Synthesis and Complexation of Functionalized Mixed Thia‐Aza‐Macrocyclic

Home , Cyclononane

WILHELM S. MALASI

AND MEDIUM SIZED LIGANDS

A Dissertation

Presented to

The Graduate Faculty of the University of Akron

In Partial Fulfillment

of the Requirement for the Degree

Doctor of Philosophy

Wilhelm Malasi

May 2009 SYNTHESIS AND COMPLEXATION OF FUNCTIONALIZED MIXED THIA‐AZA‐MACROCYCLIC

AND MEDIUM SIZED LIGANDS

Wilhelm Malasi

Dissertation

Approved: Accepted:

______Advisor Department Chair Dr. Michael J. Taschner Dr. Kim C. Calvo

______Committee Member Dean of the College Dr. David Modarelli Dr. Chand Midha

______Committee Member Dean of the Graduate School Dr. Jun Hu Dr. George R. Newkome

______Committee Member Date Dr. Wiley J. Youngs

______Committee Member Dr. Amy Milsted

ii ABSTRACT

Six ligands of mixed thia-aza donor atoms 40, 90, 100, 107, 110 and 112 have been synthesized and characterized. The metal complexes of Copper 114, Rhodium 116, and Nickel 115 with 1,8-dithia-4,11-diazacyclotetradecane 40 have been made and crystal structures grown in appropriate solvents to give good crystals suitable for X-ray crystallographic analysis. Other molecules whose crystals have been made and analyzed by X-ray crystallography are the secondary amine 82, tosylated double ligand tertiary amine 91, the seven member ring ester 100 and the perchlorate salt of the double nine member ligand tertiary amine 110. All these crystals have their analysis data in

Appendix D. The seventh ligand 113 has been adapted, and complexed with rhodium and its crystal structure 117 has been analyzed.

The curative activity of the rhodium complex 116 was tested against ovarian cancer cells Nutu-19 at 1.54 mM concentrations. The results showed that the cells became detached with extreme morphological changes and extreme internal vesicle formation causing the cells to die. Ovarian normal cells, tested at the same concentration, showed that the cells remain attached, with no morphological changes and only slightly vesicle formation. Table 4 in Chapter II shows 87% of the cancer cells died while only

30% of the normal ovarian cells died. If the toxicity of this complex can be further controlled and minimized, it may be very useful in the treatment of cancer in the future.

iii The ligand 40 was functionalized through carboxylic acid derivatives to give rise to the new ligand 90. Also ligand 107 was functionalized in the same way to give the new ligand 110, while the liands 82 and 107 were successfully joined by a butane chain to form a new ligand 112. In an attempt to synthesize the carbon bridged functionalized fourteen membered ring, ligand 99, the functionalized seven membered ring molecule

100 was isolated instead.

DEDICATION

To my mother Delfina and memory of my father Simon Lucas who passed away July 22, 2008.

Those who sow in tears shall reap rejoicing (Ps 126:5)

v ACKNOWLEDGEMENTS

Heartfelt appreciations to my mentor Dr. Michael J. Taschner for his

commitment, fraternal assistance, constant guidance and encouragement the whole period

of my course.

Special thanks to my colleagues Zin Min from Dr. Tessier’s research group for

her encouragement and computer data handling, Dr. Wiley Young’s group for X-ray

crystallography, Dr. Wedsmiotes’s group for mass spectrometry, Jacob Weingart in Dr.

Jun Hu’s group for Infrared (IR) spectra and the staff members Dr. Joe Massey, Dr.

Venkat Dudipala and Simon Stakleff for NMR instruments operations and technicalities.

Also, the chemistry department secretaries Nancy Homa and Jean Garcia for their constant availability to assist and direction. The chemstore provider and instructor Lisa

Zickefoose for promptness and efficiency.

I acknowledge my research group members and friends Swaranjali Bhide,

Wenchao Qu, Tara Scheiber and Aaron Lineberry for cooperation and providing a viable environment to work smoothly.

Special recognition to all my committee members and professors who made my course work, subsequent studies and research possible, and brought my dream to reality.

Remarkable acknowledgement to my superiors for offering me the opportunity for studies, my family, relatives and friends at home (Tanzania) for their sacrifices and patience, especially my mother for understanding.

vi TABLE OF CONTENTS

Page

LIST OF TABLES...... ix

LIST OF FIGURES ...... x

LIST OF SCHEMES...... xii

CHAPTER

I. INTRODUCTION...... 1

1.1 Synthesis and Study of Supramolecular Properties ...... 1

1.2 Metal Complexes of the Macrocyclic Ligands...... 9

1.3 Other [14] Member Ring Macrocylic Molecules ...... 18

1.4 Medium Cyclic Molecules Synthesized ...... 20

II. RESULTS AND DISCUSSIONS ...... 25

2.1 Synthesis, Complexation and Characterization of the Ligands ...... 25

2.2 The Macrocyclic Ligands Synthesized in This Work...... 26

III. SUMMARY ...... 51

IV. EXPERIMENTAL ...... 53

4.1 General Procedure...... 53

4.2 Synthesis ...... 55

4.3 Complexing the Synthesized Ligands...... 79

REFERENCES ...... 82

vii APPENDICES ...... 90

APPENDIX A. 1H AND 13C NMR SPECTRA OF THE COMPOUNDS...... 91

APPENDIX B. IR SPECTRA OF THE MOLECULES AND THE LIGANDS ...... 122

APPENDIX C. MASS SPECTRA OF SELECTED PRODUCTS ...... 133

APPENDIX D. X-RAY CRYSTAL STRUCTURES AND DATA ANALYSIS OF THE PRODUCTS...... 136

viii

LIST OF TABLES

Table Page

1. Enthalpies and Entropies of Cu(II) Complexation with 29-37...... 6

2. Summary of Some Specific Rate Constants for Aquocopper(II) Ions Reacting with Various Protonated Amino/thia Ethers2 Quadridentate and Quinquedentate Macrocycles...... 9

3. Selected Crystallography Data for 40, 114, 116 and 115...... 37

4. Activity of Rhodium Complex on Ovarian Cancer...... 39

LIST OF FIGURES

Figure Page

1. Plastocyanin6 and Rusticyanin8 as examples of blue copper protein in nature ...... 3

2. A variety of ligands with mixed donor atom...... 4

3. Various size all tetra-aza ligands used to complex copper (II) to study enthalpies and entropies of complex formation...... 5

4. Various macrocyclic ligands studied by Westerby et al...... 8

5. Demonstrating electron transfer in Cu(II/I) redox, D1-4 represent donor atoms...... 11

6. Electron transfer and geometry changes of Cu(II/I)/Fe (II/III) complexes ...... 11

7. Complexes of nickel and the ligand ...... 12

8. Arca et al.119 synthesized ligands 121-123 and Taylor et al.120 synthesized 124,125 ...... 14

9. The model of ligands functionalized at the bridging carbons ...... 15

10. Ball and stick X-ray structures developed from available data for rhodium complexed with [14]aneN2S2 and [14]aneNS3 ...... 18

11. Nine member rings reported in literature ...... 20

12. Two copper atoms complexed with [9]aneNS2 in a bridging manner...... 21

13. Copper atom sandwiched between two [9]aneNS2 ligands...... 22

14. Nickel complexed with [9]aneNS2 ...... 23

15. A crystal structure of rhodium complexed with a nine member ring ligand...... 24

16. Crystal structures of the tosylated amine 82...... 29

17. The crystal structure of the ligand 40 ...... 31

18. Crystal structure 114 of copper complexed with ligand 40...... 32

19. Crystal structure 115 of nickel complexed with ligand 40...... 34

20. Crystal structure 116 of rhodium complexed with ligand 40 ...... 36

21. The activity of the complex 116 on ovarian cancer cells ...... 38

22. The activity of complex 116 on healthy cells...... 39

23. The crystal structure of the diamine 87 ...... 41

24. Crystal structure of the seven member molecule 100...... 45

25. The crystal structure of protonated [9]aneNS2 double ligand amine 110...... 48

26. The crystal structure of the rhodium complex 117...... 50

LIST OF SCHEMES

Scheme Page

1. General synthesis of macrocylic ligands through capping type 1 ...... 3

2. General synthesis of macrocylic ligands through capping type 2 ...... 4

3. General synthesis of homoleptic ligands by Buter and Kellog ...... 7

4. Formation of a nickel complex developed by Bhasin et al...... 13

5. Synthesis of [14]ane NS3 44 ...... 16

6. Synthesis of [14]aneN2S2 39 ...... 17

7. Zervas et al.32-34 formation of carbon functionalized molecules 64 and 65 ...... 19

8. General methods of ring closure...... 25

9. Retrosynthesis of the ligand 40 ...... 27

10. Preparation of amine 75...... 27

11. Formation of acid chloride 79 ...... 28

12. Acylation of the amine 75 to form the amide 80...... 28

13. The cyclization and reduction of the amide 80 to form amine 82...... 29

14. Synthesis of the desired ligand 40 ...... 30

15. Copper complexing the ligand to form 114...... 32

16. Nickel complexing with ligand to give 115...... 34

17. Ligand complexing with Rh(III)...... 35

18. The formation of a double ligand amine 87 ...... 40

xii

19. Formation of free amine 88 ...... 41

20. Formation of the tricycloamine 90 ...... 42

21. The retrosynthetic route showing [1 + 1] condensation strategy ...... 42

22. Formation of the thia-ester alcohol 96...... 43

23. An attempt to form the macrocyclic molecule 99 ...... 44

24. Proposed mechanisms for formation of the tetracyclodecane functionalized at bridge carbons ...... 44

25. Strategies for the synthesis of nine membered ring ligands ...... 45

26. The formation of thiourenium salt 104...... 46

27. Synthesis of the nine member ring free amine 107 ...... 46

28. The formation of the double ligand amine 110 ...... 47

29. The double ligands tertiary amines 112...... 48

30. Ten member ring complexed with rhodium ...... 49

xiii

CHAPTER I INTRODUCTION

1.1 Synthesis and Study of Supramolecular Properties.

Until the late 1960s, mostly the normal size ring structures were studied. The cyclic ligands were composed mostly of carbon bridge pieces of the form (CH2)m, where m = (3-4) for small rings, (5-7) for normal rings, (8-11) for medium rings and (12-13) for large rings. Macrocyclic ligands have n ≥ 14 with three or more heteroatoms. As has been indicated by Ziegler et al., the studies for the small rings were mostly associated with the bond properties and energy strains while the rest of the rings were investigated for various reasons including ability to chelate cations and kinetics.1

In the late 1960s, larger ligands with heteroatoms were developed with m ≥ 14, with 3-5 heteroatoms and these ligands were known as macrocyclic ligands.2 The atoms in the ligand were Carbon, Oxygen, Sulfur, and/or Nitrogen. It is worthwhile noting here that the idea of polymers of macromolecular structures which can exist as long chains or huge rings was hypothesized long before 1960. The small mixed thia-aza macrocylic ligands were preceeded by the polymeric heteroatom molecules.3 However, the synthesis of huge cyclic molecules developed much later and unlike the straight chain polymers the commercial applications of cyclic polymers are still under investigation.4 On the other hand, macrocylic ligands have been synthesized and complexed with metal ions and are found to be very stable and useful for medical and biological applications.2

1 The stability of the macrocylic metal complexes and their effectiveness in medical and biological systems has triggered researchers to devote ample time towards their exploration. Formerly, open chain species were used but were found to be not as stable

as the macrocycles.2 Extensive studies were directed towards mimicking the naturally occurring ‘blue copper proteins’ with the intention of understanding the behavior of

5 copper at the active sites. Macrocylic ligands with the N2S2-donor set proved to be

more suitable as models for the copper at the active site of the ‘blue copper proteins’

since the structure determination of plastocyanine in its oxidized and reduced forms have

shown that both Cu2+ and Cu+ at higher pH are tetrahedrally coordinated by two

immidazole nitrogens, a methionine thioether and a cysteine thiolate sulfur.5 See Figure

1 for the structures of Plastocyanin and Rusticyanin as examples of the type 1 blue

copper proteins.6 In the modern studies more metals have been complexed with

macrocyclic ligands containing mixed donor atoms, including the β-emmiting

radionuclides such as Copper (64Cu), Rhodium (105Rh), Iodine (131I), Rhenium (188Re) and

Yttrium (90Y), and their studies in pharmaceutical relevances.7

2 O S Methionine OH

NH2 O

Cysteine HS OH

NH2

O Histidine HN OH N H2N

Figure 1. Plastocyanin6 and Rusticyanin8 as examples of blue copper protein in nature.

In 1984, Kaden and Siegfried synthesized ligands with N2S2 as shown in schemes

1 and 2 below, with different connective pieces of carbons in between thias and azas on the same side and sometimes alternating.9a

Scheme 1

S (CH2)m COOH a) SOCl2 S (CH2)m CONH S (CH2)m NH B2H6 (CH2)n (CH ) (CH ) (CH ) (CH ) (4) 2 n 2 n 2 n 2 n b) H2NNH2 S (CH2)m COOH S (CH2)m CONH S (CH2)m NH or (5) H2NNH2 9 n=2, m=2 1 n=2, m=1 6 n=2, m=1 10 n=2, m=3 2 n=2, m=2 7 n=2, m=2 3 n=3, m=2 8 n=3, m=2 11 n=3, m=3

Scheme 1. General synthesis of macrocylic ligands through capping type 1. 3 Scheme2

a) SOCl2 (CH ) (CH2)n COOH b) H NS (14) (CH2)n CONH (CH2)m (CH2)n NH 2 m 2 NH2 B2H6 S S S S S (CH ) COOH (CH ) NH 2 n or H2NSNH2 (15) (CH2)n CONH (CH2)m 2 n (CH2)m

12 n = 1 16 n = 1, m = 2 19 n = 2, m = 2

13 n = 2 17 n = 2, m = 2 20 n = 3, m = 2 18 n = 2, m = 3 21 n = 3, m = 3

Scheme 2. General synthesis of macrocylic ligands through capping type 2.

From these schemes Kaden and Siegfried9a synthesized the six ligands ( 22-27)

shown in Figure 2 below and their metal complexes. Earlier on, ligands with sulfur as the

only donor atom and up to five sulfurs have been studied.9b-d Also ligands with nitrogen

as the only donor atom have been studied.9e,f After these investigations they stated that

the aza ligands are more selective against hard ions whereas the thia ligands preferentially bind soft ions .9 a

S HN S HN S HN S HN S HN NH S S HN NH S

22 23 24 25

S HN S HN H3CS HN

S HN NH S H3C S HN

27 26 28

Figure 2. A variety of ligands with mixed donor atom. Helv. Chim. Acta, 1980, 67 (4).9a

4 A year later, in 1985, Micheloni and Paoletti explored the metal complexes of

these six ligands (22-27) and another one open chain 28 was included for comparison purposes. They concluded that the macrocyclic complexes show an additional stability and this they termed as the macrocyclic effect.10 They also investigated the sequence of

donor atoms to see if there is any influence on the stability of the metal complexes. Their

final results and conclusions show that the stability of the Cu2+ complexes increases from the 12 to 14 membered ring ligands and decreases when the ring rises to 16 members for

10 both cis and trans thia-aza ligand complexes. Therefore, the [14]aneN2S2 macrocyclic

ligand 24 forms the most stable metal complexes. To illustrate further this concept,

Anchini et al.9g studied the complexation enthalpies of ligands 29-36 in Figure 3 below,

and later Gallori et al.9h did the same for ligand 37. The results are shown on Table 2.

Figure 3. Various size all tetra-aza ligands used to complex copper (II) to study enthalpies and entropies of complex formation.

5 Table 1

Enthalpies and Entropies of Cu(II) Complexation with 29-37

Ligands 29 30 31 32 33 34 35 36 37 Enthalpies (ΔH), -22.7 -29.2 -32.4 -26.5 -21.6 -27.7 -25.9 -19.5 -20.0 Kcal/mol. Entropies (ΔS), 36.2 33.7 -- 22.7 19.5 16.5 13.1 12.8 8.5 calK-1mol-1.

From Table 1, enthalpies of formation for the complexes increase from [12]ane

N4 29 to [14]ane N4 31 and decrease for the complexes [15]ane N4 32 and [16]aneN4 37.

However, the entropies of the cyclic ligands diminish as the ring size increases due to an

increase in flexibility, i.e., decrease in rigidity in the ligand. This is expected to be true

also for the heteroatom donor ligands. For the straight or open chain ligands 33-36 both

enthalpies and entropies decrease as the size of the ligand increases.

This motivated even more researchers to delve into studying further the reasons for this phenomenon. The findings by Rorabacher et al. revealed that, the reasons for the thermodynamic stability based on the macrocyclic effects include: (i) the limited or diminished flexibility of the free macrocyclic ligand, which increases upon complexation entropy and, (ii) for the ligands with hydrogen-bonding donors, the minimized solvation of the macrocyclic ligands in protolytic solvents when compared to similar open chain ligands.2 A further investigation of the kinetics led to the conclusions that: (a) ligands

with only ether oxygen donors (crown ethers) are limited to reactions with alkali metal

ions and related cationic species whose inner hydration shells are too labile, (b) for ligands with all amine (cyclic polyamine) the strong basic character of nitrogen leads to extensive ligand protonation, and (c) ligands with only thiaether (polythiaether) have limited solubility in aqueous solvents making it necessary to use a mixture of protic 6 solvents. The solvents used were water/methanol mixtures.2 To circumvent most of

these barriers a more serious study was done on the 14 member quadridantate

macrocyclic skeleton with alternating ethylene and propylene bridging groups and a 15 membered ring with all ethylene bridging groups. The synthetic strategies for these

ligands were discussed by Buter and Kellog83b in 1981. They devised a general synthesis

of the ligands as shown in Scheme 3 below:

S S Cs Br DMF S S

S S Cs Br S S

Scheme 3. General synthesis of homoleptic ligands by Buter and Kellog. 83b

Buter and Kellog noted that a combination of high dilution techniques and using a

more rigid component such as an ortho substituted phenyl derivatives can improve the

yield. When a different donor atom system is required in the ligand a precursor with such

atoms is employed to get the appropriate combination and the procedure is modified

accordingly as depicted on page 29. Ligands such as these have been utilized to study metal complexation and kinetics. The following ligands (38-49) shown in Figure 4 were

some of them.2

7 S HN S HN NH S NH HN NH HN NH S S HN S HN NH S NH HN

38 39 40 41 42

S S S NH S S NH S S S S S S S NH S S

43 44 45 46

N N N HN HN S H H H S NH S S H HN S S N S

47 48 49

Figure 4. Various macrocyclic ligands studied by Westerby et al.2

Eight heteroleptic ligands (38, 39,40,41,44,45,47 and 48) are among those that have been studied.2,11,28 The homoleptic i.e ligands with uniform donor atoms, such as 42, 43,

46 and 49, and the rest of the ligands were included for comparison purposes only.

Several researchers have studied ligands with N-S donors but lack the kinetic measurements2. The aquocopper(II) ion is suitable as it has the ability to form quadridentate coordinate bonds of measurable stability with [14]aneN2S2 trans 40 (trans here refers to alternating donor atoms NSNS) with alternating ethylene and propylene bridging groups, and [15]aneNxS5-x quinquedentate with all ethylene bridging groups for

1,11 comparison. Previously only [14]aneN2S2 45 has been studied. For the purpose of kinetic studies the monoamine nitrogen donor atom with weakly bonding thiaether sulfurs covering the rest of the donor sites, i.e. [14]aneNS3 44 and [15]aneNS4 47 were of 8 interest because the protonation of the nitrogen gave the rate determining step

(RDS).1,12,13 As a conclusion, the number and arrangement of the donors atoms in a ligand are important in minimizing the ambiguity in studying their kinetics and

complexation. Table 2 from Westerby et al. 2 summarizes this idea.

Table 2

Summary of Some Specific Rate Constants for Aquocopper(II) Ions Reacting with Various Protonated Amino/thia Ethers2 Quadridentate and Quinquedentate Macrocycles

Ligand reacted KCuL/Ms KCuHL/Ms KCuH2L/Ms

5 [14]aneS4 43 1.3 x 10 Not applicable (N/a)

6 2 [14]aneNS3 44 3.2 x 10 1.4 x 10

8 3 [14]aneN2S2 45 1.6 x 10 1.3 x 10

[14]aneNSSN 39 8.2 x 107 5.0 x 103

[14]aneNSNS 40 2.0 x 109 2.9 x 105

5 [14]aneN3S 41 - 3.1 x 10 51

6 6 [14]aneN4 42 - [1.8 x 10 ] and [8.0 x 10 ] [0.39] and [0.076].

