltammetry pertaining to the electrochemical reduction of 2.13 mM 1-(4- chlorophenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile at 0.2 Vs-1 with 0.1 M Bu4NBF4 at ambient temperature.

Figure 3.11 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 2.13 mM 1-(4-chlorophenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 2.0 Vs-1, 5.0 Vs-1, and 10 Vs-1).

Figure 3.12 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to the electrochemical reduction of 2.13 mM 1-(4-chlorophenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 2.0 Vs-1, 5.0 Vs-1, and 10 Vs-1).

II.1.5 Electrochemical Reduction of 1-(4-Fluorophenylsulfonyl)indole

The electrochemical behavior of 1-(4-fluorophenylsulfonyl)indole (1e, 4FPhSO2Ind)

provided similar results to that for its 4-chloro counterpart (1d). At the scan rate of 0.2 Vs-1, the

cyclic voltammetry of 2.14 mM of 1e resulted in a single cathodic peak with Ep of -1.73 V vs.

SCE, corresponding to the irreversible reduction of 1e. Ferrocene internal standard confirmed the consumption of two electrons per molecule (Figure 3.13). The electrochemical characteristics are summarized in Table 3.5. The overlay of the cyclic voltammograms corresponding to the reduction of 1e obtained at scan rates varying from 0.1 Vs-1 up to 10 Vs-1 is shown in Figure

3.14. Once again, increasing the scan rate resulted in a slight shift of the Ep towards the more negative potentials, as seen previously for all other compounds. A transfer coefficient value of

0.44 is determined from the obtained Ep values at the varying scan rates using the Ep-log(v) plot

(Figure 3.15). In addition, the peak width (Ep-Ep/2) was also used to determine the transfer coefficient and a value of 0.40 was obtained. The determined transfer coefficients are lower than

0.5, the voltammetric behavior of 1e indicates the reaction is kinetically controlled by the electron-transfer step. The transfer coefficient values are however slightly higher than those obtained for the previous compounds (1a-d).

Figure 3.13 - Cyclic voltammetry pertaining to the electrochemical reduction of 2.14 mM 1-(4- fluorophenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile at 0.2 Vs-1 with 0.1 M Bu4NBF4 at ambient temperature.

Table 3.5 - Electrochemical characteristics for 1-(4-fluorophenylsulfonyl)indole

Ep a Slopeb Compound α c Ep‐Ep/2 d α e n f (V/SCE) Ep‐log(v) 1e ‐1.73 ‐‐0.0656 0.44 ‐0.12 0.40 2

Figure 3.14 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 2.14 mM 1-(4-fluorophenylsulfonyl)indole at varying scan rates (0.1 Vs-1, 0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, and 10 Vs-1).

Figure 3.15 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 2.14 mM 1-(4-fluorophenylsulfonyl)indole at varying scan rates (0.1Vs-1, 0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, and 10 Vs-1).

II.1.6 Electrochemical Reduction of 1-(3-Nitrophenylsulfonyl)indole

The reduction of 1-(3-nitrophenylsulfonyl)indole (1f, 3-NO2PhSO2Ind) revealed a

markedly different electrochemical behavior compared to all the previous samples (1a-e). At the scan rate of 0.2 Vs-1, the reduction of 2.08 mM of 1f showed three major reduction peaks at the

potentials of Ep1 = -0.73 V, Ep2 = -1.63 V and Ep3 = -2.50 V (Figure 3.16). A peak at -1.5 V

was only observable at low scan rates up to 1 Vs-1. Furthermore, reversing the scan after the first

o reduction peak reveals a reversible wave (E1 = -1.1 V ), corresponding to the formation of a

radical anion due to the single electron transfer as evidenced by the reversibility observed upon

reversing the scan after the initial reduction peak. A second irreversible reduction peak (Eo = -1.9

V) corresponds to a further reduction of 1f and the consumption of another electron. The third reduction peak at a more negative potential (Ep3 = -2.8 V) corresponds to the well-known

133 reduction of the nitro group to NH2 group . The electrochemical characteristics are summarized

in Table 3.6. The overlay of the cyclic voltammograms corresponding to the reduction of 1f

obtained at scan rates varying from 0.2 Vs-1 up to 100 Vs-1 is presented in Figure 3.17. Here, increasing the scan rate did not result in a pronounced shift of the Ep towards the more negative potential, as readily observed for the previous compounds. The obtained Ep1 values at the

varying scan rates enabled the determination of the transfer coefficient using the Ep1-log(v) plot

(Figure 3.18), resulting in a value of 0.83. In addition, the peak width (Ep1-Ep11/2) was also used

to determine the transfer coefficient and a value of 0.80 was obtained. Both of the determined

transfer coefficient values point to a stepwise mechanism and the formation of a radical anion

(1f ● –) as well.

Figure 3.16 - Cyclic voltammetry pertaining to the electrochemical reduction of 2.08 mM 1-(3- nitrophenylsulfonyl)indole indole on a glassy carbon working electrode in acetonitrile at 0.2 Vs-1 with 0.1 M Bu4NBF4 at ambient temperature.

Table 3.6 - Electrochemical characteristics for 1-(3-nitrophenylsulfonyl)indole

a a a b Ep1 Ep2 Ep3 Slope c d e f 0 g Compound α Ep1‐Ep1/2 α n E1 (V/SCE) (V/SCE) (V/SCE) Ep1‐log(v) 1f ‐0.73 ‐1.63 ‐2.50 ‐0.035 0.83 ‐0.06 0.80 1 ‐1.1V

a: 1st, 2nd and 3rd peak potentials in V vs. SCE; b: from Ep vs. log(v) curve in V/log(v); c: transfer coefficient determined from Ep vs. log(v) curve; d: peak width from voltammogram, in V; e : transfer coefficient determined from peak width; f: number of electron(s) consumed per molecule; g: standard reduction potential.

Figure 3.17 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 2.08 mM 1-(3-nitrophenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1).

Figure 3.18 - Slope of Ep1 vs log (v) obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 2.08 mM 1-(3-nitrophenylsulfonyl)indole at varying scan rates from (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1).

II.1.7 Electrochemical Reduction of 1-(4-Nitrophenylsulfonyl)indole

The reduction of 1-(4-nitrophenylsulfonyl)indole (1g, 4NO2PhSO2Ind) revealed yet

another markedly different electrochemical behavior compared to all the previous samples (1a-

d), but slightly resembles that observed for 1e. Reduction of 1.98 mM 1g at the scan rate of 0.2

-1 Vs revealed three major reduction peaks at the potentials of Ep1 = -0.36 V, Ep2 = -1.06 V and

Ep3 = -1.76 V (Figure 3.19). Reversing the scan after the first and the second reduction peak reveals two reversible waves (shown in dashed lines, Figure 3.19), which differs from the

o electrochemical of 1f where only the first peak was reversible. The first reduction peak (E1 = -

0.9 V) corresponds to the formation of a radical anion due to the single electron transfer as evidenced by the reversibility observed upon reversing the scan after the initial reduction peak.

o The second peak (E2 = -1.4 V) exhibits reversibility, corresponds to the subsequent reduction of

1g and the formation of a dianion, an indication that the para-nitro compound (1g) was able to better hold an additional electron in comparison to its meta-nitro counterpart (1f). The third

reduction peak, observed at a more negative potential (E3 = -2.2 V), corresponds to the reduction of the nitro group to NH2 group and is in reasonable agreement with the electrochemical

behavior observed for 1f. The electrochemical characteristics are summarized in Table 3.7. The

overlay of the cyclic voltammograms corresponding to the reduction of 1g obtained at scan rates

varying from 0.2 Vs-1 up to 100 Vs-1 is presented in Figure 3.20 Once again, increasing the scan rate did not result in a pronounced shift of the Ep towards the more negative potential, as readily observed for the previous compounds (1a-e). The obtained Ep1 values at the varying scan rates enabled the determination of the transfer coefficient using the Ep1-log(v) plot (Figure 3.21), resulting in a value of 0.90. In addition, the peak width (Ep1-Ep1/2) was also used to determine

the transfer coefficient and a value of 0.90 was obtained.