5 [15]aneS5 46 7.5 x 10 N/a

6 3 [15]aneNS4 47 8.4 x 10 1.4 x 10

7 5 [15]aneN2S3 48 8.0 x 10 2.5 x 10 Approx. 8

[15]aneN5 49 - - 9.7 x 104

1.2 Metal Complexes of the Macrocyclic Ligands

Technitium ions like Tc(v)O2+ or Tc(v)O3+ have been used to form complexes

14 with cis [14]aneN2S2 36 and [14]aneN4 (cylam) 33 and were found to be quite stable.

9 Cu2+ and Cu+ complexes with the ligands were also studied where investigation on their

absolute and relative stabilities and effect of the ring size and how Cu+ which prefers a

linear arrangement of aliphatic amino groups to adjust to steric restrictions imposed by

cis ligands. Also, whether in aqueous solution there are other complexes with the neutral ligands besides CuL+ and CuL2+. Finally, Kaden e. al. investigated how closely they can

correlate thermodynamic redox potentials calculated from the stability constants of the

Cu(II/I) complexes with those obtained from cyclic volumetry.15 More recently,

Rorabacher et al. explored the electron transfer properties of Cu(II/I) where they

demonstrated that the reduction or oxidation of the metal complexes must be

accomplished through a remarkable structural change in the ligand whether the donors

are homoleptic thiaethers or heteroleptic thia-aza-ethers.16-27 In particular five comformations have been proposed in the investigation involving 14-membered macrocycles with ethylene and propylene groups in alternating fashion.28-30 Since Cu2+ prefers square planar geometry and Cu+ prefers tetrahedral,the CuL complexes have

shown a distorted tetrahedral which is in between square planar and tetrahedral. The

angles of copper complexed with [14]aneNS3 44 reported by Rorabacher are as follows:

S1-Cu-s2 (93.72˚), S2-Cu-S3 (95.68˚), S3-Cu-N (86.53˚), S1-Cu-N (87.16˚) and S1-Cu-S3

(166.53˚) and S2-Cu-N (163.62).115 These show the distorted geometry as depicted in

Figure 5.

Figure 5. Demonstrating electron transfer in Cu(II/I) redox, D1-4 represent donor atoms.

This portrays that the copper oxidation state is constantly changing from Cu(I) to

Cu(II) and vice versa, which is caused by rapid electron transfer between Cu(I) and

Cu(II). In general, the 14-membered rings form more stable complexes with copper because the 12-membered ring is too small and the 16-membered ring is too large for

Cu(II) to form a square planar complex.14 This phenomenon has been described by

Rorabacher et al.114,115 as going through a dual pathway. He also showed the Cu/Fe redox relationships which he summarized in the following diagram.

Figure 6. Electron transfer and geometry changes of Cu(II/I)/Fe (II/III) complexes114. 11 The very recent work 115 studied in detail electron transfer kinetics on copper

complexes with two sets of macrocyclic ligands with the following donor atom systems:

1,4,8,11-tetrathiacyclotetradecane (43) and 1,4,8-trithia-11-azacyclotetradecane (44) as

set (a); and 1,4,7,11-tetrathiacyclotetradecane and 1,7,11-trithia-4-azacyclotetradecane,

as set (b). In this work Rorabacher and coworkers115 delved into the mechanism of the

electron transfer and the reasons for the distorted tetrahedral geometry noticed in the

copper complexes. The explanation for this was the constant redox activity caused by

exchange of electrons between the two oxidation states of the metal ion which at one time

is Cu(I) with tetrahedral geometry and, the other time it becomes Cu(II) preferring

tetragonal or square pyramidal. In Figure 6, Rorabacher shows a model he developed to

illustrate this phenomenon which also relates the electron transfer between two different metal cations Cu and Fe.114

Bhasin and Darshana 116,117 formed complexes of nickel with functionalized

macrocycles with alternating donor atom as shown in Figure 7.

118 119

Where n = 1, 2, 3, or 4 and,

Figure 7.116 Complexes of nickel and the ligand.

12 The complexes were formed according to the method shown in Scheme 4.117

120

Scheme 4.117 Formation of a nickel complex developed by Bhasin et al.

Bhasin and Darshan116 did not synthesize the ligand by itself rather their method

was direct complexing using a Nickel salt or any other transition metal of interest and the

precursors of the ligand as shown in Scheme 4 above117. The coordination between Ni

and the donors atoms NSNS is square planar occupying the equatorial position. The relative anions ‘x’ occupy the axial position. The whole complex therefore acquires octahedral geometry.118 Lead (Pb) has been used instead of Ni and the same coordination

was observed118. The nickel complex was tested against fungus and bacteria (e.g. S.

typhi) and indicated some activities.116

Taylor et al.120 and Arca et al.119 have synthesized and complexed other similar

ligands with NS and O (Oxygen) in different arrangements as seen in Figure 8 below. In

the copper complexes, these ligands showed highly distorted geometries .119,120 This

distortion could probably be linked to the rigidity shown in the ligands imposed by the

aromatic and the other rings attached.

13 N N M NN N N N N Cu N N X X S S S S S S S S O S S S

121 122 123 124

125

Figure 8. Arca et al.119 synthesized ligands 121-123 and Taylor et al.120 synthesized

124,125.

The study of the complexes for these types of ligands was not limited to copper

and nickel. Venkatesh and coworkers31 have used similar ligands and functionalized

them by attaching different groups on such as –OCH3, OH, SCN, NCS, Ph and COOH,

and used them to make 105Rh(III) complexes. The general representation of the ligands is shown in Figure 9 below. The X’s contain a donor atom or group that will complex with the rhodium (105R) metal. The ‘R’ groups can be side chains or a substituent of choice

attached to a carbon of the ring. The R1-R4 groups are alkyl or aryl of different sizes,

although they can all be the same. The X1-X4 are donor atoms such as( N, S or O). R1-R4

31 can also be (- CH3, - CHCH3, CH(CH3)2, -C(CH3)3, Ph ). The substituents are intended

to improve the lipophilicity of the ligand itself or its rhodium complex.31

Figure 9. The model of ligands functionalized at the bridging carbons.

Two fourteen membered ring ligands [14]ane N2S2 39 and [14]aneNS3 44 have been

synthesized and complexed with Rhodium. These ligands were synthesized following a

series of condensations with protection of the amine as a tosyl group, cyclization through

capping utilizing high dilution methods and deprotection by Red-Al.7 Schemes 5 and 6

show how these ligands were synthesized.

In the formation of the ligand 44, the thiol group being good nucleophiles attacks

the electrophilic carbon with chlorine (the leaving group), to forms the subsequent amine

50. The amine group in 50 was protected by tosylation, and the molecule was reacted

with ethylene carbonate in xylene with solid potassium hydroxide to form the diol 52.

Reacting the diol 52 with thionyl chloride, the diol was converted to the dichloride.

Cyclization was done by capping using propanedithiol as the nucleophile to afford the

product 54. Subsquent detosylation of the protected amine in 54 by means of Red-Al ,

produced the ligand 44.

7 Scheme 5. Synthesis of [14]ane NS3 44.

To form the ligand 39,1,2 ethanedithiol was reacted with 3-chloropropanol as shown in scheme 6. The thiol groups being good nucleophiles attack the electrophilic

carbons with the chlorine and forms the subsequent diol 55. The diol 55 was Reacted

with thionyl chloride to produce the dichloride 56. The cyclization was achieved by

capping, using tosylated 1,2-ethyldiamine 57 as the nucleophile to afford the product 58.

Subsquent detosylation of the protected amine in 58 by means of Red-Al , produced the ligand 39.

7 Scheme 6. Synthesis of [14]aneN2S2 39

Both ligand 44 and 39 were complexed with rhodium (III)7a, at pH 4-5, and was found that the yield of the complexes decrease significantly as the number of the nitrogen atoms in the ligand increase. Thus, the percentage yield of the complex of rhodium (III) with ligand 44 was 94%, while in the same conditions the complex with ligand 39 was

81%. When a fourteen member ring ligand with all nitrogen as donor atoms (cyclam) was used in complexing with rhodium (III), the yield was only 59%. Rhodium (III) is a relatively soft ion, and hence prefers to chelate soft bases like sulfur, rather than nitrogen which is a relatively hard base.7a Also, from the crystallographic data7a, the two chlorines in the complexes are cis to each other with an angle, Cl-Rh-Cl* ~ 90˚. The Rhodium complexes of ligands 44 and 39 were made and the crystal structures are shown in Figure

10 below.

Figure 10. Ball and stick X-ray structures developed from available data for rhodium complexed with [14]aneN2S2 and [14]aneNS3. Li, N. et al. Radiochemica acta, 75(2), 1996, 83-95. The ball and stick structures were generated from X-ray data from CIF files,36c by Panzner, M.36e at the University of Akron in 2008, using the Mercury program.36d

In both cases the complexes are positively charged, with the two chlorines in a cis conformation. The geometry of the metal complex is distorted, no straight lines or straight angles.7

1.3 Other [14] Member Ring Macrocylic Molecules

A different approach to make the [14]ane macrocycles was described by Zervas and Ferderigos and reported as it is shown in Scheme 7 below.32

Scheme 7. Zervas et al.32-34 formation of carbon functionalized molecules 64 and 65.

The alcohol 59 was reacted with benzoyl chloride. The resulting benzoate 62 was

subjected to methanolysis by using sodium methoxide leading to its β-elimination to form

the alkene 63. Through intermolecular condensation of the two of the 63 molecules, the

formation of the [14]member ring molecule 65 occurred. However, intramolecular

cyclization also takes place in a competition and the [7]member cyclic molecule 64

forms. The yield founded was in the ratio of approximately 1:1, as the fourteen member

19 ring 65 the yield was 9.8% g, while that of the seven membered ring 64 was 8.0% under

the same conditions.32

1.4 Medium Cyclic Molecules Synthesized

As stated in the beginning, cyclic molecules with 8-11 membered rings are known

as medium size rings. These also have been synthesized and studied. In 1990, nine

membered rings with nitrogen, sulfur or the mixture of the two as donor atoms were

synthesized, characterized and complexed with nickel by McAuley and Subramanian.35

Also, in 1998, Shröder et al. synthesized, functionalized and complexed the same ligands

with copper and nickel.36 The ligands are shown in Figure 11.

HN HN

NH NH

HN S S R = Me 70 67 R N 66 R = Ph S 71 R OH

S S

NH S

S S

68 69

Figure 11. Nine member rings reported in literature.35,36

The crystal structures of complexes made from these ligands with copper, nickel

and rhodium show different geometries. For instance, in Figure 12, the copper is

quinquedentate and forms a bridge with another copper in between the cyclononane

ligands. In Figure 13, the copper is octahedral and is sandwiched in between two

20 cyclononane ligands. This gives it some extra stability. In Figure 14, the nickel also forms an octahedral geometry with one cyclononane ligand, an acetic acid and a tert- butyl alcohol. In Figure 15, rhodium forms octahedral geometry with one cyclononane ligand with three chlorines being cis to each other. Also, the ions have shown different chelating potentials.37- 44 The crystal structures shown in Figures 12-15 demonstrates copper, nickel and rhodium complexes and their geometries.36a

[Cu ([9]aneNS2)2[BPh4]2

Figure 12. Two copper atoms complexed with [9]aneNS2 in a bridging manner.

[Cu ([9]aneNS2)2(PF6)2

Figure 13. Copper atom sandwiched between two [9]aneNS2 ligands.

[Ni(H[9]aneNS2)(CH3CO2)]BPh4CH3CN

Figure14. Nickel complexed with [9]aneNS2

The crystal structures are ball and stick models generated from the Crystal

Information Files (CIF)36c of the individual complexes at the University of Akron X-ray

crystallographic facility, using the Mercury 2.2 program.36d,e

36b Very recently, the [9]aneNS2 68 was synthesized and complexed with rhodium.

The complex was tested with ovarian cancer cells and showed tremendous activity and cell invasion properties compared to the existing cancer drug, cisplatin.36b The testing

was done on Nu-Tu-19 Ovarian cancer cells and it was shown that the rhodium complex

decreased the invasion by 25% while the cisplatin decreased the invasion of the same

23 cells by 35% under the same testing conditions.36b The testing for both the rhodium complex and the cisplatin was done utilizing Matrigel which is very similar to the in vivo cellular basement membrane, and has been reported. 36b At higher concentration, the cisplatin has more toxicity than the rhodium complex. The complex shows a highly distorted octahedral. The crystal structure of the rhodium complex is shown in Figure 15.

Figure 15. A crystal structure of rhodium complexed with a nine member ring ligand.

24 CHAPTER II

RESULTS AND DISCUSSION

2.1 Synthesis, Complexation and Characterization of the Ligands

This work presents syntheses of six major ligands (40, 90, 100, 107, 110 and 112) each involving several steps. The methods described in literature have been adapted with some modifications.45-51 The focus of this work is mainly on the macrocyclic and medium size ring structures. Dietrich identified three principles of ligands formation as synthesis, cyclization and ring closure.45

The synthetic principles outlined are summarized in the following scheme.

Scheme 8. General methods of ring closure.

25 The reactions in the cyclization proceed mainly by SN2 (substitution bimolecular)

or by condensation. The ring formation may occur by simple cyclization involving

joining end to end, like in the formation of 82; or by capping, joining two segments as in

the formation of 44 and 41; or by condensation joining two parts together as in the

formation of 65. In some cases cyclization may be difficult depending on the situation

and conditions of the reaction. For instance, the length of the chain of the starting

material, the nature of the fragments forming it, the rigidity of the fragments and

proximities of other functional groups may favor intramolecular rather than

intermolecular and vice versa. For simple one component cyclization mostly

intramolecular is favored, however, intermolecular may occur competitively, and larger

cycles or long chains can form as byproducts.45 Similarly, a two component cyclization proceeds first as an intermolecular condensation followed by intramolecular cyclization.

Other effects include the solvent viscosity, concentration of the reactants, temperature,

and duration of the reaction may contribute to the type of products formed.1,52-56 In

general, ring closure in macrocyclic ligands is more favorable using high dilution

techniques.45,57,58

2.2 The Macrocyclic Ligands Synthesized in This Work

The fourteen member rings and their functionalized species will be discussed as

well as the testing for the anticancer activities of the rhodium complex of the ligand.

2.2.1 The First Ligand Synthesized in This Work Was the [14]aneNSNS 40

The synthesis of this molecule has not been reported to date since the alternating

arrangement of the thia-aza donor atoms makes it difficult to use the simple capping

26 methods, or the [1+1] condensation which would give rise to mixtures of products. The

retrosynthesis is shown in Scheme 9.

Scheme 9. Retrosynthesis of the ligand 40.

To begin with, protection of the amino functional group in the cystamine (72)

with a tosyl group was necessary. 7b The cleavage of the disulfide bond with triphenyl

phosphine and subsequent SN2 nucleophilic attack of the resulting thiolate on 3- chloropropylamine (74) led to the formation of the amine 75.59,72

Scheme 10. Preparation of amine 75.

The second part of the ligand, 6-Chloro-propyl-3-thia-hexanoyl chloride 79, was prepared by reacting allyl chloride 76 with thioglycolic acid 77 in presence of a catalytic amount of AIBN.78 This reaction proceeds through radical reaction initiated by the

AIBN which decomposes at 70˚C to form Isobutylnitrile radical and abstract the

27 hydrogen atom of the thioglycolic acid. The resulting radical attacks the allyl chloride double bond to give the acid 78. The acid is reacted with thionyl chloride to produce the acid chloride 79 as shown in Scheme 11.

Scheme 11. Formation of acid chloride 79.

The acid chloride 79 and the amine 75 reacted are in the presence of Et3N and

DMAP to produce amide 80.80,81,82

Scheme 12. Acylation of the amine 75 to form the amide 80.

Finally, the ring formation was achieved through cyclization by intramolecular

61 SN2 reaction in presence of finely grounded dry K2CO3 in DMF. This gave the cyclized

amide 81 in 56% yield. Borane reduction 86 of the amide produced the free amine 82 in

88% yield, as shown in Scheme 13.

Scheme 13. The cyclization and reduction of the amide 80 to form amine 82.

The crystals of amine 82 were grown from 95% ethanol and the crystals obtained were suitable for X-ray analysis. The crystal structure of the amine 82 is shown in Figure

16. According to Dale’s convention, the cyclotetradecane alkane molecules have as the

82 Figure 16. Crystal structures of the tosylated amine 82.

29 most stable quadriangular conformer in the form of [3434].85 The conformation in the

crystal structure 82 has a distorted quadriangular conformation of [2444]. The tosyl

group on the N1 shifts its position from the relative straight line of 4 bonds to a more

distorted form, and making the angle C1-N1-C10 to be 117.2˚ compared to the free amine angle C6-N2-C5 which has an angle of 108.7˚. Also, the fourth side is shrunk to only two bonds, making the angle C3-S3-C4 100.5˚ while C8-S2-C9 has only 98.4˚. All the bond lengths remain in the normal range.

The target ligand 1,8-dithia-4,11-diazacyclotetradecane 40 was obtained by detosylation using sodium- bis-(2-methoxyethoxy) aluminum hydride (Red-Al).88-91

After obtaining the ligand 40, it was further functionalized to tertiary amine 83 by using

reductive amination with sodium cyanoborohydride and formaldehyde92-96 as shown in

Scheme 14.

Scheme 14. Synthesis of the desired ligand 40.

The ligand 40 was recrystalized from ethyl acetate and the crystals thus obtained

were suitable for X-ray crystallography. The crystal structure is shown in Figure 17. This

shows the most stable cyclotetradecane quadrangular conformation of [3434].85 The

donor atoms do not stay at the corners, but rather on the connecting chains.

Figure 17. The crystal structure of the ligand 40.

Also, the ligand 40 was complexed with three different metals: Copper, Rhodium and Nickel to form the crystal structures CuL 114, RhL 116 and NiL 115 respectively.

The crystals structures formed were suitable for X-ray analysis.

31 The copper complex was made by dissolving the ligand in chloroform and copper perchlorate hexahydrate in acetonitrile (MeCN) in equal moles and same concentration in two different test tubes and slowly pour the salt solution on ligand solution. At the

interface a greenish blue color forms and with slow evaporation the crystals grew.

Scheme 15 shows the reaction.

40 114

Scheme 15. Copper complexing the ligand to form 114.

The crystal structure of the copper complex is as shown in Figure 18.

114

Figure 18. Crystal structure 114 of copper complexed with ligand 40.

32 The crystal structure 114 reveals copper to exist in square a planar a geometry

preferred by Cu(II). The bond angles between the copper and the donor atoms directly

opposite, i.e. S1-Cu-S2, and N1-Cu-N2 are both (180˚). The bond angels (˚) are as follows: N(1)-Cu-N(1A) 180.0, N(1)-Cu-S(1) 88.14, N(1A)-Cu-S(1) 91.86, N(1)-Cu-

S(1A) 91.86, N(1A)-Cu-S(1A) 88.14 and S(1)-Cu-S(1A) 180.0. The bond lengths (S1-

Cu) equals to Cu-S(1A) 2.2877 and (N1-Cu) is equal to the (Cu-N2), indicating the absence of distortion. The bond lengths in (Å) and of the copper complex 114 are Cu-

N(1) 2.0178, Cu-N(1A) 2.0178, Cu-S(1) 2.2877 and Cu-S(1A) 2.2877.

115 Rorabacher et al. complexed Cu(II) with [14]aneNS3 and the Cu(II) was

quinquedentate as the copper picked up a water molecule. The bond lenths (Å) and bond

angels (˚) were Cu-S(1) 2.311, Cu-S2 2.286, Cu-S3 2.279 and Cu-N 2.004; S(1)-Cu-

S(2) 93.72, S(2)-Cu-S(3) 95.68, , S(3)-Cu-N 86.53, S(1)-Cu-N 87.16 S(1)-Cu-S(3)

166.53 and S(2)-Cu-N 163.62. This shows a bigger distortion from the usual square

planar geometry preferred by Cu(II) compared to the structure 114 which has no

distortion out of plane at all, so the copper metal rests in the plane of the molecule. In

the literature Copper can also form complexes with octahedral geometry.36a

The nickel perchlorate salt was dissolved in acetonitrile, and the ligand 40 was

dissolved in chloroform. The ratio of concentrations of the two solutions was 1:1. The

layering was done by pouring the nickel perchlorate solution slowly onto the ligand

solution. At the interface a grayish/green color was noted, and on slow evaporation

crystals formed. The reaction is shown in scheme 16.

40 115

Scheme 16. Nickel complexing with ligand to give 115.

The crystal structure obtained is shown in Figure 19.

115

Figure 19. Crystal structure 115 of nickel complexed with ligand 40.

34 The geometry of nickel is a distorted octahedral. The metal picks up a molecule of

acetonitrile in an equatorial position and a molecule of water in an axial position. The

bond angles (˚) for the complex 115, shown in appendix D, are as follows: N3-Ni-N2

88.04; N3-Ni-N1 173.24; N2-Ni-N1 97.14; N3-Ni-O 87.46; N2-Ni-O 175.05; N1-Ni-O

87.50 and Si-Ni-S2 176.27. These angles show clearly that nickel exhibits distortion

from the plane of the complex as there are no right angles or straight 180˚ angles.

The rhodium complex was formed following the procedure in literature.121 A solution of the ligand in 95% ethanol was added to a stired solution of Rhodium

trichloride trihydrate in 95% ethanol. The reaction mixture was refluxed for 2 h at 80˚C.

After cooling to room temperature, it was filtered and the rhodium complex crystals were obtained in 69.7% yield, and were suitable for X-ray crystallographic analysis.

40 116

Scheme 17. Ligand complexing with Rh(III).

116

Figure 20. Crystal structure 116 of rhodium complexed with ligand 40.

The geometry of the rhodium complex is a distorted octahedral with both of the chlorines occupying equatorial positions and cis to each other. From Appendix D, the bond angles (˚) of the complex 116 which shows the distortion are as follows: N2-Rh-N1

92.92; N2-Rh-S1 95.90; N1-Rh-S1 85.92; N2-Rh-S2 86.41; N1-Rh-S2 95.89; S1-Rh-S2

177.00; N2-Rh-Cl1 87.60; N1-Rh-Cl1 176.65; S1-Rh-Cl1 90.74; S2-Rh-Cl1 87.44; N2-

Rh-Cl2 176.30; N1-Rh-Cl2 88.39; S1-Rh-Cl2 87.63; S2-Rh-Cl2 90.02 and Cl1-Rh-Cl2

91.29. Also, Table 3 gives the summary of the characteristics of the crystals obtained.

36 Table 3

Selected Crystallography Data for 40, 114, 116 and 115

Entry 40 114 116 115 Emperical C10H22N2S2 C10H22Cl2CuN2O8S2 C10H20Cl3N2RhS2 C12H27Cl2N3NiO9S2 formula 234.42 496.86 457.66 551.10 Formula weight Triclinic Triclinic Orthorhombic Monoclinic

Crystal system P-1 P-1 Pna2(1) P2(1)/c

Space group 5.3666(9) 6.9206(9) 18.586(4) Cell 7.8306(13) 8.1330(11) 16.526(2) 8.1009(16) dimensions(Ǻ) 8.5240(14) 9.4154(13) 10.2493(15) 15.236(3) (a) 115.552(2) 98.281(2) 9.9523(14) 90 (b) 106.336(3) 111.395(2) 90 113.977(4) ( c ) 93.256(3) 110.396(2) 90 90 α-(degrees) 90 β-(degrees) 303.49(9) 439.60(10) 2096.1(7) γ--(degrees) 1685.7(4) 1 1 4 Volume (Ǻ3) 4 1.283 1.877 1.746 Z 1.803 0.406 1.826 1.430 Density 1.729 (Mg/m3) 2721 3918 18037 14372 Abs.coef.(mm- 1412 2040 5051 1) [R(int)=0.0270] [R(int)=0.0205] 4019 [R(int)=0.0765] [R(int)=0.0508] Reflections R1=0.0381 R1=0.0284 R1=0.0530 coll. wR2=0.0943 wR2=0.0753 R1=0.0339 wR2=0.1320 wR2=0.0733 Ind. Refl. R1=0.0401 R1=0.0288 R1=0.0731 wR2=0.0964 wR2=0.0756 R1=0.0360 wR2=0.1444 wR2=0.0740 Final R i [1>2σ(1)].

R indices (all data)

37 The rhodium (III) complex 116 was tested on ovarian cancer cells and showed some positive results. The pictures in Figure 21 on the left shows the cancer cells before treatment with the complex, and the right hand side after treatment with the complex.

Figure 21. The activity of the complex 116 on ovarian cancer cells.

The cancer cells NuTu-19 were grown at 37°C and 5% CO2 and passed (split) 1-

2 times a week in a medium of RPMI 1640 +10% FBS. The magnification used was 40x.

The testing concentration of 1.54 mM was randomly chosen for survey only, and was used to test the activity for both the cancer cells and the normal ovarian (OVepi) cells.

The number of cells used was 39,000 per well in 46 well plates. The number was determined using Hemocytometer. The imaging model was not done, only normal photos with green background, non fluorescent. The duration of testing, i.e. from the time the complex was applied on the cells to the time the activity was determined. At 24 h, 62% of the cancer cells were dead, and at 48 h 87% of the cancer cells were killed. The results of the testing are summed up in the data given in Table 4 and were done at the University of Akron.77

Also, the toxicity of the complex on healthy cells was tested. The picture in

Figure 22, on the left shows the healthy cells and on the right shows the cells after being exposed to the complex. Table 4 gives the summarized information.

Figure 22. The activity of complex 116 on healthy cells.

Table 4

Activity of Rhodium Complex on Ovarian Cancer

Type of cells Before The number remaining after 48 h The percentage

treatment treatment activity

Ovarian cancer 9.69 x104 1.25 x104 87%

Normal cells 26.6 x104 18.6 x104 30%

Since this was done as a quick survey only, testing the complex on the cancer and

normal cells at different concentrations, and conditions was not imediately done, but in

the future this can be done as a follow up.

39 2.2.2 Linking Two Fourteen Member Ring Ligands

Scheme 18. The formation of a double ligand amine 87.

As shown in Scheme 18, the secondary amine 82 undergoes a nucleophilic

attack on succinic anhydride (84) leading to the formation of the acid 85. The acid 85

was reacted with additional secondary amine 82 in the presence of DCC and DMAP to form the diamide 86 in 49% yield. The borane reduction86b gave the tertiary diamine 87

with a yield of 83%.

The crystal structure of the diamine 87 was grown from a chloroform/acetonitrile

solvent combination and the crystals obtained were suitable for X-ray analysis. The

crystal structure 87 is shown in Figure 23.

Figure 23. The crystal structure of the diamine 87.

The fourteen member rings are forming the quadrangular conformations of Dale’s

[3434]85 type, just as the ligand 40. The donor atoms are occupying the corners. The

molecule is less distorted compared to 82.

The next step is the detosylation of the diamine 87 to form the tertra-amine 88.

The tosyl groups were removed using 33% HBr in acetic acid in the presence of

phenol 35,36a to give the free amine 88 in a yield of 92% as shown in Scheme 19.

Scheme 19. Formation of free amine 88.

41 Finally, succinic anhydride (84) was reacted with the free amine 88 in the

presence of DCC and DMAP leading to the formation of the amide 89. The borane

reduction gave the final tricycloamine 90 in 39% yield as shown in scheme 20.

O S HN DCC, DCM SN N S DMAP, rt. SN N S O O O SN 3 d N 91% S O 84 NH S iv. qu 4 e 89 , 88 BH 3 ° C ) S 0 2 11 CH 3 e, ( en olu % T 39 SN N S SN N S 90

Scheme 20. Formation of the tricycloamine 90.

2.2.3 Condensation Route32,34

Scheme 21. The retrosynthetic route showing [1 + 1] condensation strategy.

42 The strategy to synthesize a functionalized fourteen member ring such as

dimethyl ester 99 is envisaged in Scheme 21. Basically two equal components will be

used to accomplish the synthesis in a [1+1] condensation process.

Scheme 22. Formation of the thia-ester alcohol 96.

From the literature32 anhydrous HCl and MeOH can convert amino acid 91 into

the serine methyl ester hydrochloride 92. Also, reacting 3-bromopropionic acid and

potassium thioacetate using the reported procedures33b lead to the formation of the acid

95. The serine methyl ester hydrochloride 92 was neutralized to the amine using

NaHCO3. Through the nucleophilic reaction the ester alcohol 96 was formed in 84%

yield.

The alcohol was converted to the benzoyl ester, and subjected to β-elimination

using sodium methoxide in an attempt to make the diester 99. However, only the seven-

membered ring lactam 100 was obtained in 40% yield.

Scheme 23. An attempt to form the macrocyclic molecule 99.

The desired fourteen member ring molecule 99 was not isolated, however, 40% of the smaller seven member ring lactam 100 was obtained. The mechanism of this reaction is outlined in Scheme 24.

Scheme 24. Proposed mechanisms for formation of the tetracyclodecane functionalized at bridge carbons.

44 The crystals for the structure determination of lactam 100 were grown from 95% ethanol and the crystal structure is shown in Figure 24 below.

Figure 24. Crystal structure of the seven member molecule 100.

2.2.4. The Formation of the Nine Member Ring Ligands

The nine membered ring 7-Aza-1,4-dithiacyclononane 107 was synthesized from the reported literature with modifications as the retrosynthetic route is shown in

Scheme 25 below.35,36,105,106

Scheme 25. Strategies for the synthesis of nine membered ring ligands.

Scheme 26. The formation of thiourenium salt 104.

The starting material diethanolamine 101 was tosylated35,35 and the tosylates

were replaced by bromides. The bromoethylamine 103 was reacted with thiourea and

formed the thiouronium salt 104 in 92% yield.

Scheme 27. Synthesis of the nine member ring free amine 107.

The thiouronium salt 104 was treated with aqueous base to hydrolyze the salts

and concentrated HCl to protonate the thiolates. The dithiol was immediately cyclized61

with 1,2-dibromoethane. The amine was detosylated using 33% HBr aceticacid/phenol

reaction36a and the ligand 107 was obtained in 90% yield.

46 The synthesis of the double ligand diamine 110 is described in Scheme 28.

Scheme 28. The formation of the double ligand amine 110.

The amine 104 is reacted with succinic anhydride to form the acid 108 in 98% yield. The acid 108 was treated with DCC in presence of DMAP and reacted with an equivalent of the amine 104 to form the diamide 109 in 79% yield. The borane reduction86 led to the formation of the tertiary amine 110 in 90% yield.

The crystals of the perchlorate salt of the amine 110 were grown from acetonitrile and chloroform and perchloric acid (HClO4). The crystals were suitable for

X-ray analysis and the structure is shown in Figure 25.

Figure 25. The crystal structure of protonated [9]aneNS2 double ligand amine 110.

2.2.5 Linking the Amine 82 to the Nine Member Ring Ligands 107 The fourteen member ring ligand [14]aneNSNS 82 was linked to the nine membered ring [9]aneNS2 107 using succinic anhydride as summarized in the following

Scheme 29.

Scheme 29. The double ligands tertiary amines 112.

The diamide 111 can be synthesized by reacting either the acid 85 and amine 107, or the

acid 108 and amine 82 in presence of DCC and DMAP. Borane reduction86 on the

diamide 111 was done, and the tertiary diamine 112 was formed in 97% yield.

48 2.2.6. Complexing a Ten Member Ring with Rhodium Metal

Ligand 113, which was previously reported in literature,122-124 was successfully synthesized,125 and was complexed with rhodium metal following the reported procedure.121 The ligand was dissolved in 95% ethanol and this was poured into an equal molar stirring solution of rhodium trichloride trihydrate in 95% ethanol. A yellow precipitate was observed, which was refluxed at 80˚C for 2 h. After cooling the system to room temperature, filtration followed, the residue was washed with cold 95% ethanol and dried on high vacuum pump to afford the complex in 81% yield. The crystals obtained were suitable for X-ray crystallographic analysis. Scheme 30 shows the ligand complexing with the rhodium, and figure 26 shows its crystal structure.

113 117

Scheme 30. Ten member ring complexed with rhodium.

Figure 26. The crystal structure of the rhodium complex 117.

From the crystal structure, presence of the three chlorines on the octahedral geometry of the complex shows the oxidation state of Rhodium to be three. The chlorines are cis to each other. The cations is therefore protruding out of the ligand cavity. From

the crystal structure, the OH group did not contribute to the complexation. However, the

presence of the OH group on the ligand offers an opportunity to further functionalize the

ligand by attaching other groups on it, which will give the ligand more chelating

potentials.

50 CHAPTER III

SUMMARY

Five aza-thia ligands (40, 90, 100, 110, and 112) have been synthesized in this work and a sixth ligand 113 has been adapted.125 The structures of 40, 87, 100 and 110 have been analyzed by X-ray crystallography. Metal complexes of 40 with copper 114, rhodium 116 and nickel 115 have been synthesized and fully characterized by X-ray crystallography. Also, the rhodium complex 117 from the adapted ligand 113 has been successfully made. The copper complex was made with the intention of mimicking the blue copper proteins.128-131 The other complexes were made to show the ability of the molecules to act as ligands in chelating metal ions as well as their biological activities.

The Rhodium complexes were tested for their potential as anticancer drugs.

Since the rhodium complexes have shown an anticancer activity, there is a great need at the moment to research antitumor drugs based on rhodium another metals similar to it. Cisplatin132,133 as a metal based antitumor agent, has been in market for over 50 years. To date, only two drugs are clinically accepted in the market, cisplatin and carboplatin.134 Rhodium complexes tested so far, have shown no evidence of nephrotoxic, but the toxic effects of some compounds have discouraged further investigation.133 The complex 116 of rhodium with ligand 40 has been tested and shown good results, which gives a good starting point to delve into the study of rhodium

51 compounds. Perhaps, if rhodium complex 117, formed from the ligand 113 was examined in the same way, some positive results, even better ones, could have been found due to the three chlorines cis conformation.

So far in this work the synthesis and complexation of some ligands have been achieved as outlined throughout the schemes and in the discussion. The ligands with free amine are potentially able to be further functionalized as in the formation of the tricycloamine ligand 90, double cyclononane ligand 110, and joining the tosylated fourteen membered rings 82 to the nine membered ring 107 by a butane chain to form the mixed double ligand 99. Another fourteen member ring molecules 65 and 99 which are very similar to the ligand 40 have functional groups attached to the ethylene and propylene chains rather than on the amine. The seven membered ring 100 was isolated and crystallographically analyzed.

The promising results obtained after testing the rhodium complexes and the positive biological activities seen, should create some stimulus in the researchers to engage in this type of work.

52 CHAPTER IV

EXPERIMENTAL

4.1 General Procedure

Instrumentation: Special acknowledgement to the analytical discipline at the

University of Akron Chemistry department for providing most of the instruments needed to analyze the synthesized products. The 1H and 13C NMR spectra were recorded on

Varian VXR or GEMINI spectrometers at 300 MHz and 75 MHz, respectively, in parts per million (ppm) on the delta scale (δ). Depending on the solvent used, the residual

proton peaks for H2O (4.80 singlet), CHCl3 (7.27 singlet), DMSO (2.50 quintet ppm)

were used as internal standards for 1H NMR. For 13C NMR, residual peaks were 77.23

triplet (CDCl3) and 39.5 septet ppm. (for DMSO). The chemical shifts and the splitting

pattern of the 1H NMR are designated as singlet (“s”), doublet (“d”), doublet of doublets

(“dd”), doublet of triplets (“dt”), triplet (“t”), quartet (“q”), quintet (“Q”), hextet (“h”), multiplet (“m”), broad region (“br”) and very broad region (“brr”). The coupling constant is denoted as “J” and has units of Hertz “Hz”. Infra red (IR) spectra were collected and recorded from a Bomem MS-100 (FT-IR) and a NICLET NEXUS 870 FT-

IR spectrometer and were reported in reciprocal centimeters (cm-1). X-ray structures

were determined by coating in paraffin oil and mounted on a CryoLoopTM and placed on

the goniometer head under a stream of nitrogen cooled to 100K. The data was collected

on a Bruker APEX CCD diffractometer with graphite-monochromated Mo Kα radiation

53 (λ=0.71073Ǻ). The unit cell was determined by using reflections from three different

orientations. The data was intergrated using SAINT and corrections done by multi-scan

SADABS. Structure solution, refinement and modeling were accomplished by using the

Bruker SHELXTL systems.126a,b,127 Mass spectra were done by Bruker Daltonic Esquire-

LC_00143 ion source ESI.

Reagents: When no other specification is reported, the reagents from commercial

suppliers were used directly without further purification. Synthesized reagents are shown

in the particular schemes with specifications from available literature as referenced

thereof. Since some of the amines and thiols are both air and moisture sensitive,

glassware used in such steps were flame dried under dry nitrogen or oven dried

overnight. When stirring was required, a mechanical stirrer or a magnetic stirrer was employed. Some solvents were distilled immediately prior to use. THF was distilled from Sodium/Benzophenone. CH2Cl2, CHCl3, Et3N, toluene and DMF were distilled

from Calcium hydride (CaH2). Reactions were monitored by thin layer chromatography

(TLC) using 0.25 mm precoated silica gel 60-F254(EM Reagents). Where it was

necessary, the products were cleaned by column chromatography using silica gel 60,250-

400 mesh (EM Reagents). High boiling solvents were removed by means of a movable

high vacuum pump and ordinary solvents were concentrated using a rotary evaporator

with an aspirator. Melting points were obtained on Thomas Hoover melting point

apparatus and are uncorrected. Unless otherwise stated, the boiling points were

uncorrected.

54 4.2 Synthesis

The ligands were synthesized and characterized step by step as ellaborated in the

subsequent procedures. The starting materials, experimental conditions, the products and

their analysis are all reported.

4.2.1 Synthesis of N,N’-Bis-(p-toluenesulfonyl)-cystamine(73)

In a 2000 mL 3-neck round bottomed reaction flask equipped with a mechanical

stirrer 14.0 g (350 mmol) of NaOH was dissolved in 350 mL of deionized water. To the

1M NaOH solution, 18.23 g (81.75 mmol) of Cystamine Dihydrochloride 72 was added

and vigorous stirring begun. After dissolving was completed, 30.88 g (162.00 mmol) of

p-toluenesulfonylchloride (TsCl) in 405 mL of methylene chloride was added dropwise

via a pressure equalizing funnel over a period of approximately 2 h to the vigorously

stirred solution at room temperature. Stirring, after the completion of the addition, was

continued overnight. Stirring was stopped and the two layers were separated. The

organic layer was washed with 3M HCl (1x50 mL), followed by dionized water (1x50

mL) and finally washed with (1x50 mL) brine . The organic layer was then dried over

sodium sulfate, vacuum filtered and concentrated in vacuo to give a solid. The product

was recrystallized from pure methanol to give the desired compound 73 as pure white

˚ crystals (33.84 g, 73.58 mmols, 90%, mp 92-93 C). Rf 0.10 (30% ethyl acetate in

1 hexanes). H NMR (CDCl3) ∂ 7.72 (d, J= 8.3Hz, 2H), 7.28 (d, J=8.3Hz, 2H), 5.29 (t,

J=5.5Hz, 1H), 3.19 (q, J=6.4Hz, 2H),2.67 (t, J=6.4Hz, 2H), and 2.40ppm. (s, 3H). 13C

NMR (CDCl3) ∂ 143.9, 136.6, 130.0, 127.2, 41.8, 38.0 and 21.7 ppm. IR (film) 3275,

2923, 2865, 1598, 1495, 1405, 1323, 1156, 1092, 910, 814, 731 and 666 cm-1.

55 4.2.2 Synthesis of N-[2-(3-Amino-propylthio)-ethyl]-4-p-toluenesulfonamide (75)

N,N’-Bis-(p-toluenesulfonyl)-cystamine (73) 28.20 g (61.30 mmol) and triphenylphosphine 16.10 g ( 61.30 mmol) were added to a 1000 mL round bottomed flask under nitrogen. Then 250 mL of tetrahydrofuran (THF) was added followed by 50 mL of deionized water. The mixture was stirred at ~66˚C in an oil bath for 2 d. When

the disulfide disappeared by thin layer chromatography (TLC), the reaction was cooled to

room temperature and 61.30 mL (122.60 mmol) of 2M NaOH was added. Then, 3-

chloropropylamine hydrochloride 15.94 g (122.60 mmol) in 2M NaOH 61.30mL

(122.60 mmol) was put in pressure equalizing addition funnel attached to the reaction

flask. The system was deoxygenated using a Firestone valve (evacuating the system and

filling it with nitrogen, and repeating this three times). After deoxygenation, stirring was

continued, and the amine solution was added dropwise at room temperature. After

addition was completed, the reaction was heated an in oil bath at ~66˚C while stirring

under nitrogen for 24 h. The reaction completion was confirmed by TLC. The system

was cooled to room temperature. A 6 M solution of HCl (about 50 mL) was added to

lower the pH to ~2. Then chloroform (70 mL ) was added and the two layers separated.