Figure 3.19 - Cyclic voltammetry pertaining to the electrochemical reduction of 1.98 mM 1-(4- nitrophenylsulfonyl)indole on a glassy carbon working electrode in acetonitrile at 0.2 Vs-1 with 0.1M Bu4NBF4 at ambient temperature.

Table 3.7 - Electrochemical characteristics for 1-(4-nitrophenylsulfonyl)indole

a a a b Ep1 Ep2 Ep3 Slope c d e f 0 g 0 g Compound α Ep1‐Ep1/2 α n E1 E2 (V/SCE) (V/SCE) (V/SCE) Ep1‐log(v) 1g ‐0.36 ‐1.06 ‐1.76 ‐0.032 0.90 ‐0.05 0.90 1 ‐0.9V ‐1.4V

Figure 3.20 - Overlay of cyclic voltammetry plots pertaining to the electrochemical reduction of 1.98 mM 1-(4-nitrophenylsulfonyl)indole at varying scan rates from (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1).

Figure 3.21 - Slope of Ep vs log (v) obtained from the cyclic voltammetry data pertaining to electrochemical reduction of 1.98 mM 1-(4-nitrophenylsulfonyl)indole at varying scan rates (0.2 Vs-1, 1.0 Vs-1, 5.0 Vs-1, 10 Vs-1, 20 Vs-1, 50 Vs-1 and 100 Vs-1).

The cyclic voltammetry data show important results. All compounds can take an initial extra electron leading either to the formation of a radical anion (compounds 1f,g) or to the immediate irreversible dissociation of a chemical bond (compounds 1a-e). The nitro-substituted compounds 1f and 1g are also are much easier to reduce than the rest of the compounds. Both of these compounds (1f,g) can take a second electron but this will cause a faster dissociation of compound 1f compared to compound 1g.

To gain further understanding of the bond dissociation, theoretical calculations are performed to determine the orbitals and the change in bond lengths as result of reduction

(calculated for 1f and 1g). In addition, bond dissociation energies are calculated in an effort to compare the effect of the substituent on the dissociation.

II.2. Theoretical Calculation Results

A theoretical study at the B3LYP level of compounds 1a-g was performed in an effort to further understand the nature of the initial electron transfer and understand the observed different electrochemical behaviors. Figure 3.23 shows the LUMOs of compounds 1a-e. Figure 3.24 shows the LUMOs of compounds 1f-g and the SOMOs of their reduced forms.

Structure LUMO

Figure 3.22 - Molecular structure and calculated LUMOs for 1a-e

Molecular Structure LUMO SOMO

Figure 3.23 - Molecular structure and calculated LUMOs and SOMOs for 1f-g

For compounds 1a-e, the LUMOs are dispersed over the entire molecule but with greater participation of the arylsulfonyl moiety compared to the indole moiety (Figure 3.22). This data along with the electrochemical results indicate that the incoming electron would likely be injected into the σ S-N bond leading to its dissociation through a concerted ET mechanism. The nitro-substituted arylsulfonyl indoles (1f and g) reveals a markedly different LUMO structure in that the presence of the nitro group shifts completely the LUMOs to be delocalized over the nitrophenyl moiety (Figure 3.23), an indication that the incoming electron would be injected into the π* yielding a radical anion intermediate. This is in agreement with a stepwise mechanism as was suggested by our electrochemical data. The SOMO structures for the reduced forms of nitro- substituted arylsulfonyl indoles (1f and 1g) provide an explanation for the intriguing difference observed in the electrochemical behavior. In the case of the 1-(3-nitrophenylsulfonyl)indole (1f), the SOMO is delocalized over the entire molecule. The delocalization of the SOMO would net the same dissociation of the reduced nitro-substituted arylsulfonyl indoles, where the additional

electron will likely be injected into the σ* S-N bond thereby leads to S-N its dissociation. On the other hand, 1-(4-nitrophenylsulfonyl)indole (1g) shows a SOMO that is completely shifted from the arylsulfonyl moiety to the indole moiety. This shows that the second electron would be injected into this moiety, leading to a dianion intermediate, before it is transferred to the S-N σ* causing the dissociation.

The theoretical bond lengths for the N-S and S-C chemical bonds for compounds 1f and

1g before and after reduction are tabulated for comparison (Table 3.9). For both compounds, an increase in the S-N bond length after the reduction, and a slight decrease in the S-C bond length after the reduction, are determined. The finding indicates the weakening of the S-N bond upon the reduction, which suggests the S-N the bond that is likely to undergo dissociation after the reduction.

Table 3.8 - S-N and S-C bond lengths for 1f and 1g before and after reduction

dS-N(1) dS-N(1+e) dS-C(1) dS-C(1+e) 1f 1.71 Å 1.75 Å 1.80 Å 1.78 Å 1g 1.71 Å 1.76 Å 1.80 Å 1.78 Å

The bond dissociation energies were also determined for the N-S chemical bond for all investigated compounds and the values are reported in Table 3.10. These values indicate that the

N-S bond strength is independent of the nature of the substituents on the aryl ring. This is an indication that the observed differences in the electrochemical behavior of the investigated compounds (ease of reduction and mechanism of the initial ET) are not related to the bond dissociation energy of the cleaved bond. The N-S bond dissociation energies being independant of the nature of the substituents is also observed for the arylsulfonyl phthalimides.19 In that study the bond dissociation energies determined for the 1-(4-methylphenylsulfonyl)phthalimide and 1-

(4-nitrophenylsulfonyl)phthalimide are 58.73 and 59.28 kcal mol-1, respectively. The similar bond dissociation energies again are indications that the N-S bond strength is independent of the nature of the substituents on the aryl ring.

Furthermore, it is important to highlight that the N-S bond dissociation energies determined for the arylsulfonyl indoles are markedly lower than those determined for the arylsulfonyl phthalimide.19 The N-S bond dissociation has been verified for arylsulfonyl phthalimides using electrolysis techniques in that study. This confirmation is of importance to the determination of the DET mechanism for the arylsulfonyl indoles. Based on the resemblance in the structures between the arylsulfonyl phthalimides and the arylsulfonyl indoles, and the similar patterns in bond dissociation energies, it will be assumed that the incoming electron will be injected into the σ S-N bond leading to its dissociation.

Table 3.9 - N-S bond dissociation energies for 1a-g

BDE ArSO -indole N-S 2 (kcal mol-1) 1a 39.44 1b 39.34 1c 39.37 1d 39.57 1e 39.57 1f 39.89 1g 39.89

III. Deduced Electron Transfer Mechanism

The electrochemical behaviors of the arylsulfonyl indoles uncovered by the CV data, and

the complementary theoretical calculations, coupled with the foundations laid out by the earlier

arylsulfoyl phthalimides, are used in conjunction to deduce the electron transfer mechanism for

each of the compounds of interest.

III.1. Deduced Electron Transfer Mechanism for compounds 1a – e

The reduction of compounds 1a-e reveals a single irreversible reduction peak, which is

indicative of a dissociation of these compounds upon injection of an extra electron. The

dissociation leads to a radical and an anion. The first reduction peak, of compounds 1a-e, is

attributed to the transfer of 2 electrons, as determined by comparison to the reduction peak of the

monoelectronic wave of ferrocene. This indicates that the initially generated radical is

immediately reduced at the electrode to the corresponding anion. This is a general process that is

observed with many organic and bioorganic compounds especially when the initial ET

mechanism is concerted.18,19,23,25,88 The reason being that the intermediate radicals are usually

easier to reduce than the parent structures and since they are generated at the electrode at

potentials that are negative enough they are immediately reduced. This leads to a global process

for compounds 1a-e, where the first peak corresponds to the exchange of 2 electrons and the formation of two anions through dissociation of the N-S bond (Scheme 3.3).

X X

Y O + 2 e + S Y N N O S O O X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e)

Scheme 3.3 - Dissociation reaction equation for 1a-e

The transfer coefficient values obtained from the CV data (peak width values and slope

of Ep vs log v plots) are all much lower than 0.5. These values are consistent with a reduction of

compounds 1a-e following a concerted DET mechanism, where both the bond dissociation and

the electron transfer occur concomitantly. The theoretical calculations on orbitals and change in

bond lengths further complements the evidence of dissociation in supporting the likelihood of the incoming electron being injected into the N-S bond, based on the greater participation of

LUMOs over the sulfonyl aryl moiety.