The aqueous layer was washed with (2 x 70 mL) chloroform. Then the pH of the

aqueous layer was raised to pH ~10 with 6 M NaOH and extracted with chloroform (3 x

70 mL). The combined extractions from the basic media were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude product was recrystallized from toluene/ethyl acetate (200:80 mL solvent combination) to afford amine 75 as white

˚ 1 crystals (29.74 g, 103.11 mmols, 84%, mp 88-90 C). Rf. 0.36 (30% MeOH in toluene). H

NMR (CDCl3) ∂ 7.76 (d, J=8.3Hz, 2H), 7.32 (d, J=8.3Hz, 2H), 3.14 (t, J=6.4Hz, 2H),

56 2.77 (t, J=6.4Hz, 2H), 2.61 (t, J=6.4Hz, 2H), 2.50 (t, J=7.0Hz, 2H), 2.43 (s, 3H) and 1.65

13 ppm (Q, J=7.0Hz, 2H). C NMR (CDCl3) ∂ 143.5, 137.2, 129.8, 127.1, 42.3, 40.8, 32.7,

32.0, 29.1 and 21.6 ppm. IR (film) 3344, 3279, 3043, 2949, 2931, 2912, 1597, 1446,

1311 and 1151 cm-1.

4.2.3 Synthesis of 6-chloro-3-thia-hexanoic Acid (78)

Allyl chloride 76, 34.30 g (448.20 mmol, 36.50 mL), distilled mercapto-acetic acid 77 37.60 g (408.20 mmol, 28.40 mL) and a catalytic amount of

azobisisobutyronitrile (AIBN) were mixed together in a resealable tube. The screw top of the sealed tube was tightened by a torque wrench to about 40 psi. The mixture was then heated in an oil bath at approximately 70˚C for 48 h. It was then allowed to cool to

room temperature and was analyzed by 1H NMR and IR to confirm the formation of

1 compound 78. H NMR (CDCl3) ∂ 11.31 (s, 1H), 3.62 (t, J=5.9Hz, 2H), 3.24 (s, 2H),

13 2.79 (t, J=7.0Hz, 2H) and 2.04 ppm (Q, J=4.8Hz, 2H). CNMR (CDCl3) ∂ 177.1, 42.3,

33.4, 31.4, 29.7 and 26.4 ppm. IR (film) 2958, 2927,2668, 2562, 1707, 1423 and 1296 cm-1

4.2.4 Synthesis of 6-chloro-3-thia-hexanoyl chloride (79)

Crude (3-chloro-propylthio)-acetic acid (78) was taken from the sealed tube via a

syringe and transferred to 500 mL single neck round bottomed flask. The product 78 was theoretically estimated to be 68.84 g (408.2 mmol). The crude acid was dissolved in approximately 210 mL of methylene chloride and, by means of a pressure equalizing addition funnel, thionyl chloride (448.00 mmols, 33.60 mL) was added to the reaction dropwise while the stirring system was protected with a CaCl2 drying tube. After the

57 completion of addition, the reaction was allowed to stir overnight at room temperature.

When the formation of 79 was verified by 1H NMR and IR, the excess of thionyl chloride

and the solvent were removed by rotary evaporation leaving a brown colored liquid

product behind. Purification by vacuum distillation gave acid chloride 79 as a clear

˚ 1 yellowish oil (51.2 g, 273.5 mmols, 67%, 96 C at 0.04mmHg). H NMR (CDCl3) ∂ 3.70

(s, 2H), 3.64 (t, J=6.8Hz, 2H), 2.80 (t, J=6.8Hz, 2H) and 2.04 ppm (q, J=6.8Hz, 2H). 13C

NMR (CDCl3) ∂ 170.4, 45.3, 43.1, 31.4 and 29.8 ppm. IR (film) 2961, 2913, 1790,

1006, 958 and 700 cm-1.

4.2.5 Synthesis of N-{N’-(3-propylthio)ethyl]-4-methylbenzenesulfonamide}-[(3- chloropropyl)thio]acetamide (80)

N-[2-(3-Amino-propylthio)-ethyl]-4-p-toluenesulfonamide (75) 25 g (86.81

mmol) and 4-dimethylaminopyridine (DMAP) 0.32 g (2.6 mmol) were mixed in a flame

dried 500 mL 2-neck round bottomed flask attached to a dropping funnel. The system

was put under nitrogen. Distilled methylene chloride 90 mL was introduced through the dropping funnel and stirring was done by a stir bar to dissolve the contents. Then distilled triethylamine (TEA) 9.02 g (89.30 mmol, 12.44 mL) was introduced through the

septum by a syringe. The mixture was stirred for about 10 min in an ice bath to lower the

temperature to 0˚C while the dropping funnel was charged with 6-chloro-3-thia-hexanoyl

chloride (79) 16.24 g (86.81 mmol in 90 mL of distilled methylene chloride). The

contents of the dropping funnel were added dropwise to the cold mixture over a period of

90 min. The ice bath was removed and the reaction mixture stirred at room temperature

for 18 h. The mixture was washed with deionized water (2 x 80 mL), 3M HCl (2 x 80

mL), and 3M NaOH (2 x 80 mL). The organic layer was dried over Na2SO4, filtered and

58 concentrated in vacuo. The brown oily product 80 was further dried by high vacuum

1 pump to give (33.16 g, 75.52 mmols, 87%). Rf. 0.35 (75% ethyl acetate in hexanes). H

NMR (CDCl3) ∂ 7.76 (d, J=8.3Hz, 2H), 7.32 (d, J=8.3Hz, 2H), 6.97 (s, br, 1H), 5.23 (s,

br, 1H), 3.65 (t, J=6.4Hz, 2H), 3.38 (q, J=6.4Hz, 2H), 3.24 (s, 2H), 3.12 (q, J=6.4Hz, 2H),

2.72 (t, J=7.0Hz, 2H), 2.6 (t, J=6.4Hz, 2H), 2.50 (t, J=7.0Hz, 2H), 2.44 (s, 3H), 2.06 (Q,

J=6.4Hz, 2H) and 1.78 ppm (Q, J=7.0Hz, 2H). 13C NMR (CDCl3) ∂ 169.2, 143.5,

136.0,129.8, 127.0, 68.0, 43.3, 42.5, 38.6, 35.9, 31.9, 29.8, 29.1, 28.2, 28.1 and 21.6 ppm.

IR (film) 3363, 3284, 2926, 2864, 1648, 1537, 1324, 1156, 1093, 815, 731 and 651 cm-1.

4.2.6 Synthesis of 11-(p-toluenesulfonyl)-1,8-dithia-4,11-diaza-cylotetradecan-3-one (81)

Finely ground potassium carbonate 8.31 g (60.12 mmol) was placed overnight in

a vacuum oven at 70˚C to completely dry. This was put in a flame dried 3 L three neck reaction flask equipped with a mechanical stirrer together with 682 mL of distilled N’N-

Dimethylformamide (DMF). While stirring, the mixture was heated with a heating

mantle to 95-100˚C, the temperature monitored by an internal thermometer. N-{N’-(3-

propylthio)ethyl]-4-methylbenzenesulfonamide}-[(3-chloropropyl)thio]acetamide (80)

13.20 g (30.06 mmol) dissolved in 300 mL of DMF was added dropwise using a pressure equalizing addition funnel, at a rate of approximately one drop every 9 seconds determined by an adjustable stopper and a stop watch. After the addition was complete,

the reaction mixture was strirred for an additional 24 h. The reaction was then cooled to

room temperature, filtered and the solvent was removed by rotary evaporator using a movable pump as the vacuum source, leaving behind a brown paste. The paste was

redissolved in 800 mL of chloroform then washed with 6 M HCl (4 x100 mL), followed

59 by deionized water ( 4 x 100 mL), and brine (1 x 100 mL). The organic layer was dried

with Na2SO4, filtered, and rotavaped to afford a crude solid 81. The crude solid was recrystallized from 95% ethanol to give pure solid 81 (6.80g, 16.90 mmols, 56.20%) mp

˚ 1 190-192 C, Rf 0.24 (75% ethyl acetate in hexanes). H NMR (CDCl3) ∂ 7.77 (d,

J=8.0Hz, 2H), 7.32 (d, 8.0Hz, 2H), 7.02 (s, brr, 1H), 3.42 (q, J=4.80Hz, 2H), 3.23 (s,

2H), 3.13 (q, J=7.76Hz, 4H), 2.78 (dd, J= 2.2, 7.0Hz, 2H), 2.64 (t, J=7.4Hz, 2H), 2.56 (t,

13 J=7.8Hz, 2H), 2.44 (s, 3H) and 1.91 ppm (m, brr, 4H). C NMR (CDCl3) ∂ 169.5,

143.9, 135.3, 130.1, 127.5, 49.5, 49.4, 38.9, 37.8, 32.1, 31.9, 30.5, 29.9, 29.6 and 21.7 ppm IR (film) 3298, 2954, 2921, 1647, 1527, 1338, 1154 and 636 cm-1.

4.2.7 Synthesis of 4-(p-toluenesulfonyl)-1,8-dithia-4,11-diaza-cyclotetradecane (82)

In a flame dried 2-neck reaction flask equipped with a stir bar and a condenser, was placed 11-(p-toluenesulfonyl)-1,8-dithia-4,11-diaza-cylotetradecan-3-one (81) 5.20 g (12.90 mmol). The system was put under a nitrogen atmosphere. Then 75 mL of distilled toluene was introduced into the flask via syringe through the septum on the other neck. After the amide dissolved, 10M Borane dimethyl sulfide (BMS) (26.00 mmols, 2.60 mL) was carefully added (gas evolved). After addition, it was stirred at room temperature for 10 minutes. The reaction mixture was then refluxed in an oil bath

for 3 d. The reaction was monitored by TLC. After completion, the reaction was allowed

to cool to room temperature. Then 10 mL of methanol was added. The mixture was stirred for 5 minutes and then rotavaped. This was followed by a second 10 mL MeOH

addition and removal of the solvent. The crude product was purified by flash chromatography using 100% ethyl acetate which gave 82 as a pure product ( 4.58 g,

60 ˚ 1 11.79 mmols, 88%, mp 103 C). Rf 0.2 (70% ethyl acetate in methanol). H NMR (CDCl3)

∂ 7.66 (d, J=8.0Hz, 2H), 7.28 (d, J=8.0Hz, 2H), 3.24 (m, 4H), 2.75 (m, 8H), 2.59 (m,

13 4H), 2.41 (s, 3H), 1.96 (m, 2H) and 1.78 ppm (m, 2H). C NMR (CDCl3) ∂ 143.6,

136.1, 129.9, 127.3, 50.2, 48.9, 47.8, 47.7, 34.5, 32.0, 30.4, 30.1, 29.2 and 21.7 ppm. IR

(film) 3361, 2929, 2865, 2815, 1457, 1333, 1157, 941 and 783 cm-1 .

4.2.8(a) Synthesis of 1,8-dithia-4,11-diazacyclotetradecane (40)

In a two neck 250 mL flame dried round bottomed flask with a stirring bar under

a nitrogen atmosphere, 4-(p-toluenesulfonyl)-1,8-dithia-4,11-diaza-cyclotetradecane (82)

3.71 g (9.55 mmol) was introduced. Distilled toluene (53.00 mL) was added through the

septum via a syringe and stirring was implemented until 82 dissolved completely. Then

sodium-bis-(2-methoxyethoxy)-aluminium hydride (SHAM or ‘Red-Al’) 14.90 g

(73.70 mmol, 14.40 mL) was carefully introduced to the reaction through the septum by

means of a syringe at room temperature. The mixture was then heated to reflux in an oil

bath for 48 h. The system was cooled to room temperature and 5 mL of 30% w/v

potassium hydroxide (KOH) was carefully added. Then stirring continued for additional

12 h. The set up was cooled in ice bath and concentrated HCl was added slowly to bring

the pH to 2 then washed with (2 x20 mL) chloroform (CHCl3). The pH of the aqueous

layer was raised to 10 by addition of 6M NaOH, and then extracted with diethyl ether (5

x 50 mL). The combined ether layers were dried with Na2SO4, filtered, and concentrated

in vacuo. The crude product was recrystallized from ethyl acetate to furnish a pure

0 yellowish product 40 (0.90 g, 3.84 mmols, 40.21% mp 101-102 C, Rf 0.1 in ethyl

1 13 acetate). H NMR (CDCl3) ∂ 2.79 (m, 3H) and 1.90 ppm (s, brr, 1H). C NMR (CDCl3)

61 ∂ 46.8, 46.5, 32.3, 28.2 and 27.3 ppm. IR (neat) 3367, 2962,2926, 2871, 2820,1457,

1333, 1307,1157, 1089, 941 and 783 cm-1 .

4.2.8 (b) Synthesis of 4,11-dimethyl-1,8-dithia-4,11-diazacyclotetradecane (83)

To a 50 mL 2-neck round bottomed flask equipped with a stirring bar, 1,8-dithia-

4,11-diazacyclotetradecane (40) 0.054 g (0.23 mmol) dissolved in 25mL of methanol was added. Then 30 µL (0.69 mmol of 37% aqueous formaldehyde was added. The

˚ reaction mixture was cooled to 0 C and 0.023 g (0,037 mmol) of NaCNBH3 was added.

The system was stirred for 3 h at pH ~7.5 and then the pH was lowered to ~6.0 by adding

glacial acetic acid. Stirring was continued at room temperature for 12 h. The reaction

was poured into 200 mL of diethyl ether and washed with 1M KOH (2 x 20 mL),

followed by brine (1 x 20 mL), dried with K2CO3, filtered, and concentrated in vacuo to

˚ afford solid product 83 (0.053 g, 0.02 mmols, 91%, mp 84-85 C ) Rf. 0.25(15% MeOH in

1 Ethyl Acetate). H NMR (CDCl3) ∂ 2.68 (m, 6H), 2.52 (m, 4H), 2.24 (s, 3H) and 1.79

13 ppm (dt, J=6.3, 7.0 Hz, 3H). C NMR (CDCl3) ∂ 55.9, 55.4, 43.3, 29.5, 29.0 and 27.3

ppm.

4.2.9 Synthesis of γ-Oxo-4-[11-(p-toluenesulfonyl)-1,8-dithia-4,11-diaza- cyclotetradecanyl]butanoic acid (85)

In a flame dried two neck 500 mL round bottomed flask, 4-(p-toluenesulfonyl)-

1,8-dithia-4,11-diaza-cyclotetradecane (82) 3.14 g (8.09 mmol) was dissolved in 150 mL

of distilled toluene. Then succinic anhydride (84) 0.81 g (8.09 mmols) was added. The

system was heated at 86˚C in an oil bath while stirring under nitrogen for 72 h. A cloudy

suspension of the product was observed over the course of time. After the reaction was

62 completed, the system was cooled to room temperature and rotavaped to dryness. The

solid was further dried under high vacuum for two hours to give the product 85 as a white

˚ 1 powder (3.58 g, 7.32 mmols, 91%, mp 137 C). Rf 0.1 acetone. H NMR (CDCl3) ∂

7.68(d, J=8.3Hz, 2H), 7.33(d, J=8.3Hz, 2H), 3.53(m, br, 3H), 3.24 (m, br, 3H), 2.81 (dd,

J=7.8, 15.2Hz, 3H), 2.64 (m, brr, 6H), 2.44(s, 3H) 1.94 (m, 4H) and 1.63 ppm (s, 3H).

13 C NMR (CDCl3) ∂ 172.1, 143.9, 130.0, 127.4, 49.9, 49.4, 48.9, 47.6, 46.0, 45.5, 31.9,

31.5, 30.2, 29.8, 29.3, 29.1, 28.3, 28.3, 28.2, 27.5 and 21.7 ppm. IR (film) ~3200-2800

br, 2926, 1734, 1636, 1457, 1338, 1158, 1091, 914, 816, 733 and 647 cm-1.

4.2.10 Synthesis of 4,4’-(1,4-dioxo-1,4-butanediyl)bis[11’-p-toluenesulfonyl)-1’,8’- dithia-4’,11’-diazacyclotetradecane (86)

In a flame dried 250 mL two neck round bottomed flask equipped with a stir bar,

was placed(3.58 g, 7.33 mmols) of γ-Oxo-4-[11-(p-toluenesulfonyl)-1,8-dithia-4,11-

diaza-cyclotetradecanyl]butanoic acid (85) and 80 mL of distilled methylene chloride under a nitrogen atmosphere. To this solution, 4-(p-toluenesulfonyl)-1,8-dithia-4,11- diaza-cyclotetradecane(82) 2.85 g (7.33 mmol), DCC 2.11 g (10.23 mmol) and a catalytic amount of DMAP was added. The system stirred at room temperature for 3 d.

The reaction was monitored by TLC. When it was done, it was filtered, and the residue was washed with methylene chloride. The filtrate was concentrated in vacuo. The crude product was recrystallized from 95% ethanol to afford the amide 86 (3.03 g, 3.53 mmols,

˚ 1 48.19% mp 158-160 C). Rf 0.45 (50% ethyl acetate in acetone. H NMR (CDCl3) ∂ 7.69

(d,J= 8.1Hz, 2H), 7.33(d, J=8.1Hz, 2H), 3.53 (m, 4H), 3.24 (m, 4H), 2.79 (dd, J=7.8,

13 15.5Hz, 3H), 2.66 (m, 6H), 2.44 (s, 3H) and 2.00 ppm (m, br, 4H). C NMR (CDCl3) ∂

172.0, 143.8, 130.0, 127.34,103.6, 71.7, 69.8, 49.3, 48.9, 45.4, 31.72, 29.51, 29.3, 29.1,

63 27.6,21.7 and 12.8 ppm. IR (film) 2934, 2856, 2803, 1598, 1454, 1340, 1158, 1092,

815, 733 and 659 cm-1.

4.2.11 Synthesis of 4,4’-(1,4-butanediyl)bis(11-p-toluenesulfonyl)-1,8-dithia-4,11- diazacyclotetradecane (87)

In a 250 mL two neck flame dried round bottomed flask, 4,4’-(1,4-dioxo-1,4- butanediyl)bis[11’-p-toluenesulfonyl)-1’,8’-dithia-4’,11’-diazacyclotetradecane (86) 0.50 g (0.58 mmol) was dissolved in 60 mL of distilled toluene. Then 4 equivalents of 10M

BMS 0.19 g (2.40 mmol, 0.24 mL) was introduced through the septum slowly with a syringe. After the addition of the BMS, stirring was continued at room temperature for ten minutes and then the temperature was raised to 110˚C and stirring continued under

nitrogen for 72 h. The system was then cooled to room temperature. The contents were

transferred to a single neck 250 mL round bottomed flask and 10 mL of methanol was

added, followed by rotary evaporation. After drying, an additional 10 mL of methanol

was added and then rotary evaporated to dryness. The residue was cleaned further by

flash column chromatography using pure ethyl acetate and a pure product 87 was

˚ afforded as a solid (0.36 g, 0.43 mmols, 75%, mp 129-130 C) Rf 0.1 (3% MeOH in ethyl

1 acetate). H NMR (CDCl3) ∂ 7.70 (d, J=8.1Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 3.27 (m, br,

2H), 2.75 (m, br, 2H), 2.60 (m, brr, 2H), 2.48 (t, J=6.1Hz, 2H), 2.44 (s, 3H), 2.37 (s, br,

1H), 1.91 (Q, J=7.2Hz, 2H), 1.71 (Q, J=7.2Hz, 2H) and 1.38 ppm (s, br, 1H) 13C NMR

(CDCl3) ∂ 143.6, 136.3, 129.9, 127.3, 55.0, 53.5, 52.5, 49.4, 48.1, 30.8, 29.6, 29.5, 28.8,

28.30, 25.01 and 21.7 ppm. IR (film) 2939, 2860, 2802, 1456, 1340, 1157, 1091, 913,

815, 731 and 646 cm-1.

64 4.2.12 Synthesis of 4,4’-(1,4-butanediyl)bis-1,8-dithia-4,11-diaza-cyclotetradecane (88)

In a three neck 50 mL flame dried round bottomed flask equipped with a stir bar,

was added phenol (1.42 g, 15.04 mmols), 4,4’-(1,4-butanediyl)bis(11-p-toluenesulfonyl)-

1,8-dithia-4,11-diazacyclotetradecane (87) 1.00 g (1.20 mmol), and 18 mL of 33% HBr in acetic acid. The system was heated to 80˚C by a heating mantle with the temperature

monitored internally with a thermometer and the condenser was protected from moisture

by attaching a drying tube filled with calcium chloride (CaCl2). The color changed from

the original whitish to brownish and later to dark brown almost black. After 48 h of

heating, an additional 6 mL of 33% HBr in acetic acid was added and heating continued

for a further 24 h. The system was then cooled to room temperature and the contents

were transferred to 250 single neck round bottomed flask followed by 80 mL of toluene,

and then rotary evaporated to dryness. The black residue was dissolved in 20 mL of

deionized water and washed with methylene chloride until the the organic layer was colorless. The combined organic layers were washed with 20 mL of deionized water.