Taken altogether the CV data and theoretical calculations, as well as the previously confirmed N-S dissociation behavior for the similar compouds, the arylsulfonyl phthalimides, it is safe to rule out the possibilities of the S-C bond dissociation (Scheme 3.3, pathways C and D).

Thus, the mechanistic investigation is limited to the two remaining possible pathways pertaining to the N-S bond dissociation (Scheme 3.4, pathways A and B). Pathway A depicts the first possibility of the N-S bond dissociation where the decompositions of 1a-e leads to an indolyl

radical and the corresponding substituted phenylsulfonyl anion. Pathway B depicts the alternate

possibility where the decomposition leads to and indolyl anion and the corresponding substituted

phenylsulfonyl radical.

X Y + N e S O O

A B X X

O O + S Y + S Y N O N O X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e)

Scheme 3.4 - Possible DET pathways for compounds 1a-e upon taking into account the CV

Comparison of the oxidation potentials of the two possible anions (indolyl and

arylsulfinate) can in principle provide insight for the dissociation mechanism. The standard

oxidation potential for the indolyl anion has been previously estimated (E0 = 1.04 V/ SCE).165

For the sulfinate anions, the only available values are those corresponding to the oxidation peak potentials. The values range from 0.45 V/SCE (for 4-methylphenyl sulfinate) to 0.65 V/SCE (for

4-nitrophenyl sulfinate).19 Based on the oxidation potentials, it is more difficult to oxidize indole

than to oxidize the respective phenylsulfonyls. Hence, it is reasonable to assume that at least for

compounds 1a-e that the decomposition will lead to the indolyl anion and the corresponding

substituted phenyl sulfonyl radical (Scheme 3.4B).

The CV data and the theoretical calculations collectively allow for the determination of

the DET mechanism for 1a-e. As per the electrochemical characteristics, the initial DET to

compounds 1a-e follows a concerted mechanism where the electron transfer and the N-S bond

dissociation are simultaneous, resulting in the indolyl anion and the corresponding arylsulfonyl

radical (Scheme 3.5A). The produced phenyl sulfonyl radical is immediately reduced at the electrode since it is easier to reduce than the parent phenyl sulfonyl indole (Scheme 3.5B).

X X (A) Y O N + e + S Y S N O O O X X

(B) O O S Y + e S Y O O X = H, Y = H (1a); X = H, Y = Me (1b); X = H, Y = OMe (1c); X = H, Y = Cl (1d); X = H, Y = F (1e)

Scheme 3.5 - Deduced concerted electrochemical reduction mechanism of compounds 1a-e

III.2 - Deduced Electron Transfer Mechanism for Compounds 1f and 1g

The transfer coefficient values obtained from the CVs data of the nitro-substituted

arylsulfonyl indoles (1f and 1g) indicate that the reduction of both compounds follows a stepwise

DET mechanism. The CV results reveal that both 1f and 1g exhibit a reversible wave at the first reduction potential. The reversibility indicates that the initial reduction of compounds 1f and 1g leads to the corresponding radical anion (1f● – and 1g● –, respectively, Scheme 3.6A), which are

stable within the CV timescale. The theoretical calculations showed the radical anions for

compounds 1f and 1g show real minima supporting the electrochemical data. These calculations

further show that the presence of the nitro substituent predominantly shifted the location of

LUMO to the nitrophenyl group, where the nitro functionality served as an electron sink holding

the electron to form the radical anion.

Under the CV conditions, when the applied potential is rapidly scanned to more negative

values, additional electrons can be injected to the radical anions (1f● – and 1g● –) before their

dissociation. The broadness and irreversibility of the second peak in the CV of 1-(3-

nitrophenylsulfonyl)indole (1f) indicates that the addition of the second electron caused the

immediate and most likely concerted dissociation of the N-S bond (Scheme 3.6, pathway A).

This is further supported by the theoretical calculations showing a delocalized SOMO and a

relatively weak N-S chemical bond. For 1-(4-nitrophenylsulfonyl)indole (1g), the second peak in

the CV shows some reversibility, which is an indication of the formation of a relatively stable

dianion (1g2 –) in the CV timescale (Scheme 3.6, pathway B). The localized SOMO on the indole

moiety is in agreement with the electrochemical data.

X Y + e N S O O A B

X 2 X Y O + S Y N N O S O O Scheme 3.6 - Possible dissociative mechanisms for 1f (X=NO2, Y=H) and 1g (X=H, Y= NO2)

It is important to note that the mechanisms of Scheme 3.6 are followed under CV

conditions. The intermediates are generated at the surface of the electrode whose potential is

changed rapidly. The weakening of the S-N bond, determined based on the change in bond

length after the reduction, also needs to be taken into account for the mechanistic determination.

The weakening of the S-N bond suggests that when given enough time, both radical

anions (1f●– and 1g●–) eventually dissociate, yielding a radical and an anion. In the case of

compounds 1f and 1g it is not possible to deduce with certainty whether the extra electron of the

radical anion will end up in the nitrophenylsulfonyl moiety or on the indolyl moiety (Scheme

3.7), solely based on the previously determined oxidation potentials. It is possible in this case

that the dissociation leads to an indolyl radical and a nitrophenylsulfinate anion. This aspect will

need to be further investigated.

X X Y Y + e N N S S O O O O A B

X X

O O + S Y + S Y N N O O

Scheme 3.7 - possible dissociative mechanisms of compounds for 1f (X=NO2, Y=H) and 1g (X=H, Y= NO2)

III.3. Comparison with Other Arylsulfonyl Compounds

The electrochemical reduction of substituted arylsulfonyl chlorides and phthalimides has

been investigated by previous members of our group.18,19,23,25 The study of these series allowed

investigation of the nature of the leaving group. While both the chloride and phthalimide anions

are excellent leaving groups their sizes, oxidation potentials and effect on the LUMO of the

initial structures are different. The study of the arylsulfonyl indoles provides the means to

investigate the effect of a completely different potential leaving group, the indole. Important

differences exist between the present series and the two previous ones.

With the arylsulfonyl chlorides,18 while a concerted ET mechanism was also observed for

the Me, H, Cl and F substituents major differences were observed for the global mechanism and

for the nitro-substituted derivative. The latter compounds did not show a stepwise ET mechanism

but a rather a “sticky” dissociative mechanism in which, the reduction of the parent molecule

does not lead to a radical anion but to a radical/anion pair. So the molecule dissociates through a

concerted process but the two generated fragments interact together before complete diffusion.18

The main difference though is the occurrence of an autocatalytic mechanism as shown in Scheme

3.8. Autocatalytic processes have an impact on the electrochemical behavior and on the chemical

and biological properties of the involved compounds since they are reduced much easier than

expected. The presence of such an autocatalytic process for the arylsulfonyl chlorides is due to

the intermediate formation of a dimer, which plays the role of the catalyst since it is easier to

reduce than the parent molecule. The absence of such a mechanism for the arylsulfonyl indoles is

due to their more difficult reduction compared arylsulfonyl chlorides which prevents an electron

transfer from the arylsulfinates. Such an electron transfer is possible to the arylsulfonyl

chlorides, due to their easier reduction and leads to the formation of the dimer catalyst166

(Scheme 3.8 reaction B and C).

ArSO2Cl + 2e ArSO2 + Cl (A)

ArSO2 + ArSO2Cl 2ArSO2 + Cl (B)

2ArSO2 ArSO2SO2Ar (C)

ArSO2SO2Ar + 2e 2ArSO2 (D)

ArSO2 + ArSO e 2 (E)

Scheme 3.8 - Reduction mechanism of arylsulfonyl chlorides

The electrochemical behavior in terms of the radical anions formation of the arylsulfonyl

indoles is also totally different than that of the arylsulfonyl phthalimides. With the latter

compounds a stepwise mechanism is observed for all compounds including the ones with

electron donating substituents.19 The electrochemical reduction of the 1-(4-nitrophenylsulfonyl)

phthalimide showed even the formation of a radical anion that decomposes faster than the rest of

the compounds. The reason being that it was the only compound among that series that had a

LUMO located on the arylsulfonyl moiety. With the other substituents the LUMO was located

on the phthalimide group.

Figure 3.24 – LUMO structures of (a) 1-(4-methylphenylsulfonyl)phthalimide and (b) 1-(4- nitrophenylsulfonyl)phthalimide. III.4. Reduction of Nitroaromatics and the Futile Cycle

As previously discussed, the presence of the nitro functionality and the accompanying

free-radical reaction are likely responsible for the toxicity as well as the therapeutic activity of

nitro aromatic compounds. In the biological system, most nitro aromatic compounds undergo

enzymatic reduction to form the radical anions.108,134 The nitroreductase (NTR) enzymes are

responsible for the bio-activation of nitro aromatic compounds through either one or two electron

sequential activation.108,134,167 The type I NTR enzymes are oxygen-insensitive and perform two-

electron reductions while the type II NTR enezymes are oxygen-sensitive and perform one-

electron reduction.85 The products of a sequential two-electron reduction of the functionality via type I NTR catalyzed bioactivation are the nitroso and the hydroxylamine intermediates. The type II NTR product is the nitro radical anion (Scheme 3.9).167

As seen in shceme 3.9, the one-electron reduction of a nitro group produces a nitro

radical anion. Under aerobic condition the radical anion is reoxidized back to the nitro group by

molecular oxygen. The oxygen is in turn reduced to form a reactive superoxide anion. The futile

cycle between the nitro group and the nitro radical anion initiated by the one-electron reduction

of the nitro group provides a continuous source of superoxide, which can exert toxic effects and

can be attributed to the toxic and therapeutic effects of the nitro compounds. In addition, the nitro

radical anion generated as a result of the type II NTR reduction is capable of bringing about the

subsequent reactive species such as the nitroso and hydroxylamine intermediates can react with

biomolecules to elicit toxic and even mutagenic cellular response.134,167 Furthermore,

hydroxylamines can be converted to reactive nitrenium ions that reactive with DNA.167

On the basis of the nitro radical anion and its participation in futile cycle, the more

readily the nitro compound undergoes the one-electron reduction, the more readily its radical

anion would participate in the futile cycle. Our data pertaining to the electrochemical reduction

of the nitro phenyl sulfonyl indoles can be extrapolated as a simplified view of the extent to

which these compounds can be readily bio-activated.

In conclusion, the nitro radical anion is extremely potent at producing a variety of

reactive species in the biological system. Hence, the nitro radical is critically important to the

therapeutic activities of nitro aromatic drugs.

O O H N 2e N 2e N 2e NH2 Ar O Ar Ar OH Ar (Type I NTR) (Type I NTR) (Type I NTR)

O2 e O (Type II NTR) N Ar O

O2 O O N N O Ar Ar O

Scheme 3.9 - One- and two-electron reduction of nitro-aromatics

Chapter 4 – Results Pertaining to the Synthesis of Arylsulfonyl Indoles

I.1 – Phenylsulfonyl Indole Yields

As a preliminary study, phenylsulfonyl indole (1a) was synthesized using both the

reported hyride and phase transfer catalyst approach, using indole and phenylsulfonyl chloride as

the starting reagents. The feasibility of synthesizing the compound without the use of phase

transfer catalysts was investigated as well. As seen in Table 2.1, the use of phase transfer catalyst

resulted in significantly higher yields, while the yields obtained through the use of phase transfer

catalyst is similar to that obtained for the hydride method. In addition, our results indicate increasing the molar ratio of NaOH or KH had negligible effect on the yield.

Table 4.1 - Molar ratios and yields pertaining to the synthesis of 1-(phenylsulfonyl)indole

Base + Cl N N S S H O O O O indole pheyl sulfonyl chloride Molar Ratio Reaction a Yield Indole PhSO2Cl Base PTC 1 1.5 1.0 1.5 (NaOH) 0 45% 2 1.5 1.0 2.0 (NaOH) 0 66% 3 1.5 1.0 5.0 (NaOH) 0 65% 0.1 4 1.5 1.0 1.5 (NaOH) 88% (TBAHS) 0.1 5 1.5 1.0 2.0 (NaOH) 88% (TBAHS) 0.1 6 1.5 1.0 5.0 (NaOH) 86% (TBAHS) 0.5 7 1.5 1.0 1.5 (NaOH) 87% (TBAHS) 8 1.5 1.0 1.2 (KH) 0 19% 9 5.0 1.0 1.2 (KH) 0 85% 10 5.0 1.0 2.5 (KH) 0 82% a: PTC (Phase Transfer Catalyst)

I.2 – Yields Pertaining to the Synthesis of 1b-g

The rest of the arylsulfonyl indoles (1b-g) were synthesiszed using the phase transfer catalyst method. Indole and the respective substituted phenylsulfonyl chloride were used as the starting material. NaOH was used in conjunction with the phase transfer catalyst (TBAHS).

Table 4.2 – Molar ratios and yields pertaining to the synthesis of 1b-g

Molar Ratio Product Substitued- Yield Indole Base PTCa PhSO2Cl 0.1 1b 1.5 1.0 1.5 (NaOH) 75% (TBAHS) 0.1 1c 1.5 1.0 1.5 (NaOH) 90% (TBAHS) 0.1 1d 1.5 1.0 1.5 (NaOH) 80% (TBAHS) 0.1 1e 1.5 1.0 1.5 (NaOH) 80% (TBAHS) 0.1 1f 1.5 1.0 1.5 (NaOH) 85% (TBAHS) 0.1 1g 1.5 1.0 1.5 (NaOH) 86% (TBAHS) a: PTC (Phase Transfer Catalyst)

II. 1H and 13C NMR Experiment and Data

Phenylsulfonyl indole (1a) 1 H NMR (CD3CN, 400 MHz) 7.98-7.96 (m, 1H), 7.92-7.88 (m, 2H), 7.64-7.61 (m, 1H), 7.60- 7.54 (m, 2H), 7.51-7.45 (m, 2H), 7.35-7.29 (m, 1H), 7.26-7.21 (m, 1H), 6.75-6.74 (m, 1H); 13C NMR (CD3CN, 400 MHz, JMOD) 129.26 (C), 127.52 (C), 125.98 (C), 125.61 (C), 125.08 (C), 122.98 (C), 122.76 (C), 118.29 (C), 114.29 (C), 111.46 (C) 4-methylphenylsulfonyl indole (1b) 1 H NMR (CD3CN, 400 MHz) 7.99-7.97 (m, 1H), 7.76-7.73 (m, 2H), 7.55-7.49 (m, 2H), 7.31- 7.29 (m, 1H), 7.24-7.23 (m, 2H), 7.22-7.18 (m, 1H), 6.64-6.29 (m, 1H), 2.32-2.29 (m, 3H); 13C NMR (CD3CN, 400 MHz, JMOD) 144.88 (C), 135.29 (C), 134.79 (C), 130.71 (C), 129.83 (C), 126.78 (C), 126.30 (C), 124.51 (C), 123.23 (C), 121.33 (C), 113.50 (C), 108.99 (C), 77.32 (C), 77.00 (C), 76.68 (C). 4-methoxylphenylsulfonyl indole (1c) 1 H NMR (CD3CN, 400 MHz) 7.99-7.96 (m, 1H), 7.82-7.78 (m, 2H), 7.55-7.53 (m, 1H), 7.52- 7.49 (m, 1H), 7.31-7.26 (m, 1H), 7.22-7.18 (m, 1H), 6.87-6.83 (m, 2H), 6.64-6.62 (m, 1H), 3.16 (3H); 13C NMR (CD3CN, 400 MHz, JMOD) 163.71 (C), 134.76 (C), 130.72 (C), 129.72 (C), 129.04 (C), 126.31 (C), 124.47 (C), 123.17 (C), 121.33 (C), 114.41 (C), 113.48 (C), 108.87 (C), 77.32 (C), 77.00 (C), 76.68 (C). 4-chlorophenylsulfonyl indole (1d) 1 H NMR (CD3CN, 400 MHz) 7.90-7.87 (m, 1H), 7.74-7.70 (m, 2H), 7.46-7.44 (m, 2H), 7.33- 7.29 (m, 2H), 7.18-7.17 (m, 1H), 7.16-7.14 (m, 1H), 6.60-6.59 (m, 1H); 13C NMR (CD3CN, 400 MHz, JMOD). 13C NMR (CD3CN, 400 MHz) 135.56 (C), 133.18 (C), 132.30 (C), 131.98 (C), 129.71 (C), 127.56 (C), 126.05 (C), 124.99 (C), 122.72 (C), 122.61 (C), 118.22 (C), 114.26 (C), 111.38 (C). 4-florophenylsulfonyl indole (1e) 1 H NMR (CD3CN, 400 MHz) 7.98-7.91 (m, 3H), 7.65-7.59 (m, 1H), 7.58-7.53 (m, 1H), 7.36- 7.31 (m, 1H), 7.28-7.17 (m, 3H), 6.60-6.59 (m, 1H); 13C NMR (CD3CN, 400 MHz) 135.51 (C), 133.25 (C), 132.29 (C), 131.96 (C), 129.70 (C), 127.52 (C), 126.03 (C), 125.01 (C), 122.57 (C), 118.95 (C), 118.18 (C), 114.20 (C), 111.46 (C). 3-nitrophenylsulfonyl indole (1f) 1 H NMR (CD3CN, 400 MHz) 8.61-8.60 (m, 1H), 8.39-8.36 (m, 1H), 8.27-8.24 (m, 1H), 8.02- 8.00 (m, 1H), 7.76-7.71 (m, 1H), 7.69-7.68 (m, 1H), 7.59-7.58 (m, 1H), 7.37-7.35 (m, 1H), 7.29- 7.25 (m, 1H), 6.82-6.80 (m, 1H); 13C NMR (CD3CN, 400 MHz) 135.51 (C), 133.20 (C), 132.33 (C), 131.98 (C), 129.70 (C), 127.52 (C), 126.06 (C), 124.99 (C), 122.72 (C), 122.58 (C), 118.20 (C), 114.25 (C), 111.42 (C). 4-nitrophenylsulfonyl indole (1g) 1 H NMR (CD3CN, 400 MHz) 8.26-8.20 (m, 2H), 8.12-8.08 (m, 2H), 8.00-7.97 (m, 1H), 7.66- 7.65 (m, 1H), 7.59-7.57 (m, 1H), 7.39-7.37 (m, 1H), 7.35-7.25 (m, 1H), 6.82-6.80 (m, 1H); 13C NMR (CD3CN, 400 MHz, JMOD) 129.20 (C), 127.52 (C), 126.07 (C), 125.68 (C), 125.04 (C), 122.98 (C), 122.76 (C), 118.29 (C), 114.29 (C), 111.46 (C)