The aqueous layers were combined and the pH adjusted to 12-14 using 6M NaOH. The

aqueous layer was extracted with chloroform (5 x 20 mL). The combined organic layers

were then dried with Na2SO4, filtered and rotavaped. The product was recrystallized

from absolute ethanol to afford a pure white solid 88 ( 0.58 g, 1.11 mmols, 92%, mp 105-

˚ 1 106 C). Rf 0.7 in ethyl acetate. H NMR (CDCl3) ∂ 2.73 (m, brr,10H, 1.80 (tt, J=6.3Hz,

13 2H) and 1.43 ppm (s, 1H). C NMR (CDCl3) ∂ 58.9, 54.5, 53.7, 52.1, 47.1, 46.9, 33.0,

31.4, 29.5, 29.4, 28.5, 27.6 and 24.9 ppm.

65 4.2.13 Synthesis of tricyclic amide 89

Into a flame dried 100 mL round bottomed flask with a stir bar, was added 4,4’-

(1,4-butanediyl)bis-1,8-dithia-4,11-diaza-cyclotetradecane (88) 0.200 g (0.38 mmol), succinic anhydride (84) 0.038 g (0.38 mmol), DCC 0.079 g (0.38 mmol), a catalytic amount of DMAP, and 38 mL of methylene chloride. The system was stirred under a nitrogen atmosphere for 3 d. The contents were vacuum filtered and the residue washed with cold methylene chloride. The filtrate was concentrated in vacuo and the resulting solid was recrystallized from 95% ethanol to give a pure 89 product as a yellowish solid

˚ 1 (0.21 g, 0.32 mmols, 91% mp 156-158 C). Rf 0.2 in 50% MeOH:Hexanes. H NMR

(CDCl3) ∂ 2.76 (m, br, 12H), 2.52 (t, J=6.4Hz, 2H), 2.41 (s, br, 2H), 1.80 (m, br, 4H) and

13 1.42 ppm (s, br, 2H). C NMR (CDCl3) ∂ 178.2, 157.0, 54.2, 53.4, 51.7, 46.6, 34.1, 31.6,

29.8, 29.4, 25.8, 25.1 and 24.7 ppm. IR 2929, 2848, 2799, 1637, 1425, 1371, 1270,

1164, 919 730 and 640 cm-1.

4.2.14 Synthesis of Tricyclic amine 90

Into a 25 mL flame dried three neck round bottomed flask with a stir bar, tricyclic

amide 89, 0.200 g (0.331 mmol) was dissolved in 10 mL of distilled toluene. A condenser was attached and the temperature internally monitored, was raised to 80˚C using a heating mantle. The system was placed under a nitrogen atmosphere. Borane dimethyl sulfide BMS (0.11 g, 1.45 mmol, 0.15 mL) was injected slowly into the hot solution through a septum. A gas evolved and white suspension was observed. The temperature was raised to approximately 105˚C and the heating continued for 3 d. Then

triethanolamine 0.26 g (1.74 mmol) in 5 mL distilled toluene was added slowly and

66 heating continued for additional 3 d. The system was allowed to cool to room

temperature the contents were transferred to a 100 mL single neck round bottomed flask

along with 25 mL of toluene. Then the solvent and excess borane dimethy sulfide was

removed by rotary evaporation to dryness. The crusty solid obtained was dried under

high vacuum. The product was recrystallized from 95% ethanol to give a pure solid

˚ 1 product 90 (0.037 g, 0.064 mmols 39%, mp 117-120 C). Rf 0.1 in Ethyl acetate. H NMR

(CDCl3) ∂ 2.62 (s, 10H), 2.53 (s, br, 2H), 1.76 (d, br, J=6.3Hz, 3H), 1.42 (s, br, 2H) and

13 1.25 ppm (s, 1H) C NMR (CDCl3) ∂ 55.1, 53.1, 52.4, 29.9, 29.5, 29.2, 27.5, 25.2 and

14.2 ppm. IR (film) 2927, 2848, 2799, 1461, 1104, 911 and 731 cm-1. MS (ESI) Calcd

+ for C28H56N4S4 ([M +H] ) 577.04 observed 577.4.

4.2.15 Synthesis of Serine methyl ester hydrochloride (92)

A 250 mL 3-neck round bottomed flask with a magnetic stir bar, was equipped with a dropping funnel, and a reflux condenser attached with a drying tube filled with calcium chloride. The dropping funnel was charged with 23 mL of acetyl chloride. The flask was filled with 150 mL methanol and chilled in ice bath. Acetyl chloride was added

to the stirred methanol approximately over 10 min period.a Stirring was continued for a

further 5 min. Then solid DL-Serine 91 12.00 g (114 mmol) was added in one portion

and the solution was heated at 64˚C for 2 h. The system was then cooled to room

temperature and the solvent was removed through rotary evaporation to afford the white

crystalline solid product 92 (17.26 g, 111 mmols, 97%, mp 138-139˚C) which was used

1 without further purification. H NMR (CDCl3) ∂ 4.27 (dd-apparent t, J=4.2, 3.4 Hz, 1H),

67 4.09 (dd, J=4.2,12.5Hz, 1H), 3.98 (dd, J=3.4, 12.5Hz, 1H) and 3.84 ppm (s, 3H). 13C

NMR (CDCl3) ∂ 169.0, 59.3, 54.8 and 53.8 ppm.

4.2.16 Synthesis of 3-Acetylthiapropionic acid (95)

In a flame dried 100 mL 2-neck round bottomed flask with a magnetic stir bar,

potassium thioacetate (93) 2.55 g (22.37 mmol) was mixed with 3-bromopropionic acid

(94) 3.11 g (20.33 mmol), a catalytic amount of thioacetic acid 0.066 g (0 .87 mmol,

0.062 mL) and 25 mL of absolute ethanol. The system was stirred under a nitrogen

atmosphere for 6 h at room temperature. Then it was filtered and the residue was washed

with methylene chloride. The filtrate was rotary evaporated and a sticky semi-solid

product 95 was obtained (5.92 g, 40.0 mmols, 99%). Rf 0.55 in 75% ethyl acetate in

1 hexanes. H NMR (CDCl3) ∂ 9.50 (s, 1H), 3.12 (t, J= 6.8Hz, 2H), 2.65 (t, J=6.8Hz, 2H)

13 and 2.34ppm (s, 3H). C NMR (CDCl3) ∂ 196.2, 35.0, 30.7 and 24.4 ppm.

4.2.17 Synthesis of N-[3-(acetylthio)-1-oxo-propyl]-serine methyl ester (96)

In a flame dried 1.5 L two-neck round bottomed flask with a magnetic stirrer,

Serine methyl ester hydrochloride (92) 11.08 g (71.27 mmol) was mixed with sodium bicarbonate 6.59 g (78.40 mmol), DCC 16.17 g (78.40 mmol), 3-Acetylthiapropionic acid

(95) 10.55 g (71.27 mmol) and 720 mL distilled methylene chloride. The system was

stirred at room temperature under nitrogen conditions for 3 d. By TLC, the

disappearance of the starting materials was confirmed. The reaction mixture was vacuum

filtered, and the residue rinsed with cold methylene chloride. The filtrate was dried with

Na2SO4, filtered and rotavaped to afford a crude product 96 as a yellowish, muddy solid.

The crude product was redissolved in distilled methylene chloride and chilled in freezer

68 for a day where some impurities precipitated out. Then it was filtered again rinsing the

residue with cold methylene chloride, dried the filtrate with Na2SO4 and concentrated in

vacuo to afford the pure product 96 as a viscous oily liquid (14.91 g, 59.81 mmols, 84%).

1 Rf 0.35 in 40% ethyl acetate in hexanes. H NMR (CDCl3) ∂ 7.00 (s, br, 1H), 4.61 (s, m,

1H), 3.90 (dd, J=4.8, 11.4Hz, 2H), 3.74 (s, 3H), 3.11 (t, J=7.0Hz, 2H), 2.51 (t, J=7.0Hz,

13 2H) and 2.30 ppm (s, 3H). C NMR (CDCl3) ∂ 196.4, 171.4, 171.1, 62.9, 54.8, 52.8,

36.0, 30.7 and 24.0 ppm. IR (film) 3363, 2929, 2853, 1725, 1684, 1653, 1540, 1456,

1273, 1115, 714 and 631 cm-1.

4.2.18 Synthesis of N-[3-(Acetylthio)-1-oxo-propyl]-o-benzoyl serine methyl ester (98)

In a 1 L flame dried 2-neck round bottomed flask with a magnetic stirrer, N-[3-

(acetylthio)-1-oxo-propyl]-serine methyl ester (96) 12.20 g (48.94 mmol) was mixed with benzoyl chloride (97) 8.27 g (58.80 mmol, 6.83 mL), triethylamine (TEA) 6.94 g

(68.60 mmol, 9.56 mL), a catalytic amount DMAP and 500 mL of distilled methylene chloride. The reaction was allowed to stir at room temperature for 3 d and monitored by

TLC for the disappearance of the starting material 96. The mixture was then washed with deionized water (2x 50 mL), 1M HCl (2x 50 mL) and with brine (1x 50 mL). The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The crude

product was chromatographed using 50% ethyl acetate in hexanes to give a pure product

˚ 98 as white crystals (12.46 g, 35.25 mmols, 72%, mp 101-102 C). Rf 0.22 in 50% ethyl

1 acetate in hexanes. H NMR (CDCl3) ∂ 8.00 (dd, J=1.5, 7.0Hz, 2H), 7.60 (tt, J=2.2,

7.4Hz, 1H), 7.46 (td, J=1.5, 7.6Hz, 2H), 6.42 (s, br, 1H), 5.00 (tt, J=3.3, 7.6Hz, 1H), 4.65

(d, J=3.0Hz, 1H), 3.81 (s, 3H), 3.15 (td, J=1.5, 7.0Hz, 2H), 2.59 (dt, J=2.6, 7.0Hz, 2H)

69 13 and 2.28ppm (s, 3H). C NMR (CDCl3) ∂ 196.2, 170.8, 170.1, 166.2, 133.6, 129.9,

129.4, 128.7, 64.6, 53.1, 52.0, 36.1, 34.0, 30.7 and 24.8ppm. IR (film) 3357, 3318,

3063, 2934, 2855, 1747, 1726, 1689, 1602, 1538, 1452, 1273, 1114, 714 and 623 cm-1.

4.2.19 Synthesis of Hexahydro-5-oxo-1,4-thiazepine-3-carboxylic acid methyl ester (100)

In a flame dried 2-neck 100 mL round bottomed flask with a magnetic stir bar, N-

[3-(Acetylthio)-1-oxo-propyl]-o-benzoyl serine methyl ester (98) 0.51 g (1.44 mmol) was dissolved in 30 mL of freshly distilled and de-aerated methanol. Then 1M sodium methoxide freshly made from dry de-aerated methanol and sodium metal 0.16 g (2.89 mmol, 2.90 mL) was slowly introduced through a septum by using a clean dry syringe and the system was stirred under a nitrogen atmosphere for 45 min. Then glacial acetic acid 0.17 g (2.89 mmol, 17 mL) was injected to quench the reaction. The system was rotary evaporated to dryness and the residue was dissolved in 200 mL chloroform and washed with de-ionized water (3x 20 mL), dried over Na2SO4, filtered and concentrated

in vacuo. The product was dried over high vacuum pump for 2 h to give a crude solid

multiple products. After chromatograph in 75% ethyl acetate in hexanes, followed by

pure ethyl acetate, only the white crystalline product Hexahydro-5-oxo-1,4-thiazepine-3-

carboxylic acid methyl ester (100) was isolated (0.10 g, 0.57 mmols, 40%, mp 140-

˚ 1 141 C). Rf 0.35 in 5% methanol in ethyl acetate. H NMR (CDCl3) ∂ 6.52 (s, br, 1H),

13 4.51 (dd, J=5.7, 7.6Hz, 1H), 3.84 (s, 3H) and 2.91ppm (m, 6H). C NMR (CDCl3) ∂

174.9, 170.2, 59.0, 41.4, 35.1, 34.1 and 24.9 ppm. IR (film) 3251, 2954, 1745, 1650,

1437, 1408, 1283, 1221, 1181, 1013, 982, 916, 850 and 752 cm-1.

70 4.2.20 Synthesis of N,N-Bis-[2-(p-tolylsulfonyloxy)ethyl]-p-toluenesulfonamide (102)

In a three neck 1 L flame dried round bottomed flask equipped with a mechanical

stirrer, diethanolamine (101) 23.3 g (222 mmol) was dissolved in 450 mL of

triethylamine (TEA). The temperature of the solution was lowered to 0˚C by using an ice

bath and p-toluenesulfonyl chloride 127 g (666 mmol) was introduced in small amounts

over a period of 20 min. The ice bath was then removed and the solution was stirred for

1 h when a brown solid developed that hindered any further stirring. The thick brown

suspension was then filtered and washed with a lot of water to give a crude brown

product which was recrystallized from ethanol/toluene (5:1) to give a white solid product

˚ 1 102 (110.71 g, 0.195 mols, 88%, mp 93-94 C). Rf 0.6 in 50% ethyl acetate in hexanes. H

NMR (CDCl3) ∂ 7.78 (d, J=8.3Hz, 2H), 7.63 (d, J=8.3Hz, 1H), 7.37 (d, J=7.9Hz, 2H),

7.31 (d, J=7.9Hz, 1H), 4.12 (t, J=6.0Hz, 4H), 3.39 (t, J=6.0Hz, 4H), 2.47 (s, 3H) and 2.44

13 ppm (s, 3H). C NMR (CDCl3) ∂ 145.5, 132.6, 130.3, 130.2, 128.2, 127.5, 68.5, 48.7,

21.9 and 21.8 ppm. IR (film) 3051, 2954, 2918, 1358, 1190, 1176, 1095, 978, 942,

901,816, 766, 721 and 662 cm-1.

4.2.21 Synthesis of N-(p-toluenesulfonyl)bis(2-bromoethyl)amine (103)

N,N-Bis-[2-(p-tolylsulfonyloxy)ethyl]-p-toluenesulfonamide (102) 72 g (0.127

mol) was put in a flame dried 1 L 3-neck round bottomed flask together with LiBr 24.93

g (0.287 mol) and 600 mL of distilled acetone. The system was heated at 56˚C while mechanically stirring under a nitrogen atmosphere for 24 h. The temperature was internally monitored by a thermometer. A silvery, shinning precipitate was observed.

The system was allowed to cool to room temperature and then filtered through glass

71 wool, and the residue washed with acetone. The filtrate was concentrated in vacuo giving

a brown solid which was dissolved in methylene chloride and insoluble particles were

filtered out and the filtrate was concentrated in vacuo to dryness affording a brown solid

˚ product 103 (46.89 g, 0.122 mols, 96%, mp 68-69 C). Rf 0.5 in 20% ethyl acetate in

1 hexanes. H NMR (CDCl3) ∂ 7.73 (d, J= 8.3Hz, 2H), 7.36 (d, J= 8.3Hz, 2H), 3.52 (s, 8H)

13 and 2.46 ppm (s, 3H). C NMR (CDCl3) ∂ 144.3, 135.7, 130.1, 127.3, 51.5, 29.7 and

21.7 ppm. IR (film) 3059, 2954, 2918, 1358, 1190, 1176, 1095, 978, 942, 901, 816, 766,

721 and 662 cm-1.

4.2.22 Synthesis of N-(p-toluenesulfonyl)bis(2-mercaptoethyl)amine (105)

In a 250 mL 2-neck round bottomed flask with a magnetic stirrer, N-(p-

toluenesulfonyl)bis(2-bromoethyl)amine (103) 6.09 g (0.016 mol), thiourea 2.66 g

(0.035 mol) and 50 mL of de-aerated absolute ethanol were mixed under a nitrogen

atmosphere. The system was refluxed at 80˚C while stirring for overnight. The system

was then cooled to room temperature, chilled in ice bath for 10 min, vacuum filtered, and

the solid washed with cold anhydrous diethyl ether. The solid was left to air dry yielding

a white crystalline thiouronium salt 104 (7.91 g, 0.015 mols, 92%, mp 181-182˚C). 1H

NMR (D2O) ∂ 7.74 (d, J=8.7Hz, 2H), 7.45 (d, J=8.7Hz, 2H), 3.53 (t, J=6.5Hz, 4H), 3.33

13 (t, J=6.5Hz, 4H) and 2.40ppm (s, 3H). C NMR (D2O) ∂ IR (film) 3032, 2970, 2913,

1341, 1158, 1116, 1090, 941, 815, 727, 666 and 643 cm-1.

72 4.2.23 Convertion of the thiouronium salt 104 into N-(p-toluenesulfonyl)bis(2- mercaptoethyl)amine (105)

In a 2 L 2-neck round bottomed flask with a stir bar, KOH (30.00 g, 0.535 mols)

was dissolved in 540 mL of distilled water and was de-aerated by bubbling nitrogen

through the solution for 1 h. Then thiouronium salt 104 40 g (0.074 mol) was added in

small portions while stirring for 30 min. The temperature was raised to 100˚C by using a heating mantle for 45 min under nitrogen atmosphere. The system was allowed to cool to

room temperature, then it was filtered through a glass wool to remove the silky byproduct

(N-(p-toluenesulfonyl)thiomopholine). The filtrate was further diluted by addition 550

mL of distilled de-aerated water and the temperature lowered to 0˚C by an ice bath. Then

while in ice bath the pH was lowered to 0-1 by dropwise addition of de-aerated

concentrated HCl. (The HCl was de-aerated by bubbling nitrogen through for 10 min in the hood). When pH was distinctly acidic, extraction with methylene chloride (5 x 100

mL) followed. The organic layers were combined and washed with 200 mL de-aerated

distilled water. The CH2Cl2 layer was dried with Na2SO4, filtered and concentrated in

vacuo to give the required product 105 as pinkish oily liquid (18.44g, 0.063 mols, 85%).

1 Rf 0.3 in 30% ethyl acetate in hexanes. H NMR (CDCl3) ∂ 7.65 (d, J= 8.2 Hz, 2H), 7.28

(d, J=8.2Hz, 2H), 3.24 (t, 7.0Hz, 4H), 2.65 (q, J=7.0Hz, 3H), 2.39 (s, 3H) and 1.41ppm

13 (t, J=8.5Hz, 1H). CNMR (CDCl3) ∂ 143.8, 136.0, 129.9, 127.1, 52.7, 24.0 and 21.5

ppm. IR (film) 2938, 2857and 1156 cm-1

4.2.24 Synthesis of 1-[p-toluenesulfonyl]-1-aza-4,7-dithiacyclononane (106)

A 3 L 3-neck round bottomed flask was equipped with pressure equalizer

addition funnel, a reflux condenser and mechanical stirrer then flame dried under a steady

73 stream of nitrogen. Cesium carbonate pre-dried overnight in a vacuum oven at 70˚C (26 g, 0.08 mols) was added to the flask followed by 1700 mL of dry DMF. An addition funnel was charged with 770 mL of the dry DMF containing 22.18 g of N-(p- toluenesulfonyl)bis(2-mercaptoethyl)amine (105) (0.077 mol) and 1,2-dibromoethane

14.40 g (0.077 mol, 7.30 mL). The contents of both the flask and the addition funnel were de-aerated by bubbling nitrogen through for 30 min. The temperature monitored by an internal thermometer was raised to 55-60˚C using a heating mantle, then the addition

was done drop-wise over a period of 3 d, at an approximate rate of one drop every 15 sec, while vigorously stirring. The system continued to stir at 55˚C for an additional 24 h, and

then cooled to room temperature. The solvent was removed by rotary evaporation aided with a movable vacuum pump. The residue was dissolved in 700 mL methylene chloride and washed with de-ionized water (2 x 200 mL), dried over Na2SO4 and concentrated in

vacuo to give a yellowish solid that was recrystallized from 95% ethanol to give white

˚ solid product 106 (18.58 g, 0.059 mols, 76%, mp 128-130 C). Rf 0.15 in methylene

1 chloride (DCM). H NMR (CDCl3) ∂ 7.70 (d, J=8.3Hz, 2H), 7.34 (d, J= 8.3Hz, 2H), 3.41

(t, J=4.8Hz, 4H), 3.17 (s, 4H), 3.15 (d, J=4.8Hz, 2H) and 2.45 ppm (s, 3H). 13C NMR

(CDCl3) ∂ 144.0, 130.0, 127.7, 53.7, 34.4, 32.6 and 21.8 ppm.

4.2.25 Synthesis of 1-Aza-4,7-dithiacyclononane (107)

In 100 mL 3-neck dry round bottomed flask with a condenser and a stir bar,

phenol 1.20 g (0.013 mol) was mixed with 30 mL solution of 33% hydrobromic acid in acetic acid and 1-[p-toluenesulfonyl]-1-aza-4,7-dithiacyclononane (106) 0.647 g (0.002

mol). By using a heating mantle, the system was refluxed at 80˚C for 2 d, protected from

74 moisture by attaching a drying tube filled with CaCl2. Then an additional 10 mL of 33% hydrobromic acid in acetic acid was slowly added to the hot reaction and reflux continued for another 24 h. The reaction was allowed to cool to room temperature, and the contents were transferred to a 250 mL one neck round bottomed flask. Then, 50 mL of toluene was added and the solution concentrated in vacuo. The resulting dark brownish residue was dissolved in 50 mL of de-ionized water and washed with methylene chloride until the organic layer was colorless. The organic layers were combined and washed once more with 50 mL of de-ionized water. The aqueous layers were combined and its pH was raised to 12-14 by adding 6M NaOH. The aqueous layer was then extracted with chloroform (5 x 50 mL), and the combined organic layers were dried with Na2SO4,

filtered and concentrated in vacuo to give the solid white product 107 (0.30 g, .0018

˚ 1 mols, 90%, mp 76-78 C). Rf 0.48 in 10% MeOH in methylene chloride. H NMR

13 (CDCl3) ∂ 3.01 (s, 4H), 3.00 (t, J=5.3Hz, 4H) and 2.80 ppm (t, J=5.3Hz, 4H). C NMR

(CDCl3) ∂ 48.0, 33.2 and 33.1 ppm. IR (film) 3346, 3252, 3171, 3084, 2670, 1646,

1443, 1332, 1213, 1153, 1088, 940, 861, 725 and 644 cm-1.

4.2.26 Synthesis of γ-oxo-1-(1-aza-4,7-dithiacyclononanyl)butanoic acid (108)

A 50 mL 3-neck round bottomed flask with a stir bar was flame dried, and then

attached a reflux condenser. 1-Aza-4,7-dithiacyclononane (107) (.298 g, 1.83 mmol) was

introduced together with succinic anhydride (84) (0.183 g, 1.83 mmol) and 20 mL of distilled toluene. The stirring system was put under a nitrogen atmosphere and heated at

80˚C for 3 d. Then the system was cooled and rotavaped to dryness. A clean white powder product 108 was obtained (0.47 g, 1.78 mmols, 98%, mp. 117-119˚C). Rf 0.25 in

75 1 5% MeOH in ethyl acetate. HNMR (CDCl3) ∂ 8.50 (s, brr, 1H), 2.40 (dd, J=4.4, 5.9Hz,

2H), 2.34 (m, 2H), 1.70 (m, 4H), 1.63 (dd, J=5.9, 7.0Hz, 2H), 1.49 (m, 2H) and 1.42

13 ppm (dd, J=5.1, 7.4Hz, 2H). CNMR (CDCl3) ∂ 177.6, 173.2, 70.5, 53.0, 52.0, 37.5,

31.3, 31.0, 30.9 and 29.2 ppm. IR (film) 2917, 1729, 1638, 1471, 1142, 1367, 1169,

949, 913, 833, 731 and 633 cm-1.

4.2.27 Synthesis of 1,1’-(1,4-dioxo-1,4-butanediyl)bis-1-aza-4,7-dithiacyclononane (109)

In a 250 mL flame dried 3-neck round bottomed flask with a stir bar, γ-oxo-1-(1- aza-4,7-dithiacyclononanyl)butanoic acid (108) 2.42 g (9.20 mmol) was dissolved in

120 mL of methylene chloride, along with DCC 2.67 g (10.11 mmol), a catalytic amount of DMAP and 1-Aza-4,7-dithiacyclononane (107). The system was put under a nitrogen atmosphere, and stirred at room temperature for 3 d. When the reaction completion was confirmed by TLC, it was vacuum filtered, and the residue was washed with methylene chloride. The filtrate was concentrated in vacuo. The resulting yellowish solid was recrystallized from 95% ethanol to afford the desired product 109 (3.10 g, 7.28

1 mmols, 79%, mp. 88-90˚C). Rf 0.2 in ethyl acetate. H NMR (CDCl3) ∂ 3.76 (m, 4H),

3.64 (m, 4H), 3.49 (m, 4H), 2.99 (m, 8H), 2.93 (s, 4H), 2.81 (m, 4H), 1.59 (s, 2H) and

13 1.25ppm (t, J=7.0Hz, 1H). C NMR (CDCl3) ∂ 173.5, 52.9, 52.1, 37.2, 35.1, 34.2, 32.0,

31.5, 31.2, 29.4, 25.6 and 24.9 ppm.

4.2.28 Synthesis of 1,1’-(1,4-butanediyl)bis-1-aza-4,7-dithiacyclononane 110

In a flame dried 100 mL 3-neck round bottomed flask with a reflux condenser,

and a magnetic stirrer, 1,1’-(1,4-dioxo-1,4-butanediyl)bis-1-aza-4,7-dithiacyclononane

76 (109) 2.49 g (5.85 mmol) was slowly dissolved in warm 30 mL of distilled toluene while stirring. When a uniform suspension was obtained, 10M borane dimethyl sulfide 1.78 g

(22.40 mmol, 2.34 mL), was slowly introduced through the septum. A gas evolved and the solution became cloudy. The system was heated at 110˚C under a nitrogen atmosphere

for 72 h. Then it was cooled to room temperature and 10 mL CH3OH was added. The

solution was stirred for 10 min then rotary evaporated to dryness. Another 10 mL of

methanol was added and again rotary evaporated to dryness. The resulting solid was

recrystallized from 95% ethanol to afford the product 110 as a white solid (2.01 g, 5.28

˚ 1 mmols, 90%, mp 55-56 C). Rf 0.6 in ethyl acetate. H NMR (CDCl3) ∂ 3.20 (s,2H), 2.90

(m, brr, 2H), 2.80 (m, brr, 2H), 2.53 (t, J=7.0Hz, 1H) and 1.50 ppm (m, br, 1H). 13C

NMR (CDCl3) ∂ 58.5, 58.0, 34.9, 33.3 and 26.1 ppm. IR (film) 2929, 2901, 2852,

2790,1299 and 1107 cm-1.

4.2.29 Synthesis of 1-[4-(1-aza-4,7-dithiacyclononan-1-yl)-1,4-dioxo-butyl]-4-(11-p- toluenesulfonyl)-1,8-dithia-4,11-diazacyclotetradecane (111)

In a flame dried, 25 mL 3-neck round bottomed flask with a stir bar, γ-Oxo-4-[11-

(p-toluenesulfonyl)-1,8-dithia-4,11-diaza-cyclotetradecanyl]butanoic acid (85) 0.424 g

(0.870 mmol) was dissolved in 10 mL Distilled methylene chloride. Then DCC, 0.270 g

(1.30 mmol), 1-Aza-4,7-dithiacyclononane (107) 0.142 g (0.870 mmol) and a catalytic amount of DMAP were added. The system was stirred at room temperature under a nitrogen atmosphere for 3 d. The system was filtered and the residue was washed with cold methylene chloride. The filtrate was concentrated in vacuo. The crude product was recrystallized from 95% ethanol to give the product 111 as a yellowish solid (0.48 g, 0.76

˚ 1 mmols, 87%, mp 129-130 C). Rf 0.2 in ethyl acetate. H NMR (CDCl3) ∂ 7.66 (d,

77 J=8.1Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 4.19 (s, br, 1H), 3.60 (m, 10H), 3.25 (s, 4H), 2.79

13 (m, 14H), 2.42 (s, 3H), 1.96 (m, 6H) and 1.31ppm (m, 3H). C NMR (CDCl3) ∂ 173.7,

171.5, 143.8, 135.7, 130.0, 127.3, 52.8, 52.1, 49.7, 48.9, 47.5, 37.2, 35.1, 34.1, 31.9, 31.2,

29.1, 28.4, 25.8, 25.1 and 21.7ppm. IR (film) 2928, 2117, 1636, 1456, 1419, 1339,

1228, 1158, 1091, 1041, 948, 914, 816 and 730 cm-1.

4.2.30 Synthesis of 1,4’-(1,4-butanediyl)-1-aza-4,7-dithiacyclononane-4’-(11’-p- toluenesulfonyl)-1’8’-dithia-4’,11’-diazacyclotetradecane (112)

In a 50 mL round bottomed flask with a stirrer, 1-[4-(1-aza-4,7-dithiacyclononan-

1-yl)-1,4-dioxo-butyl]-4-(11-p-toluenesulfonyl)-1,8-dithia-4,11-diazacyclotetradecane

(111) 0.40 g (0.63 mmol) was dissolved in 14 mL of distilled toluene. Borane dimethyl

sulfide 10M 0.21 g (2.77 mmol, 0.277 mL) was injected through the septum. The stirring

system was heated in an oil bath at 110˚C under a nitrogen atmosphere for 3 d. The

system was then cooled to room temperature, and the contents were transferred to a 100

mL single neck round bottomed flask. Then 10 mL MeOH was added, stirred for 10

minutes and rotary evaporated to dryness. A further 10 mL MeOH was added to the residue swirled for 15 minutes and again rotary evaporated to dryness. The product was dried by a high vacuum and a solid 112 was obtained (0.37 g, 0.61 mmols, 97%, mp

˚ 1 159-161 C). Rf 0.2 in ethyl acetate. HNMR (CDCl3) ∂ 7.70 (d, J=7.7Hz, 2H), 7.32 (d,

J=7.7Hz, 2H), 3.74 (d, J=6.7, 1H), 3.29 (d, br, J=8.1Hz, 2H), 3.17 (s, 3H), 2.89 (s, br,

2H), 2.77 (m, br, 2H), 2.62 (m, br, 3H), 2.44 (m, brr, 2H),1.92 (s, brr, 1H), 1.60 (s, br,

13 2H) and 1.25ppm (s, br, 3H). CNMR (CDCl3) ∂ 172.0, 143.8, 135.6, 130.0, 127.4,

52.9, 49.8, 48.9, 37.3, 31.5, 29.7, 28.4 and 21.7 ppm. IR (film) cm-1. MS (ESI) Calcd for

+ C27H47N3O2S5 605.2 observed[M+H] 606.3.

78 4.3 Complexing the Synthesized Ligands

After the ligands were successfully synthesized and satisfactorily charecterized

through the indicated analytical procedures, metallation process followed. The results were also confirmed by appropriate analytical instruments and the results are reported in the following reports.

4.3.1 The Formation of Copper Complex 114

The ligand 1,8-dithia-4,11-diazacyclotetradecane (40) 0.047 g (0.200 mmol) was dissolved in 2.00 mL of chloroform in a vial. Copper perchlorate salt 0.052 g (0.200 mmol) was dissolved in 2.00 mL of acetonitrile in a test tube. The copper perchlorate

solution was gently poured onto the surface of the ligand solution and the tube covered with a parafilm. The parafilm was punched with a thin needle to allow very slow evaporation of the solvents. Crystals formed slowly at the interface and after three weeks some crystals were analyzed by X-ray crystallography. The copper ligand [Cu(II)L] complex 114 was established. X-ray data is given in table 3. No other analysis was done on this complex.

4.3.2 Formation of the Nickel Complex 115

The ligand 1,8-dithia-4,11-diazacyclotetradecane (40) 0.047 g, (0.200 mmol) was dissolved in 2.00 mL of chloroform in a vial. In a test tube, nickel perchlorate 0.052 g (0.200 mmol) was dissolved in 2.00 mL of acetonitrile. The nickel solution was slowly poured into the vial, then covered with parafilm. The interaction between the two solutions occurred slowly. Changes begin to be seen at the interface. After three weeks, the parafilm was punctured by a thin pin to allow for gentle evaporation of the solvents.

79 Eventually, a precipitate appeared, it was left to grow mature crystals. After two months,

the crystals were analyzed by X-ray crystallography, and the nickel ligand [Ni(II)L]

complex 115 was determined and the data is given in Table 3. There was no other

investigations conducted.

4.3.3 Forming the Rhodium Complex 116

The ligand 40 (0.102 g, 0.435 mmols) was dissolved in 3.5 mL of 95% ethanol,

then Rhodium trichloride trihydrate (0.112 g, 0.425 mmols) dissolved in 3.0 mL of 95%

ethanol were mixed in a 2-neck 25 mL round bottomed flask with a stir magnet. A

yellowish brown precipitate was seen and then refluxed121 for 2 h at ~80˚C. After cooling

the reaction was filtered and the residue washed with absolute ethanol 3 x 5 mL and left

to air dry for one day. The product 116 was obtained as crystals (0.14 g, 82% mp 256˚C decompose).

4.3.4 The Ligand 3,6,9-trithiacyclodecan-1-ol 113 Was Complexed with Rhodium to Form Complex 117

In complexing the ligand 113 which was previously made in our lab by Cheng125 with Rhodium, the procedure which was described above for complexing ligand 40 with

Rhodium was adapted. In a flame dried 50 mL 2-neck round bottomed flask with stir bar under nitrogen conditions equipped with a reflux condenser, 3,6,9-trithiadecanol 113

(0.105 g. 0.500 mmols) was dissolved in 8.0 mL of 95% ethanol and warmed to enhance solubility. When all solid was dissolved, a solution of Rhodium trichoride trihydrate

(0.132 g, 0.500 mmols) in 15 mL of 95% ethanol was poured in. A yellow precipitate appeared and the mixture was refluxed for 6 h. The reaction was monitored by TLC for

80 the disappearance of the ligand. Then the system was cooled to room temperature,

vacuum filtered and the residue was washed with absolute ethanol and was left to dry.

The filtrate was concentrated in vacuo and allowed to crystallize. The combined weight

of the residue and from the fitrate yielded 0.25 g, 81% of the complex 117, mp 332˚C

decompose.

4.3.5 Complexing Ligand 110 with Rhodium to Form Complex 126

In a 2 neck round bottomed flask equipped with a stir bar, rhodium trichloride

trihydrate 0.14 g (0.53 mmol) was mixed with 12 mL of absolute ethanol. The system

was stirred and heated in an oil bath at 80˚C. Then ligand 110 0.2 g (0.53 mmol)

dissolved in 12 mL absolute ethanol was added and the solution refluxed for 2 h. The reaction was cooled to room temperature, filtered, and washed the residue with cold ethanol. The solid was left to air dry to afford (0.29 g, 0.49 mmols, 93%) of complex 126.

+ MS (ESI) calcd for C16H31N2S4Cl3Rh 588.2 observed [M+ H] 589.

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APPENDICES

APPENDIX A

1H AND 13C NMR SPECTRA OF THE SYNTHESIZED COMPOUNDS

Figure A.1. 1H and 13C NMR spectra of the cystamine. 73 91

Figure A.2. 1H and 13C NMR spectra of the amine 75.

Figure A.3 1H and 13C NMR spectrum of 6-Chloro-3-thia-hexanoic acid (78).

Figure A.4. 1H and 13C NMR spectra of the acid chloride 79.

Figure A.5. 1H and 13C NMR spectra uncyclized amide 80.

Figure A.6. 1H and 13C NMR spectra cyclized amide 81.

Figure A.7. 1H and 13C NMR spectra cyclized amine 82.

Figure A. 8. 1H and 13C NMR spectra of the secondary amine 40.

Figure A. 9. 1H and 13C NMR spectra tertiary amine 83.

Figure A.10. 1H and 13C NMR spectra of butyric acid 85.

100

Figure A.11. 1H and 13C NMR spectra of double ligand amide 86.

101

Figure A.12. 1H and 13C NMR spectra of double ligand amine 87.

102

Figure A.13. 1H and 13C NMR spectra of double ligand amine 88.

103

Figure A.14. 1H and 13C NMR spectra of tricyclic amide 89.

104

Figure A.15. 1H and 13C NMR spectra of tricyclic amine 90.

105

Figure A.16. 1H and 13C spectra of Serine Ester Hydrochloride 92.

106

Figure A.17. 1H and 13C NMR for thiaacid 95.

107

Figure A.18. 1H and 13C NMR for ester alcohol 96.

108

Figure A.19. 1H and 13C NMR for Benzoate serine ester 98.

109

Figure A.20. 1H and 13C NMR for 7-membered ring 100.

110

Figure A.21. 1H and 13C NMR of the tritosylated diethanolamine 102.

111

Figure A.22. 1H and 13C NMR of the tosylatediethylaminobromide 103.

112

Figure A.23. 1H and 13C NMR of the bis-mercaptoamine salt 104.

113

Figure A.24. 1H and 13C NMR of the thiols 105.

114

Figure A.25. 1H and 13C NMR of the tosylated amide 106.

115

Figure A.26. 1H and 13C NMR of the free amine 107.

116

Figure A.27. 1H and 13C NMR of the [9]butyric acid 108.

117

Figure A.28. 1H and 13C NMR of the [9]diamide 109.

118

Figure A.29. 1H and 13C NMR of the [9]diamine 110.

119

Figure A.30. 1H and 13C NMR of the[14] /[9]diamide 111.

120

Figure A.31. 1H and 13C NMR of the[14] /[9]diamine 112.

121

APPENDIX B

IR SPECTRA OF THE MOLECULES AND THE LIGANDS

73.

Figure B.1. IR spectrum for tosyl cystamine.

122

Figure B.2. IR spectrum of amine 75

Figure B.3. IR spectrum for the thio-acid 78.

123

Figure B.4. IR Spectrum of the acid chloride 79.

Figure B.5. IR Spectrum of the amide 80.

124

Figure B.6. IR Spectrum of the ligand amine 82.

Figure B.7. IR spectrum of the free amine 40.

125

Figure B.8. IR spectrum of the acid 85.

Figure B.9. IR spectrum of the ligand amide 86.

126

Figure B.10 IR spectrum of the amine 87.

127

Figure B.11. IR spectra of the tricycloamide 89 (upper)s and tricycloamine 90 (lower).

128

Figure B.12. IR spectrum of thioester alcohol 96.

Figure B.13. IR spectrum of Serine methyl ester benzoate 98.

129

Figure B.14. IR spectrum of [9]ane free amine 107.

130

Figure B.15. IR spectrum of [9]anebutyric acid 108.

131

Figure B.16. IR Spectrum of [14]/[9] amide 111.

132

APPENDIX C

MASS SPECTRA OF SELECTED PRODUCTS

Figure C.1. Mass Spectrum of ligand: 9,21,27,33-tetrathia-1,6,13,18- tetraazatricyclo[16.6.6.66,13]hexatriacontane 90.

133

Figure C.2. Mass Spectrum of ligand: 4’-(4’’-[1-Aza-4,7-dithiacyclononan-butyl]-11-p- toluenesulfonyl)-1’,8-dithia-4’,11-diazacyclotetradecane (112).

134

Figure C.3. The Mass Spectrum of Rhodium complexed with the ligand: N,N’-Bis-[1- Aza-4,7-dithia-cyclononanyl-butane (110).

135

APPENDIX D

X-RAY CRYSTAL STRUCTURES AND DATA ANALYSIS OF THE PRODUCTS

C10H22N2S2 Molecule

Figure D.1. Crystal structure and data of 1,8-dithia-4,11-diazacyclotetradecane 40.

Table 1

Crystal Data and Structure Refinement for C10H22N2S2

Identification code C10H22N2S2 Empirical formula C10 H22 N2 S2 Formula weight 234.42 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 5.3666(9) Å α= 115.552(2)°. b = 7.8306(13) Å β= 106.336(3)°. c = 8.5240(14) Å γ = 93.256(3)°.