Chapter 5 – Conclusion and Future Work

I.1 - Conclusion

A series of anti-HIV active N-arylsulfonyl indole derivatives was successfully synthesized using indole and the respective phenylsulfonyl chlorides, coupled with a deprotonating agent. Using NaOH alone did not result in appreciable yield. However, a substantial increase in yield is achieved with the use of NaOH coupled with the phase transfer catalyst. Alternatively, the compounds may also be synthesized following a hydride method, in which case no phase transfer catalyst is required. The yields for both phase transfer catalyst and hydride synthetic approaches are comparable.

The reduction of the synthesized compounds was investigated using cyclic voltammetry.

Theoretical calculations along with application of the dissociative electron transfer theory allowed rationalization of the data.

A special attention was given to determining the ease of electron transfer to the investigated compounds, the initial electron transfer mechanism, the potential for bond cleavage and the global mechanism. The study was also intended to further investigate the fundamental aspects of electron transfer to organic molecules in general and to arylsufonyl derivatives in particular. Previous members of the Houmam group have already studied the electrochemical reduction of arylsulfonyl chlorides and arylsulfonyl phthalimides. The results of the present study were compared to those obtained for these related compounds.

The reduction of the substituted arylsulfonyl indole derivatives revealed that all investigated compounds can readily accept extra electrons. It further showed that, the nitro- substituted derivatives are much easier to reduce than the rest of the investigated compounds.

The difference between the 4-nitropheylsulfonyl indole, which show the highest HIV-1

inhibition activity, and the phenylsulfonyl indole, is as much as 1.2 V.

The study also showed an interesting difference in the electron transfer mechanism as a function of the substituent. For the nitro substituted compounds, the initial electron transfer follows a stepwise mechanism and leads to a stable radical anion intermediate that is easily detected by cyclic voltammetry. With all other substituents (H, Me, MeO, Cl and F), the electron transfer mechanism is concerted and no radical anion intermediate is formed. The initial electron transfer is simultaneous with the cleavage of a chemical bond leading to the formation of a radical and an anion.

Theoretical calculations showed that, for the nitro-substituted arylsulfonyl indoles, the transferred electron is injected strictly to the nitrophenyl group leading to the formation of a stable radical anion as suggested by the electrochemical data. For the other investigated compounds, the LUMOs show a certain contribution of the indole moiety, which is slightly dependent on the nature of the substituent. This is also in line with concerted mechanism deduced from the electrochemical data.

Analysis of the electrochemical data for compounds 1a-e and use of the dissociative electron transfer theory show that the dissociated bond is the N-S bond and that the extra electron ends up in the indole moiety. This suggests that the bond cleavage leads to a substituted arylsulfonyl radical and to the indole anion. However, it is not possible to deduce with certainty whether the extra electron of the radical anion will end up in the nitrophenylsulfonyl moiety or the indolyl moiety.

A comparison with the already investigated, and structurally related, substituted arylsulfonyl chlorides shows a number of interesting differences. The later compounds are easier

to reduce thanks to the electron withdrawing character of the Cl group, the good leaving ability of its anion and the weak S-Cl bond. This difference affects the global mechanism which showed

the occurrence of an autocatalytic process in the arylsulfonyl chlorides which is not present for

the arylsulfonyl indoles. Another important difference is the absence of a stepwise electron

transfer mechanism for arylsulfonyl chlorides including the nitro-substituted ones.

The arylsulfonyl indoles also present major differences with the aryulsulfonyl

phthalimides. The later compounds all follow a stepwise electron transfer mechanism including

the ones with electron donating substituents. This difference is due to the ability of the

phthalimidyl group to host electrons. The LUMOs of these compounds are located on the

phthalimidyl group.

I.2 - Electrochemical Techniques and Drug Discovery

Due to their highly chemically reactive nature, the presence of free radicals in a

biological system bring forth reactions that oftentimes result in cellular toxicity.134 In this regard,

the survival of our species depends upon the actions of free radical scavengers such as

glutathione and ubiquinol in the biological system. In fact, studies have shown the presence

of the nitro radicals are directly responsible for various cytotoxicity issues including

carcinogenicity, hepatotoxicity mutagenicity, and bone-marrow suppression.108,134,136 With this

in mind, it is important to stress the fact the anti-HIV activities of the arylsulfonyl indoles

reported by Fan et al are determined by in vitro experiments and are solely based on death of the

HIV-infected T cells115. It is important to come to the admission that the nitro compound-elicited

cellular destruction is of an indiscriminate nature, meaning the healthy uninfected cells, if

present, will be subject to the damaging radical reaction as well. In other words, we as as

scientific community are still at our infancy with respect to utilizing the nitro arylsulfonyl indoles in actual HIV treatment.

Having said that, researche that aimed at selectively targeting the infectious cells with the vehicles of radical anions are emerging. Hence, in order to harness the free-radical reactions for their therapeutic use, breakthroughs are needed to impose selectivity to radicals in killing diseased cells. In this regard, electrochemistry may once again prove to be of great use.

The design of drugs that interact with the redox machinery of the cell is an emerging field in drug development.146 An example of the progression in such drug design is the hypoxia- selective drugs,168-170 which are able to exploit the hypoxia environment in the diseased cell. The ability to exploit the particular redox status of cells is particularly advantageous for drug molecules that are activated by oxidation or reduction, making it possible to impose selectivity on drug activity, thereby allowing the drug molecules to remain inactive in healthy cells. The current research initiatives are aimed at taking advantage of perturbations of the redox environment within cells to create novel therapeutics.146

II – Future Work

II.1 – Electrolysis to Provide Further Confirmation of the N-S Bond Dissociation

Electrolysis is an electrochemical technique whereby a measurable amount of electricity

is applied to the target compound, resulting in the complete electrolysis of the compound.