136 Table 1

Crystal Data and Structure Refinement for C10H22N2S2 (continued)

Volume 303.49(9) Å3 Z 1 Density (calculated) 1.283 Mg/m3 Absorption coefficient 0.406 mm-1 F(000) 128 Crystal size 0.34 x 0.18 x 0.09 mm3 Theta range for data collection 2.82 to 28.31°. Index ranges -7 ≤ h ≤ 7, -10 ≤ k ≤ 10, -11 ≤ l ≤ 11 Reflections collected 2721 Independent reflections 1412 [R(int) = 0.0270] Completeness to theta = 26.30° 98.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9644 and 0.8743 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1412 / 0 / 68 Goodness-of-fit on F2 1.064 Final R indices [I>2sigma(I)] R1 = 0.0381, wR2 = 0.0943 R indices (all data) R1 = 0.0401, wR2 = 0.0964 Largest diff. peak and hole 0.412 and -0.347 e.Å-3

137 Table 2

Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (Å2x

103) for C10H22N2S2. U(eq) Is Defined as One Third of the Trace of the Orthogonalized Uij Tensor ______x y z U(eq) ______S(1) 11466(1) 3398(1) 2944(1) 17(1) N(1) 6914(3) 595(2) -2171(2) 17(1) C(1) 12271(3) 2333(2) 4488(2) 18(1) C(2) 7877(3) 2635(2) 1999(2) 18(1) C(3) 6714(3) 3375(2) 614(2) 19(1) C(4) 7707(3) 2689(2) -1021(2) 17(1) C(5) 8263(3) -132(2) -3527(2) 18(1) ______

138 Table 3

Bond Lengths [Å] and Angles [°] for C10H22N2S2 ______S(1)-C(1) 1.8117(16) S(1)-C(2) 1.8154(16) N(1)-C(4) 1.459(2) N(1)-C(5) 1.461(2) C(1)-C(5)#1 1.522(2) C(2)-C(3) 1.528(2) C(3)-C(4) 1.523(2)

C(1)-S(1)-C(2) 100.71(7) C(4)-N(1)-C(5) 112.48(12) C(5)#1-C(1)-S(1) 114.74(11) C(3)-C(2)-S(1) 110.37(11) C(4)-C(3)-C(2) 114.68(13) N(1)-C(4)-C(3) 111.76(13) N(1)-C(5)-C(1)#1 110.94(13) ______Symmetry transformations used to generate equivalent atoms: #1 -x+2,-y,-z

139 Table 4

Anisotropic Displacement Parameters (Å2x 103) for C10H22N2S2

The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______S(1) 15(1) 17(1) 19(1) 9(1) 5(1) 2(1) N(1) 19(1) 17(1) 17(1) 7(1) 8(1) 4(1) C(1) 20(1) 20(1) 13(1) 6(1) 5(1) 4(1) C(2) 15(1) 21(1) 17(1) 9(1) 7(1) 3(1) C(3) 18(1) 19(1) 19(1) 9(1) 7(1) 8(1) C(4) 18(1) 17(1) 17(1) 9(1) 6(1) 4(1) C(5) 18(1) 20(1) 17(1) 10(1) 8(1) 5(1) ______

140 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for C10H22N2S2 ______x y z U(eq) ______

H(1A) 14173 2829 5253 22 H(1B) 11233 2768 5332 22 H(2A) 7383 1205 1377 21 H(2B) 7134 3144 3013 21 H(3A) 4759 2956 137 22 H(3B) 7137 4806 1272 22 H(4A) 6989 3329 -1780 21 H(4B) 9667 3071 -558 21 H(5A) 10197 384 -2900 21 H(5B) 7637 324 -4459 21 H(3) 7320(40) 70(30) -1480(30) 24(5)

141 Asymmetric Unit Cation

Anions Figure D.2. Crystal Structure of with 1,8-dithia-4,11-diazacyclotetradecane 40 Copper complex 114

Table 1

Crystal Data and Structure Refinement for C10H22Cl2CuN2O8S2.

Identification code C10H22Cl2CuN2O8S2 Empirical formula C10 H22 Cl2 Cu N2 O8 S2 Formula weight 496.86 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 6.9206(9) Å α= 98.281(2)°. b = 8.1330(11) Å β= 111.395(2)°. c = 9.4154(13) Å γ = 110.396(2)°. Volume 439.60(10) Å3 Z 1 Density (calculated) 1.877 Mg/m3 Absorption coefficient 1.826 mm-1 F(000) 255 Crystal size 0.37 x 0.28 x 0.20 mm3 Theta range for data collection 2.44 to 28.30°. Index ranges -9 ≤ h ≤ 9, -10 ≤ k ≤ 10, -12 ≤ l ≤ 12 Reflections collected 3918 142 Table 1

Crystal Data and Structure Refinement for C10H22Cl2CuN2O8S2 (continued)

Independent reflections 2040 [R(int) = 0.0205] Completeness to theta = 26.30° 99.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7115 and 0.5514 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2040 / 0 / 119 Goodness-of-fit on F2 1.069 Final R indices [I>2sigma(I)] R1 = 0.0284, wR2 = 0.0753 R indices (all data) R1 = 0.0288, wR2 = 0.0756 Largest diff. peak and hole 0.792 and -0.484 e.Å-3

143 Table 2 Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (Å2x

103) for C10H22Cl2CuN2O8S2. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______Cu 5000 5000 5000 10(1) Cl(1) 6813(1) 1913(1) 7547(1) 14(1) S(1) 7509(1) 5071(1) 3938(1) 12(1) O(1) 6772(3) 3173(2) 6613(2) 24(1) O(2) 8709(3) 1474(2) 7739(2) 23(1) O(3) 4706(3) 251(3) 6711(2) 42(1) O(4) 7067(3) 2746(3) 9089(2) 35(1) N(1) 7484(3) 7387(2) 6711(2) 12(1) C(1) 9171(3) 7551(2) 4793(2) 16(1) C(2) 9653(3) 7992(3) 6542(2) 15(1) C(3) 8062(3) 7455(2) 8413(2) 14(1) C(5) 6124(3) 7279(3) 8871(2) 15(1) C(6) 4128(3) 5356(3) 8183(2) 15(1) ______

144 Table 3

Bond Lengths [Å] and Angles [°] for C10H22Cl2CuN2O8S2. ______Cu-N(1) 2.0178(15) Cu-N(1)#1 2.0178(15) Cu-S(1) 2.2877(5) Cu-S(1)#1 2.2877(5) Cl(1)-O(4) 1.4303(16) Cl(1)-O(2) 1.4329(14) Cl(1)-O(3) 1.4337(17) Cl(1)-O(1) 1.4435(14) S(1)-C(6)#1 1.8075(18) S(1)-C(1) 1.8113(19) N(1)-C(2) 1.484(2) N(1)-C(3) 1.491(2) C(1)-C(2) 1.516(3) C(3)-C(5) 1.521(3) C(5)-C(6) 1.524(3) C(6)-S(1)#1 1.8075(18) N(1)-Cu-N(1)#1 180.0 N(1)-Cu-S(1) 88.14(5) N(1)#1-Cu-S(1) 91.86(5) N(1)-Cu-S(1)#1 91.86(5) N(1)#1-Cu-S(1)#1 88.14(5) S(1)-Cu-S(1)#1 180.0 O(4)-Cl(1)-O(2) 109.54(10) O(4)-Cl(1)-O(3) 110.10(12) O(2)-Cl(1)-O(3) 108.99(11) O(4)-Cl(1)-O(1) 109.83(10) O(2)-Cl(1)-O(1) 109.28(9) O(3)-Cl(1)-O(1) 109.07(10) C(6)#1-S(1)-C(1) 105.68(9) C(6)#1-S(1)-Cu 104.87(6) C(1)-S(1)-Cu 93.55(6) C(2)-N(1)-C(3) 108.22(14) C(2)-N(1)-Cu 111.91(11) C(3)-N(1)-Cu 117.12(11) C(2)-C(1)-S(1) 105.76(12) N(1)-C(2)-C(1) 111.38(14) N(1)-C(3)-C(5) 114.63(15) C(3)-C(5)-C(6) 115.06(15) C(5)-C(6)-S(1)#1 108.22(12) ______Symmetry transformations used to generate equivalent atoms: #1 -x+1,-y+1,-z+1

145 Table 4

Anisotropic Displacement Parameters (Å2x 103) for C10H22Cl2CuN2O8S2. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______Cu 11(1) 10(1) 8(1) 2(1) 4(1) 4(1) Cl(1) 18(1) 16(1) 13(1) 6(1) 7(1) 10(1) S(1) 14(1) 13(1) 10(1) 4(1) 5(1) 7(1) O(1) 38(1) 21(1) 21(1) 14(1) 14(1) 20(1) O(2) 28(1) 29(1) 23(1) 13(1) 14(1) 22(1) O(3) 24(1) 35(1) 41(1) 16(1) 3(1) -4(1) O(4) 56(1) 55(1) 18(1) 15(1) 21(1) 45(1) N(1) 14(1) 11(1) 11(1) 3(1) 5(1) 6(1) C(1) 16(1) 13(1) 16(1) 4(1) 8(1) 4(1) C(2) 14(1) 14(1) 14(1) 2(1) 6(1) 4(1) C(3) 16(1) 13(1) 10(1) 2(1) 4(1) 6(1) C(5) 21(1) 14(1) 11(1) 2(1) 7(1) 8(1) C(6) 19(1) 17(1) 9(1) 5(1) 7(1) 9(1) ______

146 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for C10H22Cl2CuN2O8S2. ______x y z U(eq) ______

H(1A) 10630 7948 4697 19 H(1B) 8284 8186 4238 19 H(2A) 10566 7366 7081 18 H(2B) 10578 9338 7077 18 H(3A) 9418 8638 9120 17 H(3B) 8506 6447 8615 17 H(5A) 5512 8155 8508 18 H(5B) 6774 7651 10056 18 H(6A) 3132 5279 8729 18 H(6B) 4724 4421 8350 18 H' 6990(40) 8160(30) 6560(30) 19(6) ______

147 Cation

Asymmetric Unit

Figure D.3. Crystal Structure of with 1,8-dithia-4,11-diazacyclotetradecane 40 Rhodium complex 116.

Table 1

Crystal Data and Structure Refinement for C10H20Cl3N2ORhS2

Identification code C10H20Cl3N2ORhS2 Empirical formula C10 H20 Cl3 N2 O Rh S2 Formula weight 457.66 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Orthorhombic Space group Pna2(1) Unit cell dimensions a = 16.526(2) Å α= 90°. b = 10.2493(15) Å β= 90°. c = 9.9523(14) Å γ = 90°. Volume 1685.7(4) Å3 Z 4 Density (calculated) 1.803 Mg/m3 Absorption coefficient 1.729 mm-1 F(000) 920 Crystal size 0.11 x 0.11 x 0.10 mm3 Theta range for data collection 2.34 to 28.29°. Index ranges -21 ≤ h ≤ 21, -13 ≤ k ≤ 13, -13 ≤ l ≤ 13 Reflections collected 14372

148 Table 1

Crystal Data and Structure Refinement for C10H20Cl3N2ORhS2 (continued)

Independent reflections 4019 [R(int) = 0.0508] Completeness to theta = 28.29° 98.2 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.8461 and 0.8326 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4019 / 1 / 173 Goodness-of-fit on F2 1.082 Final R indices [I>2sigma(I)] R1 = 0.0339, wR2 = 0.0733 R indices (all data) R1 = 0.0360, wR2 = 0.0740 Absolute structure parameter 0.02(4) Largest diff. peak and hole 0.956 and -0.763 e.Å-3

Table 2 Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Aarameters (Å2x

103) for C10H20Cl3N2ORhS2. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______Rh 1191(1) 8012(1) 2191(1) 10(1) Cl(1) 1692(1) 8797(1) 4262(1) 16(1) Cl(2) -8(1) 7263(1) 3231(1) 17(1) Cl(3) 2064(1) 7989(1) 8214(1) 27(1) S(1) 531(1) 9970(1) 1810(1) 15(1) S(2) 1819(1) 6045(1) 2682(1) 16(1) O 514(2) 6861(3) 6519(4) 34(1) N(1) 708(2) 7417(3) 337(3) 14(1) N(2) 2295(2) 8578(3) 1328(4) 16(1) C(1) 214(3) 9687(4) 85(5) 19(1) C(2) 5(3) 8263(4) -51(5) 20(1) C(3) 462(3) 6021(4) 131(5) 19(1) C(4) 1145(3) 5068(4) 273(5) 23(1) C(5) 1366(3) 4740(4) 1717(5) 21(1) C(6) 2757(2) 6316(4) 1774(5) 20(1) C(7) 2957(2) 7748(4) 1879(4) 20(1) C(8) 2553(3) 9971(4) 1407(5) 21(1) C(9) 1997(3) 10930(4) 761(5) 21(1) C(10) 1252(3) 11278(4) 1575(5) 18(1) ______

149 Table 3

Bond Lengths [Å] and Angles [°] for C10H20Cl3N2ORhS2 ______Rh-N(2) 2.099(3) Rh-N(1) 2.101(3) Rh-S(1) 2.3145(10) Rh-S(2) 2.3200(10) Rh-Cl(1) 2.3626(11) Rh-Cl(2) 2.3628(10) S(1)-C(10) 1.809(4) S(1)-C(1) 1.818(5) S(2)-C(5) 1.808(4) S(2)-C(6) 1.816(4) N(1)-C(2) 1.499(5) N(1)-C(3) 1.501(5) N(2)-C(7) 1.491(5) N(2)-C(8) 1.492(5) C(1)-C(2) 1.506(6) C(1)-H(1A) 0.9900 C(1)-H(1B) 0.9900 C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900 C(3)-C(4) 1.499(6) C(3)-H(3A) 0.9900 C(3)-H(3B) 0.9900 C(4)-C(5) 1.520(7) C(4)-H(4A) 0.9900 C(4)-H(4B) 0.9900 C(5)-H(5A) 0.9900 C(5)-H(5B) 0.9900 C(6)-C(7) 1.508(6) C(6)-H(6A) 0.9900 C(6)-H(6B) 0.9900 C(7)-H(7A) 0.9900 C(7)-H(7B) 0.9900 C(8)-C(9) 1.491(6) C(8)-H(8A) 0.9900 C(8)-H(8B) 0.9900 C(9)-C(10) 1.517(6) C(9)-H(9A) 0.9900 C(9)-H(9B) 0.9900 C(10)-H(10A) 0.9900 C(10)-H(10B) 0.9900

150 Table 3

Bond Lengths [Å] and Angles [°] for C10H20Cl3N2ORhS2 (continued) ______N(2)-Rh-N(1) 92.92(14) N(2)-Rh-S(1) 95.90(10) N(1)-Rh-S(1) 85.92(10) N(2)-Rh-S(2) 86.41(10) N(1)-Rh-S(2) 95.89(10) S(1)-Rh-S(2) 177.00(4) N(2)-Rh-Cl(1) 87.60(10) N(1)-Rh-Cl(1) 176.65(10) S(1)-Rh-Cl(1) 90.74(4) S(2)-Rh-Cl(1) 87.44(4) N(2)-Rh-Cl(2) 176.30(10) N(1)-Rh-Cl(2) 88.39(10) S(1)-Rh-Cl(2) 87.63(4) S(2)-Rh-Cl(2) 90.02(4) Cl(1)-Rh-Cl(2) 91.29(4) C(10)-S(1)-C(1) 100.7(2) C(10)-S(1)-Rh 110.72(14) C(1)-S(1)-Rh 98.77(15) C(5)-S(2)-C(6) 101.6(2) C(5)-S(2)-Rh 110.22(15) C(6)-S(2)-Rh 98.29(14) C(2)-N(1)-C(3) 107.9(3) C(2)-N(1)-Rh 110.6(3) C(3)-N(1)-Rh 119.9(3) C(7)-N(2)-C(8) 108.4(3) C(7)-N(2)-Rh 109.3(3) C(8)-N(2)-Rh 119.4(3) C(2)-C(1)-S(1) 107.8(3) C(2)-C(1)-H(1A) 110.2 S(1)-C(1)-H(1A) 110.2 C(2)-C(1)-H(1B) 110.2 S(1)-C(1)-H(1B) 110.2 H(1A)-C(1)-H(1B) 108.5 N(1)-C(2)-C(1) 111.1(3) N(1)-C(2)-H(2A) 109.4 C(1)-C(2)-H(2A) 109.4 N(1)-C(2)-H(2B) 109.4 C(1)-C(2)-H(2B) 109.4 H(2A)-C(2)-H(2B) 108.0 C(4)-C(3)-N(1) 113.9(3) C(4)-C(3)-H(3A) 108.8

151 Table 3

Bond Lengths [Å] and Angles [°] for C10H20Cl3N2ORhS2 (continued) ______N(1)-C(3)-H(3A) 108.8 C(4)-C(3)-H(3B) 108.8 N(1)-C(3)-H(3B) 108.8 H(3A)-C(3)-H(3B) 107.7 C(3)-C(4)-C(5) 114.4(4) C(3)-C(4)-H(4A) 108.7 C(5)-C(4)-H(4A) 108.7 C(3)-C(4)-H(4B) 108.7 C(5)-C(4)-H(4B) 108.7 H(4A)-C(4)-H(4B) 107.6 C(4)-C(5)-S(2) 116.0(3) C(4)-C(5)-H(5A) 108.3 S(2)-C(5)-H(5A) 108.3 C(4)-C(5)-H(5B) 108.3 S(2)-C(5)-H(5B) 108.3 H(5A)-C(5)-H(5B) 107.4 C(7)-C(6)-S(2) 107.5(3) C(7)-C(6)-H(6A) 110.2 S(2)-C(6)-H(6A) 110.2 C(7)-C(6)-H(6B) 110.2 S(2)-C(6)-H(6B) 110.2 H(6A)-C(6)-H(6B) 108.5 N(2)-C(7)-C(6) 111.6(3) N(2)-C(7)-H(7A) 109.3 C(6)-C(7)-H(7A) 109.3 N(2)-C(7)-H(7B) 109.3 C(6)-C(7)-H(7B) 109.3 H(7A)-C(7)-H(7B) 108.0 C(9)-C(8)-N(2) 115.5(4) C(9)-C(8)-H(8A) 108.4 N(2)-C(8)-H(8A) 108.4 C(9)-C(8)-H(8B) 108.4 N(2)-C(8)-H(8B) 108.4 H(8A)-C(8)-H(8B) 107.5 C(8)-C(9)-C(10) 115.2(4) C(8)-C(9)-H(9A) 108.5 C(10)-C(9)-H(9A) 108.5 C(8)-C(9)-H(9B) 108.5 C(10)-C(9)-H(9B) 108.5 H(9A)-C(9)-H(9B) 107.5 C(9)-C(10)-S(1) 115.4(3)

152 Table 3

Bond Lengths [Å] and Angles [°] for C10H20Cl3N2ORhS2 (continued) ______C(9)-C(10)-H(10A) 108.4 S(1)-C(10)-H(10A) 108.4 C(9)-C(10)-H(10B) 108.4 S(1)-C(10)-H(10B) 108.4 H(10A)-C(10)-H(10B) 107.5 ______Symmetry transformations used to generate equivalent atoms:

Table 4

Anisotropic Displacement Parameters (Å2x 103) for C10H20Cl3N2ORhS2. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______Rh 11(1) 10(1) 11(1) 0(1) 0(1) 0(1) Cl(1) 18(1) 16(1) 14(1) -3(1) -1(1) -1(1) Cl(2) 16(1) 18(1) 17(1) 2(1) 3(1) -4(1) Cl(3) 34(1) 25(1) 21(1) -3(1) 9(1) -8(1) S(1) 17(1) 12(1) 16(1) 2(1) 1(1) 2(1) S(2) 19(1) 11(1) 16(1) -1(1) -4(1) 2(1) O 35(2) 38(2) 29(2) 9(2) 3(2) -4(2) N(1) 17(2) 11(2) 14(2) 1(1) -5(1) 1(1) N(2) 11(2) 14(2) 22(2) -2(2) 0(1) -3(1) C(1) 20(2) 16(2) 22(2) 5(2) -5(2) 0(2) C(2) 20(2) 22(2) 19(2) 4(2) -7(2) -4(2) C(3) 21(2) 16(2) 20(2) -4(2) -8(2) -5(2) C(4) 27(2) 18(2) 24(2) -7(2) -3(2) -4(2) C(5) 25(2) 11(2) 27(2) -2(2) -9(2) -1(2) C(6) 15(2) 21(2) 25(2) -7(2) -1(2) 8(2) C(7) 13(2) 26(2) 22(3) -4(2) 1(2) 5(2) C(8) 20(2) 18(2) 25(3) -1(2) 5(2) -5(2) C(9) 22(2) 19(2) 24(2) 0(2) 4(2) -8(2) C(10) 25(2) 10(2) 20(2) -1(2) -1(2) 0(2)

153 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for C10H20Cl3N2ORhS2. ______x y z U(eq) ______

H(1A) -263 10232 -131 23 H(1B) 656 9918 -543 23 H(2A) -464 8058 532 24 H(2B) -151 8075 -992 24 H(3A) 37 5797 792 22 H(3B) 225 5929 -777 22 H(4A) 1629 5431 -180 28 H(4B) 997 4251 -198 28 H(5A) 1746 3994 1707 25 H(5B) 870 4450 2186 25 H(6A) 3197 5785 2169 24 H(6B) 2692 6063 820 24 H(7A) 3048 7976 2834 24 H(7B) 3464 7926 1381 24 H(8A) 2614 10208 2366 25 H(8B) 3093 10052 983 25 H(9A) 1820 10571 -114 26 H(9B) 2304 11740 578 26 H(10A) 973 12013 1125 22 H(10B) 1428 11588 2470 22

154 Asymmetric Unit

Molecule

Figure D.4. Crystal Structure of with 1,8-dithia-4,11-diazacyclotetradecane 40 nickel complex 115.