Analysis of the electrolytic products may provide evidence of the N-S bond dissociation.

The electrolysis experiments can be carried out in a special voltammetric cell with a

rectangular glassy carbon plate as the working electrode. The counter electrode can be a

platinum wire, situated inside the specially-made glass casing with porous glass frit as a means

of separating it from the cathode. A specially-made glass casing with porous glass frit separates

the counter electrode from the main solution. The reference electrode can be a strand of silver

wire immersed in a solution containing the supporting electrode. The electrolysis of the

arylsulfonyl indoles is to be performed at their respective first reduction peak potential. The

disappearance of the starting material and the formation of the products were tracked in situ

using CV.

At the end of the electrolysis, the electrolytic products can be analyzed in HPLC in an

attempt to identify the fragments by comparing with the indole and the respective substituted

arylsulfonyl standards.

II.2 – Expansion of the Indole Library

Future electrochemistry studies should be aimed at assessing the susceptibility of the

arylsulfonyl indoles to accept electrons from biological donors, as well as the metabolic fate of

the indoles. However, in order to extend the apparent simplicity of redox dependences to the complex biological environment in eucaryotic cells, further studies should also take into account

the effect of physiological pH, as well as the presence of other species such as oxygen, on the

electron transfer. Furthermore, future studies focus on the electrochemical behavior of various

nitro-substituted arylsulfonyl indoles. A more in-depth look at the relevant nitro compounds

warrants an expansion of the existing library of arylsulfonyl indoles to include more variants of

the nitro-substituted arylsulfonyl indoles, as well as additional substituents on the phenyl moiety.

II.3 Surface Modification by 1-(4-Nitrophenylsulfonyl)indole

Surface modification is a process of altering the surface property through the introduction

of a single or multiple uniform layers of a chemical entity, thereby allows the tailoring of the

physical or chemical properties of the material for its intended applications. Surface modification

has important applications in the fabrication of electronics and nanodevices.

CV serves as a convenient preliminary means of investigating surface modification. The

surface of the working electrode can be electrochemically modified by galvanostatic,

potentiostatic, or cyclic polarization means. Voltammogram is used to detect the modification, as

well as tracking its progress.

As an example, the surface of the glassy carbon electrode has shown electrochemical

modification as result of repeated CV scans of the para-nitrophenylsulfonyl indole (1g). As

detailed in Figures 1A to 1D, the evidence of surface modification is seen as a gradual loss of the

cyclic voltammogram profile. Figure 1A shows the initial scan of the para-nitrophenylsulfonyl

indole (shown in solid line) at 0.2 Vs-1 is followed by a subsequent cyclic scan at the 2nd reversible peak (shown in dashed line). Figures 1B to 1D are the cyclic voltammogram recorded for the subsequent scans overlaid with the initial full scan for clarity in presentation. The CV profile no longer changes upon the fourth scan and all subsequent scans resulted in the same profile as Figure 1D. This preliminary result indicates an electrochemical modification of the

glassy carbon surface, as evidenced by the gradual loss of cyclic voltammogram profile. In

addition, our results indicate electrochemical modification is due to the second reduction peak.

Finally, it is worth noting that electrode modification is only observed for 1g.

The exact root cause to the modification and how the para-nitrophenylsulfonyl indole differs in electrochemical modification behavior compared to the meta-nitro counterpart remain as topics for future investigation.

Figure 5.1 – Electrode modification of 1g: (a): first scan at the second reversible peak; (b, c and d): subsequent scan without polishing the electrode at the second reversible peak

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Appendix

1 – Total Energies and Coordinates

Indole Total Energy: - 363.84329053 a.u.

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.242954 0.737425 0.009936 2 6 0 -0.239442 -0.681902 0.006787 3 6 0 0.945426 -1.423631 -0.007325 4 6 0 2.144540 -0.712348 -0.000303 5 6 0 2.164640 0.695905 0.005302 6 6 0 0.980731 1.426719 0.003302 7 6 0 -1.620833 1.166414 0.001317 8 6 0 -2.402532 0.051968 -0.002019 9 1 0 0.931010 -2.505694 -0.047312 10 1 0 3.082286 -1.259695 -0.013438 11 1 0 3.118187 1.215499 0.001156 12 1 0 0.998232 2.512789 -0.004960 13 1 0 -1.980214 2.185891 -0.025194 14 1 0 -3.475007 -0.063208 -0.030207 15 7 0 -1.587348 -1.093022 -0.027539 16 1 0 -1.940514 -1.997728 0.210748 ------

Indole Radical Total Energy: - 363.81091451 a.u.

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.242954 0.737425 0.009936 2 6 0 -0.239442 -0.681902 0.006787 3 6 0 0.945426 -1.423632 -0.007325 4 6 0 2.144540 -0.712348 -0.000303 5 6 0 2.164640 0.695905 0.005302 6 6 0 0.980731 1.426719 0.003302 7 6 0 -1.620833 1.166414 0.001317 8 6 0 -2.402532 0.051968 -0.002019 9 1 0 0.931010 -2.505694 -0.047312 10 1 0 3.082286 -1.259695 -0.013438 11 1 0 3.118188 1.215499 0.001156 12 1 0 0.998232 2.512789 -0.004960 13 1 0 -1.980215 2.185891 -0.025194 14 1 0 -3.475008 -0.063208 -0.030207 15 7 0 -1.587348 -1.093022 -0.027539 16 1 0 -1.940514 -1.997728 0.210748 ------93

Sulfonyl Indole Total Energy: - 912.35232664 a.u.

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.535360 0.945417 -0.025412 2 6 0 0.653702 -0.165378 -0.083074 3 6 0 1.115231 -1.484663 -0.055642 4 6 0 2.491981 -1.677807 0.049741 5 6 0 3.384954 -0.590388 0.110823 6 6 0 2.918500 0.719662 0.066955 7 6 0 0.730183 2.140795 -0.098998 8 6 0 -0.573000 1.758429 -0.191551 9 1 0 0.432405 -2.321093 -0.138107 10 1 0 2.882122 -2.690953 0.071020 11 1 0 4.451756 -0.779994 0.183144 12 1 0 3.609619 1.556963 0.101628 13 1 0 1.087546 3.161292 -0.107396 14 1 0 -1.478097 2.337949 -0.287569 15 7 0 -0.649933 0.354932 -0.212923 16 16 0 -2.113149 -0.473521 0.098143 17 8 0 -2.742858 0.069345 1.219448 18 8 0 -2.833800 -0.635812 -1.086298 19 1 0 -1.553635 -1.517009 0.395205 ------

1-(Phenylsulfonyl)indole Total Energy: -1138.20869017

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -2.109286 0.790241 0.338682 2 6 0 -1.220219 0.232909 -0.653275 3 6 0 -0.496359 1.072200 -1.473092 4 6 0 -0.642278 2.459345 -1.316789 5 6 0 -1.494300 2.990860 -0.358975 6 6 0 -2.240476 2.156675 0.482842 7 6 0 -2.730242 -0.324861 1.029940 8 6 0 -2.246090 -1.506414 0.467402 9 1 0 0.177565 0.673899 -2.237540 10 1 0 -0.068874 3.132161 -1.967801 11 1 0 -1.590091 4.079995 -0.256689 12 1 0 -2.912968 2.588038 1.234363 13 1 0 -3.457094 -0.230917 1.831501 14 1 0 -2.550205 -2.507339 0.765018 15 7 0 -1.311257 -1.224255 -0.550761 16 16 0 0.252396 -1.907909 -0.228594 17 8 0 0.127852 -2.678838 0.932663 18 8 0 0.734388 -2.481250 -1.410495 19 6 0 1.284737 -0.509793 0.173054 20 6 0 2.177082 -0.002200 -0.771916 21 6 0 1.214262 0.065204 1.440761 22 6 0 2.994897 1.079031 -0.450405 23 1 0 2.239247 -0.459213 -1.767301 24 6 0 2.030167 1.149160 1.761163 25 1 0 0.516664 -0.335708 2.186858 26 6 0 2.920409 1.655990 0.816045 27 1 0 3.697490 1.476100 -1.194236 28 1 0 1.972703 1.601944 2.759315 29 1 0 3.564263 2.507983 1.069388 ------

1-(4-Methylphenylsulfonyl)indole Total Energy: -1177.24991354

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.516282 1.850762 -0.409956 2 6 0 1.208555 0.877175 0.611063 3 6 0 0.219674 1.142243 1.534282 4 6 0 -0.470151 2.361858 1.453198 5 6 0 -0.174450 3.292834 0.467420 6 6 0 0.827497 3.044925 -0.479122 7 6 0 2.591704 1.300141 -1.214430 8 6 0 2.928471 0.051618 -0.690382 9 1 0 -0.026251 0.423956 2.322193 10 1 0 -1.257869 2.578252 2.186670 11 1 0 -0.729335 4.239521 0.425538 12 1 0 1.054592 3.789334 -1.252026 13 1 0 3.051084 1.800139 -2.062136 14 1 0 3.719318 -0.590284 -1.071727 15 7 0 2.105976 -0.261841 0.412105 16 16 0 1.191923 -1.718693 0.169570 17 8 0 1.620184 -2.270306 -1.043194 18 8 0 1.243858 -2.472379 1.347416 19 6 0 -0.487680 -1.166401 -0.064182 20 6 0 -1.411630 -1.270216 0.976017 21 6 0 -0.884170 -0.647367 -1.295319 22 6 0 -2.727585 -0.853809 0.785955 23 1 0 -1.102890 -1.686112 1.943105 24 6 0 -2.199969 -0.227683 -1.484239 25 1 0 -0.160309 -0.569289 -2.116291 26 6 0 -3.122844 -0.330683 -0.444313 27 1 0 -3.453235 -0.937752 1.605134 28 1 0 -2.509966 0.182277 -2.454045 29 6 0 -4.575364 0.129982 -0.654159 30 1 0 -5.170281 -0.699494 -0.979380 31 1 0 -4.967278 0.509670 0.267648 32 1 0 -4.602567 0.900969 -1.397308 ------

1-(4-Methoxylphenylsulfonyl)indole Total Energy: -1251.89243197

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.106266 2.005633 -0.233683 2 6 0 1.140696 0.862080 0.650273 3 6 0 0.096848 0.619867 1.520345 4 6 0 -0.991732 1.507987 1.523446 5 6 0 -1.024889 2.607322 0.673528 6 6 0 0.029010 2.868439 -0.218050 7 6 0 2.337781 1.980079 -1.013108 8 6 0 3.088094 0.859217 -0.612064 9 1 0 0.108353 -0.244837 2.198402 10 1 0 -1.829695 1.325239 2.212640 11 1 0 -1.888935 3.288141 0.694908 12 1 0 -0.012127 3.741759 -0.883765 13 1 0 2.607484 2.713456 -1.769531 14 1 0 4.058826 0.575108 -1.017254 15 7 0 2.392367 0.161056 0.392976 16 16 0 1.899634 -1.429288 0.002953 17 8 0 2.375681 -1.782761 -1.260772 18 8 0 2.123094 -2.280223 1.086719 19 6 0 0.175108 -0.998566 -0.091336 20 6 0 -0.674450 -1.283352 0.978065 21 6 0 -0.326915 -0.376254 -1.234249 22 6 0 -2.025850 -0.946476 0.904212 23 1 0 -0.278512 -1.774673 1.878664 24 6 0 -1.678502 -0.038319 -1.307886 25 1 0 0.342565 -0.151565 -2.077125 26 6 0 -2.528012 -0.323434 -0.238971 27 1 0 -2.695669 -1.171482 1.746833 28 1 0 -2.073961 0.452711 -2.208983 29 8 0 -3.913636 0.021912 -0.314364 30 6 0 -4.660246 -1.101019 -0.790285 31 1 0 -4.576914 -1.906863 -0.091307 32 1 0 -5.688848 -0.826185 -0.896790 33 1 0 -4.273627 -1.410243 -1.738866 ------

1-(4-Chlorophenylsulfonyl)indole Total Energy: -1597.10362156

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -2.451923 -0.157293 0.989670 2 6 0 -1.659051 -0.095129 -0.158582 3 6 0 -1.922882 0.803006 -1.187832 4 6 0 -2.995571 1.657409 -1.022537 5 6 0 -3.796690 1.615138 0.124625 6 6 0 -3.536886 0.708326 1.130040 7 6 0 -1.920356 -1.214041 1.825640 8 6 0 -0.864740 -1.737121 1.191511 9 1 0 -1.334730 0.817620 -2.083306 10 1 0 -3.226579 2.362048 -1.801362 11 1 0 -4.627711 2.291643 0.214183 12 1 0 -4.158786 0.665522 2.006616 13 1 0 -2.308529 -1.542761 2.768182 14 1 0 -0.218280 -2.542597 1.464838 15 7 0 -0.677400 -1.093149 -0.038998 16 16 0 0.748105 -1.197064 -0.878696 17 8 0 1.276747 -2.483048 -0.559326 18 8 0 0.461218 -0.818287 -2.222401 19 6 0 1.815770 0.026205 -0.175058 20 6 0 1.868449 1.293378 -0.736697 21 6 0 2.583905 -0.304266 0.933412 22 6 0 2.693879 2.249643 -0.166175 23 1 0 1.288489 1.521080 -1.609917 24 6 0 3.404796 0.658469 1.495900 25 1 0 2.552238 -1.299429 1.334478 26 6 0 3.456722 1.932874 0.947808 27 1 0 2.744676 3.233773 -0.595081 28 1 0 4.007012 0.412372 2.351425 29 17 0 4.506343 3.150524 1.664205 ------

1-(4-Fluorophenylsulfonyl)indole Total Energy: -1242.28876962

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.153667 0.720411 0.000019 2 6 0 2.301575 1.599379 -0.000010 3 6 0 2.132579 2.969325 -0.000147 4 6 0 0.824705 3.482390 -0.000127 5 6 0 -0.278886 2.637355 0.000027 6 6 0 -0.124702 1.240922 0.000162 7 6 0 3.068069 -0.591134 -0.000092 8 6 0 3.487803 0.752515 -0.000010 9 1 0 2.994934 3.650465 -0.000318 10 1 0 0.677443 4.572749 -0.000236 11 1 0 -1.293122 3.063817 0.000176 12 1 0 -1.007242 0.586186 0.000384 13 1 0 3.730574 -1.456180 -0.000166 14 1 0 4.511468 1.119731 0.000161 15 7 0 1.661956 -0.645762 -0.000066 16 16 0 0.684330 -2.048740 0.000008 17 8 0 0.830547 -2.735491 -1.206456 18 8 0 0.830781 -2.735539 1.206422 19 6 0 -0.840247 -1.130011 0.000167 20 6 0 -1.438055 -0.770410 -1.208048 21 6 0 -1.437344 -0.769678 1.208134 22 6 0 -2.632337 -0.050054 -1.208202 23 1 0 -0.966663 -1.053975 -2.160216 24 6 0 -2.632505 -0.049956 1.208154 25 1 0 -0.966407 -1.053173 2.160488 26 6 0 -3.229979 0.310004 0.000268 27 1 0 -3.103267 0.233966 -2.160491 28 1 0 -3.103274 0.233657 2.160737 29 9 0 -4.386012 1.007204 -0.000188 ------

1-(4-Nitrophenylsulfonyl)indole Total Energy: -1347.98050507

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.000000 0.000000 0.000000 2 6 0 0.000000 0.000000 1.445779 3 6 0 1.190440 0.000000 2.144467 4 6 0 2.392928 0.000130 1.417972 5 6 0 2.392927 0.000256 0.028009 6 6 0 1.190462 0.000252 -0.698541 7 6 0 -2.205199 -0.000326 0.722621 8 6 0 -1.393559 -0.000136 1.872756 9 1 0 1.206973 -0.000147 3.243254 10 1 0 3.348170 0.000131 1.963939 11 1 0 3.348136 0.000494 -0.517996 12 1 0 1.207164 0.000454 -1.797303 13 1 0 -3.294794 -0.000513 0.722722 14 1 0 -1.724342 0.000021 2.908768 15 7 0 -1.393719 -0.000238 -0.427004 16 16 0 -1.913292 -0.000250 -2.056158 17 8 0 -2.547320 -1.206786 -2.357556 18 8 0 -2.547751 1.206091 -2.357447 19 6 0 -0.256973 0.000067 -2.708084 20 6 0 0.393200 -1.208083 -2.961302 21 6 0 0.390910 1.208094 -2.965898 22 6 0 1.691211 -1.208111 -3.471584 23 1 0 -0.117567 -2.160296 -2.757217 24 6 0 1.688953 1.208237 -3.477263 25 1 0 -0.121445 2.160396 -2.766548 26 6 0 2.339208 0.000416 -3.729999 27 1 0 2.203980 -2.160347 -3.670609 28 1 0 2.199380 2.160866 -3.680826 29 7 0 3.707258 0.000053 -4.267900 30 8 0 4.616128 0.213699 -3.515084 31 8 0 3.859896 -0.213878 -5.438089 ------

100

1-(3-Nitrophenylsulfonyl)indole Total Energy: -1347.48948215

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.000000 0.000000 0.000000 2 6 0 0.000000 0.000000 1.445779 3 6 0 1.190440 0.000000 2.144467 4 6 0 2.392928 0.000130 1.417972 5 6 0 2.392927 0.000256 0.028009 6 6 0 1.190462 0.000252 -0.698541 7 6 0 -1.393719 -0.000238 -0.427004 8 6 0 -2.205199 -0.000326 0.722621 9 1 0 1.206973 -0.000147 3.243254 10 1 0 3.348170 0.000131 1.963939 11 1 0 3.348136 0.000494 -0.517996 12 1 0 1.207164 0.000454 -1.797303 13 1 0 -1.724163 -0.000252 -1.463133 14 1 0 -3.294794 -0.000500 0.722722 15 7 0 -1.393559 -0.000154 1.872756 16 16 0 -1.514420 1.376083 2.880459 17 8 0 -2.500828 2.238347 2.398732 18 8 0 -1.532174 0.988800 4.221455 19 6 0 0.099086 1.985938 2.441058 20 6 0 1.179502 1.782141 3.299917 21 6 0 0.283373 2.667460 1.238097 22 6 0 2.443747 2.260382 2.956125 23 1 0 1.033728 1.245476 4.248591 24 6 0 1.548141 3.145049 0.893595 25 1 0 -0.568017 2.828016 0.560982 26 6 0 2.628247 2.941753 1.752418 27 1 0 3.295262 2.100334 3.633327 28 1 0 3.625163 3.318686 1.481537 29 7 0 1.742071 3.862773 -0.374539 30 8 0 2.639606 3.519960 -1.092403 31 8 0 0.995009 4.762489 -0.640654 ------

101

4-Methoxyphenylsulfonyl radical.

Total Energy: - 894.75438521 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.198939 -0.271539 0.076918 2 6 0 -0.082806 -0.507719 1.438616 3 6 0 1.077602 -0.092386 2.106311 4 6 0 2.130606 0.513080 1.421291 5 6 0 2.012740 0.751693 0.051131 6 6 0 0.846599 0.357515 -0.624875 7 1 0 -1.091040 -0.560864 -0.468169 8 1 0 -0.887764 -0.982970 1.988592 9 1 0 3.023023 0.819539 1.956276 10 1 0 2.824914 1.242358 -0.470869 11 16 0 1.265938 -0.462072 3.862587 12 8 0 2.283586 0.477840 4.417119 13 8 0 -0.100607 -0.577179 4.450455 14 8 0 0.632576 0.539427 -1.952415 15 6 0 1.644868 1.166841 -2.738183 16 1 0 2.572866 0.583274 -2.726942 17 1 0 1.249042 1.201672 -3.753102 18 1 0 1.843050 2.186426 -2.387542 ------

4-Methylphenylsulfonyl radical. Total Energy: -819.54523656 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.000571 -0.292767 -0.037386 2 6 0 -0.048895 -0.353555 1.353926 3 6 0 1.119372 -0.095817 2.075527 4 6 0 2.328792 0.183381 1.438518 5 6 0 2.351931 0.239048 0.044135 6 6 0 1.195833 -0.000088 -0.714112 7 1 0 -0.908719 -0.471634 -0.607113 8 1 0 -0.976255 -0.569172 1.873389 9 1 0 3.222456 0.378395 2.021311 10 1 0 3.284381 0.476274 -0.460699 11 16 0 1.086108 -0.232052 3.882938 12 8 0 2.225202 0.569566 4.416558 13 8 0 -0.318139 0.004705 4.326812 14 6 0 1.232840 0.036956 -2.222823 15 1 0 2.155160 0.494847 -2.589970 16 1 0 1.175142 -0.976044 -2.639441 17 1 0 0.386993 0.602473 -2.627327 ------

102

Phenylsulfonyl radical. Total Energy: -780.22316376 a.u.

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.005875 -0.003775 0.012185 2 6 0 -0.016895 0.043891 1.407799 3 6 0 1.206177 0.085319 2.080251 4 6 0 2.430253 0.046259 1.409444 5 6 0 2.421234 -0.001460 0.013831 6 6 0 1.208167 -0.028652 -0.681675 7 1 0 -0.945812 -0.019711 -0.530890 8 1 0 -0.947732 0.072787 1.963503 9 1 0 3.360307 0.077052 1.966360 10 1 0 3.361928 -0.015652 -0.527977 11 16 0 1.205099 0.082394 3.898441 12 8 0 2.507163 0.653295 4.348107 13 8 0 -0.099452 0.648843 4.346514 14 1 0 1.208939 -0.069020 -1.766767 ------

4-Chlorophenylsulfonyl radical. Total Energy: -1239.81570375 a.u.

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.011932 0.001051 0.011281 2 6 0 -0.014310 0.045543 1.405135 3 6 0 1.206174 0.085855 2.082250 4 6 0 2.427637 0.047766 1.406708 5 6 0 2.427196 0.003171 0.012881 6 6 0 1.208084 -0.021499 -0.670398 7 1 0 -0.945096 -0.013815 -0.540625 8 1 0 -0.948154 0.072838 1.955928 9 1 0 3.360768 0.076926 1.958623 10 1 0 3.361094 -0.010143 -0.537817 11 16 0 1.205262 0.077494 3.897229 12 8 0 2.508136 0.647135 4.344618 13 8 0 -0.100538 0.641542 4.343175 14 17 0 1.209294 -0.082405 -2.419860 ------

103

4-Fluorophenylsulfonyl radical.

Total Energy: -879.46239993 a.u.

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.004477 0.262496 -0.054123 2 6 0 -0.050697 0.329010 1.338178 3 6 0 1.118173 0.091424 2.066316 4 6 0 2.340313 -0.175052 1.442458 5 6 0 2.387310 -0.241963 0.050452 6 6 0 1.214049 -0.019154 -0.665018 7 1 0 -0.889465 0.421935 -0.660058 8 1 0 -0.982504 0.537142 1.852529 9 1 0 3.230289 -0.351361 2.036533 10 1 0 3.308437 -0.463342 -0.477096 11 9 0 1.260058 -0.081463 -2.015260 12 16 0 1.071837 0.241340 3.873172 13 8 0 -0.333124 -0.007430 4.304190 14 8 0 2.216526 -0.546147 4.414117 ------

4-Nitrophenylsulfonyl radical.

Total Energy: -984.72647834 a.u.

------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.016126 0.410182 -0.042183 2 6 0 -0.013549 0.464177 1.350572 3 6 0 1.131130 0.095093 2.060067 4 6 0 2.312949 -0.297737 1.428467 5 6 0 2.341273 -0.351354 0.035673 6 6 0 1.193460 0.006181 -0.671215 7 1 0 -0.850280 0.672567 -0.636514 8 1 0 -0.913016 0.764144 1.876310 9 1 0 3.182020 -0.576897 2.013452 10 1 0 3.229164 -0.663657 -0.499913 11 7 0 1.225472 -0.047280 -2.149670 12 8 0 2.273988 -0.407174 -2.682748 13 8 0 0.201879 0.272500 -2.752217 14 16 0 1.112587 0.224741 3.879172 15 8 0 -0.309331 0.120316 4.309386 16 8 0 2.169498 -0.690528 4.392374 ------

104