Table 1

Crystal Data and Structure Refinement for C12H27Cl2N3NiO9S2

Identification code C12H27Cl2N3NiO9S2 Empirical formula C12 H27 Cl2 N3 Ni O9 S2 Formula weight 551.10 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 18.586(4) Å α= 90°. b = 8.1009(16) Å β= 113.977(4)°. c = 15.236(3) Å γ = 90°. Volume 2096.1(7) Å3 Z 4 Density (calculated) 1.746 Mg/m3 Absorption coefficient 1.430 mm-1 F(000) 1144 Crystal size 0.39 x 0.25 x 0.05 mm3 155

Table 1

Crystal Data and Structure Refinement for C12H27Cl2N3NiO9S2 (continued)

Theta range for data collection 1.20 to 28.36°. Index ranges -23 ≤ h ≤ 24, -10 ≤ k ≤ 10, -20 ≤ l ≤ 20 Reflections collected 18037 Independent reflections 5051 [R(int) = 0.0765] Completeness to theta = 28.36° 96.6 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9319 and 0.3861 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5051 / 0 / 370 Goodness-of-fit on F2 1.049 Final R indices [I>2sigma(I)] R1 = 0.0530, wR2 = 0.1320 R indices (all data) R1 = 0.0731, wR2 = 0.1444 Largest diff. peak and hole 1.658 and -0.893 e.Å-3

156 Table 2

Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (Å2x

103) for C12H27Cl2N3NiO9S2. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______Ni(1) 2517(1) 7180(1) 985(1) 12(1) Cl(1) 993(1) 534(1) 7917(1) 22(1) Cl(2) 4075(1) 2701(1) 3435(1) 16(1) S(1) 1950(1) 8932(1) 1798(1) 18(1) S(2) 3101(1) 5300(1) 254(1) 15(1) O(1) 2398(2) 5076(3) 1741(2) 19(1) O(2) 1101(2) 1151(4) 8831(2) 38(1) O(3) 243(2) -108(6) 7418(3) 63(1) O(4) 1599(2) -637(5) 8023(3) 58(1) O(5) 1100(3) 1887(7) 7369(3) 83(2) O(6) 3358(2) 2327(4) 3525(2) 36(1) O(7) 3893(2) 3749(3) 2605(2) 25(1) O(8) 4603(2) 3547(3) 4262(2) 30(1) O(9) 4433(2) 1215(3) 3291(2) 28(1) N(1) 1436(2) 6514(4) -131(2) 17(1) N(2) 2704(2) 9347(3) 350(2) 16(1) N(3) 3619(2) 7544(3) 2100(2) 17(1) C(1) 732(2) 6455(5) 87(3) 23(1) C(2) 489(2) 8121(5) 320(3) 24(1) C(3) 895(2) 8662(5) 1355(3) 23(1) C(4) 2006(2) 10826(4) 1191(3) 20(1) C(5) 2727(2) 10778(4) 972(3) 20(1) C(6) 3409(2) 9398(4) 133(3) 19(1) C(7) 3405(2) 8142(5) -612(3) 21(1) C(8) 3690(2) 6431(4) -237(3) 20(1) C(9) 2215(2) 4880(5) -800(3) 22(1) C(10) 1524(2) 4889(4) -529(3) 20(1) C(11) 4227(2) 7526(4) 2703(3) 15(1) C(12) 4998(2) 7469(5) 3489(3) 21(1) ______

157 Table 3

Bond Lengths [Å] and Angles [°] for C12H27Cl2N3NiO9S2 ______Ni(1)-N(3) 2.083(3) Ni(1)-N(2) 2.100(3) Ni(1)-N(1) 2.108(3) Ni(1)-O(1) 2.119(3) Ni(1)-S(1) 2.3920(10) Ni(1)-S(2) 2.3921(10) Cl(1)-O(3) 1.390(3) Cl(1)-O(2) 1.415(3) Cl(1)-O(4) 1.431(3) Cl(1)-O(5) 1.439(4) Cl(2)-O(8) 1.420(3) Cl(2)-O(6) 1.427(3) Cl(2)-O(9) 1.434(3) Cl(2)-O(7) 1.444(3) S(1)-C(3) 1.809(4) S(1)-C(4) 1.816(4) S(2)-C(9) 1.805(4) S(2)-C(8) 1.806(4) N(1)-C(1) 1.476(5) N(1)-C(10) 1.487(5) N(2)-C(6) 1.477(5) N(2)-C(5) 1.486(5) N(3)-C(11) 1.130(5) C(1)-C(2) 1.510(5) C(2)-C(3) 1.511(6) C(4)-C(5) 1.509(5) C(6)-C(7) 1.521(5) C(7)-C(8) 1.510(5) C(9)-C(10) 1.500(5) C(11)-C(12) 1.448(5) N(3)-Ni(1)-N(2) 88.04(12) N(3)-Ni(1)-N(1) 173.24(12) N(2)-Ni(1)-N(1) 97.14(12) N(3)-Ni(1)-O(1) 87.46(11) N(2)-Ni(1)-O(1) 175.05(11) N(1)-Ni(1)-O(1) 87.50(12) N(3)-Ni(1)-S(1) 89.32(9) N(2)-Ni(1)-S(1) 86.16(9) N(1)-Ni(1)-S(1) 95.33(9) O(1)-Ni(1)-S(1) 91.72(9) N(3)-Ni(1)-S(2) 89.32(9)

158

Table 3

Bond Lengths [Å] and Angles [°] for C12H27Cl2N3NiO9S2 (continued) N(2)-Ni(1)-S(2) 97.26(9) N(1)-Ni(1)-S(2) 85.74(9) O(1)-Ni(1)-S(2) 84.75(9) S(1)-Ni(1)-S(2) 176.27(3) O(3)-Cl(1)-O(2) 112.3(2) O(3)-Cl(1)-O(4) 112.5(3) O(2)-Cl(1)-O(4) 109.4(2) O(3)-Cl(1)-O(5) 108.2(3) O(2)-Cl(1)-O(5) 107.7(3) O(4)-Cl(1)-O(5) 106.4(3) O(8)-Cl(2)-O(6) 110.59(19) O(8)-Cl(2)-O(9) 110.18(17) O(6)-Cl(2)-O(9) 110.19(18) O(8)-Cl(2)-O(7) 108.98(18) O(6)-Cl(2)-O(7) 108.25(18) O(9)-Cl(2)-O(7) 108.59(17) C(3)-S(1)-C(4) 100.98(18) C(3)-S(1)-Ni(1) 112.00(14) C(4)-S(1)-Ni(1) 96.27(13) C(9)-S(2)-C(8) 102.35(19) C(9)-S(2)-Ni(1) 96.42(13) C(8)-S(2)-Ni(1) 109.60(12) C(1)-N(1)-C(10) 108.6(3) C(1)-N(1)-Ni(1) 117.9(3) C(10)-N(1)-Ni(1) 109.2(2) C(6)-N(2)-C(5) 108.8(3) C(6)-N(2)-Ni(1) 117.0(2) C(5)-N(2)-Ni(1) 109.0(2) C(11)-N(3)-Ni(1) 171.1(3) N(1)-C(1)-C(2) 113.6(3) C(1)-C(2)-C(3) 115.7(3) C(2)-C(3)-S(1) 115.4(3) C(5)-C(4)-S(1) 109.3(3) N(2)-C(5)-C(4) 111.3(3) N(2)-C(6)-C(7) 114.3(3) C(8)-C(7)-C(6) 115.9(3) C(7)-C(8)-S(2) 116.4(3) C(10)-C(9)-S(2) 109.1(3) N(1)-C(10)-C(9) 111.4(3) N(3)-C(11)-C(12) 178.4(4) ______Symmetry transformations used to generate equivalent atoms:

159 Table 4

Anisotropic Displacement Parameters (Å2x 103) for C12H27Cl2N3NiO9S2. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______Ni(1) 12(1) 7(1) 19(1) 1(1) 7(1) 0(1) Cl(1) 16(1) 26(1) 25(1) -5(1) 8(1) 2(1) Cl(2) 17(1) 9(1) 23(1) 1(1) 9(1) 1(1) S(1) 20(1) 13(1) 22(1) 0(1) 12(1) 3(1) S(2) 15(1) 9(1) 24(1) -1(1) 10(1) 0(1) O(1) 19(1) 13(1) 28(2) 7(1) 13(1) 4(1) O(2) 46(2) 40(2) 29(2) -9(1) 17(1) 4(2) O(3) 24(2) 86(3) 71(3) -32(2) 10(2) -14(2) O(4) 43(2) 60(2) 56(2) -20(2) 4(2) 29(2) O(5) 101(4) 94(4) 68(3) 29(3) 52(3) -10(3) O(6) 29(2) 33(2) 53(2) 8(1) 24(2) -4(1) O(7) 29(1) 20(1) 30(2) 11(1) 17(1) 9(1) O(8) 27(2) 26(2) 31(2) -10(1) 5(1) 4(1) O(9) 34(2) 10(1) 37(2) -1(1) 11(1) 10(1) N(1) 14(1) 12(1) 25(2) 2(1) 8(1) 0(1) N(2) 16(1) 8(1) 23(2) 1(1) 7(1) -1(1) N(3) 19(2) 10(1) 24(2) -1(1) 11(1) -1(1) C(1) 15(2) 20(2) 36(2) 2(2) 11(2) 0(2) C(2) 16(2) 21(2) 35(2) 3(2) 11(2) 3(2) C(3) 18(2) 16(2) 40(2) 6(2) 17(2) 8(1) C(4) 26(2) 11(2) 29(2) 2(2) 16(2) 2(1) C(5) 24(2) 9(2) 30(2) -1(2) 13(2) -2(1) C(6) 18(2) 13(2) 30(2) 2(2) 14(2) -2(1) C(7) 23(2) 16(2) 31(2) -2(2) 18(2) -4(2) C(8) 20(2) 14(2) 33(2) -3(2) 15(2) -3(1) C(9) 20(2) 22(2) 24(2) -6(2) 8(2) -5(2) C(10) 20(2) 13(2) 25(2) -3(2) 7(2) -2(1) C(11) 18(2) 9(2) 21(2) -1(1) 10(2) -1(1) C(12) 16(2) 19(2) 27(2) 2(2) 6(2) -1(2) ______

160 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for C12H27Cl2N3NiO9S2. ______x y z U(eq) ______

H(1') 1290(30) 7180(60) -580(40) 35(14) H(2') 2290(20) 9460(50) -160(30) 19(11) H(1'A) 2170(30) 5120(60) 2050(30) 31(14) H(1'B) 2830(30) 4790(70) 2010(40) 45(16) H(1A) 840(20) 5770(50) 630(30) 21(11) H(2A) -100(30) 8090(50) 210(30) 24(11) H(3A) 650(20) 9740(60) 1380(30) 26(11) H(4A) 1520(30) 10780(50) 560(30) 30(12) H(5A) 2720(20) 11770(50) 650(30) 16(10) H(6A) 3850(20) 9260(50) 720(30) 14(10) H(7A) 2820(30) 8100(50) -1200(30) 30(12) H(8A) 4190(20) 6520(50) 280(30) 16(10) H(9A) 2240(30) 3780(60) -1090(30) 35(13) H(10A) 1070(20) 4640(50) -1090(30) 15(10) H(12A) 5400(40) 7650(70) 3300(50) 70(20) H(1B) 270(30) 6000(50) -460(30) 35(13) H(2B) 560(30) 8960(60) -70(30) 33(13) H(3B) 800(30) 7920(60) 1690(30) 30(13) H(4B) 2050(20) 11630(60) 1630(30) 27(11) H(5B) 3190(30) 10710(50) 1560(30) 25(11) H(6B) 3400(20) 10630(50) -110(30) 20(10) H(7B) 3780(20) 8470(50) -870(30) 10(9) H(8B) 3680(30) 5710(60) -770(30) 36(13) H(9B) 2140(30) 5770(50) -1260(30) 27(11) H(10B) 1650(20) 4100(50) 0(30) 13(9) H(12B) 5050(30) 6540(70) 3830(40) 44(14) H(12C) 5080(50) 8250(120) 3840(60) 120(30) ______

161

Asymmetric Unit with H atoms Asymmetric Unit without H atoms.

Figure D.5. The crystal structure of 4-(p-toluenesulfonyl)-1,8-dithia-4,11-diazacyclotetradecane (82).

Table 1

Crystal Data and Structure Refinement for C17H28N2O2S3..

Identification code C17H28N2O2S3 Empirical formula C17 H28 N2 O2 S3 Formula weight 388.59 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Orthorhombic Space group Pna2(1) Unit cell dimensions a = 25.006(3) Å α= 90°. b = 15.0033(16) Å β= 90°. c = 5.3716(6) Å γ = 90°. Volume 2015.2(4) Å3 Z 4 Density (calculated) 1.281 Mg/m3 Absorption coefficient 0.380 mm-1 F(000) 832 Crystal size 0.30 x 0.05 x 0.05 mm3 Theta range for data collection 1.58 to 28.31°. Index ranges -33 ≤ h ≤ 32, -19 ≤ k ≤ 19, -7 ≤ l ≤ 7 Reflections collected 17350 Independent reflections 4836 [R(int) = 0.0391] Completeness to theta = 28.31° 98.6 % Absorption correction Semi-empirical from equivalents Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4836 / 1 / 222

162 Table 1

Crystal Data and Structure Refinement for C17H28N2O2S3..(continued) Goodness-of-fit on F2 1.077 Final R indices [I>2sigma(I)] R1 = 0.0724, wR2 = 0.1980 R indices (all data) R1 = 0.0783, wR2 = 0.2030 Absolute structure parameter 0.43(14) Largest diff. peak and hole 4.276 and -0.437 e.Å-3

163 Table 2

Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (Å2x

103) for C17H28N2O2S3. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______S(1) 4150(1) 7714(1) 2116(2) 16(1) S(2) 4341(1) 4964(1) 2750(2) 22(1) S(3) 2510(1) 5093(1) 5277(3) 24(1) O(1) 3766(1) 7843(2) 190(6) 21(1) O(2) 4698(1) 7521(2) 1493(6) 22(1) N(1) 3933(1) 6877(2) 3766(7) 17(1) N(2) 3196(1) 3528(2) 2578(7) 19(1) C(1) 3353(2) 6831(3) 4253(9) 21(1) C(2) 3059(2) 6315(3) 2201(10) 22(1) C(3) 2504(2) 6009(3) 3056(11) 23(1) C(4) 2287(2) 4179(3) 3297(10) 23(1) C(5) 2692(2) 3856(3) 1393(9) 22(1) C(6) 3610(2) 3413(3) 609(9) 25(1) C(7) 4164(2) 3185(3) 1607(10) 27(1) C(8) 4353(2) 3801(3) 3716(10) 20(1) C(9) 4222(2) 5466(3) 5766(8) 18(1) C(10) 4291(2) 6476(3) 5631(9) 20(1) C(11) 4155(2) 8689(3) 3931(9) 17(1) C(12) 4494(2) 8749(3) 5978(9) 18(1) C(13) 4500(2) 9536(3) 7397(9) 20(1) C(14) 4179(2) 10253(3) 6783(9) 18(1) C(15) 3843(2) 10179(3) 4694(9) 19(1) C(16) 3827(2) 9406(3) 3255(9) 19(1) C(17) 4184(2) 11086(3) 8316(10) 26(1) ______

164 Table 3

Bond Lengths [Å] and Angles [°] for C17H28N2O2S3 ______S(1)-O(1) 1.426(3) S(1)-O(2) 1.438(3) S(1)-N(1) 1.629(4) S(1)-C(11) 1.759(5) S(2)-C(9) 1.811(5) S(2)-C(8) 1.821(5) S(3)-C(3) 1.821(5) S(3)-C(4) 1.823(5) N(1)-C(10) 1.471(6) N(1)-C(1) 1.475(5) N(2)-C(6) 1.489(6) N(2)-C(5) 1.495(6) C(1)-C(2) 1.535(7) C(2)-C(3) 1.532(6) C(4)-C(5) 1.519(7) C(6)-C(7) 1.526(7) C(7)-C(8) 1.536(7) C(9)-C(10) 1.528(6) C(11)-C(12) 1.392(6) C(11)-C(16) 1.401(6) C(12)-C(13) 1.405(6) C(13)-C(14) 1.382(6) C(14)-C(15) 1.405(7) C(14)-C(17) 1.497(6) C(15)-C(16) 1.393(6)

O(1)-S(1)-O(2) 120.0(2) O(1)-S(1)-N(1) 105.97(19) O(2)-S(1)-N(1) 106.79(19) O(1)-S(1)-C(11) 107.0(2) O(2)-S(1)-C(11) 106.9(2) N(1)-S(1)-C(11) 110.0(2) C(9)-S(2)-C(8) 98.4(2) C(3)-S(3)-C(4) 100.5(2) C(10)-N(1)-C(1) 117.2(4) C(10)-N(1)-S(1) 118.9(3) C(1)-N(1)-S(1) 117.4(3) C(6)-N(2)-C(5) 108.7(4) N(1)-C(1)-C(2) 111.6(4) C(3)-C(2)-C(1) 111.7(4) C(2)-C(3)-S(3) 114.5(3)

165 Table 3

Bond Lengths [Å] and Angles [°] for C17H28N2O2S3 (continued) C(5)-C(4)-S(3) 115.3(3) N(2)-C(5)-C(4) 112.4(4) N(2)-C(6)-C(7) 114.1(4) C(6)-C(7)-C(8) 113.8(4) C(7)-C(8)-S(2) 111.2(4) C(10)-C(9)-S(2) 110.6(3) N(1)-C(10)-C(9) 111.7(4) C(12)-C(11)-C(16) 120.8(4) C(12)-C(11)-S(1) 119.7(3) C(16)-C(11)-S(1) 119.5(4) C(11)-C(12)-C(13) 119.3(4) C(14)-C(13)-C(12) 121.2(4) C(13)-C(14)-C(15) 118.4(4) C(13)-C(14)-C(17) 120.9(4) C(15)-C(14)-C(17) 120.7(4) C(16)-C(15)-C(14) 121.8(4) C(15)-C(16)-C(11) 118.5(4) ______Symmetry transformations used to generate equivalent atoms:

166 Table 4

Anisotropic Displacement Parameters (Å2x 103) for C17H28N2O2S3. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______S(1) 16(1) 16(1) 16(1) -4(1) 3(1) 0(1) S(2) 29(1) 19(1) 18(1) -2(1) 0(1) 6(1) S(3) 27(1) 21(1) 24(1) 3(1) 2(1) -1(1) O(1) 21(2) 22(2) 19(2) 0(1) 1(1) -3(1) O(2) 16(1) 23(2) 28(2) -6(1) 5(1) -1(1) N(1) 13(2) 17(2) 21(2) -1(2) 1(2) -1(1) N(2) 18(2) 21(2) 18(2) -4(2) -2(1) -2(1) C(1) 16(2) 20(2) 26(2) 0(2) 5(2) 2(2) C(2) 22(2) 23(2) 21(2) 3(2) -1(2) -1(2) C(3) 19(2) 19(2) 32(3) 9(2) 4(2) -2(2) C(4) 19(2) 21(2) 31(3) 2(2) 1(2) -4(2) C(5) 20(2) 23(2) 22(2) -1(2) -5(2) -2(2) C(6) 25(2) 29(2) 21(2) -6(2) 2(2) -2(2) C(7) 27(2) 28(2) 27(3) -9(2) 3(2) 0(2) C(8) 20(2) 16(2) 25(2) -1(2) -4(2) 3(2) C(9) 23(2) 17(2) 15(2) -3(2) -1(2) 3(2) C(10) 21(2) 19(2) 18(2) -5(2) -6(2) 3(2) C(11) 15(2) 16(2) 21(2) -1(2) 4(2) 0(2) C(12) 18(2) 16(2) 20(2) -1(2) -3(2) 0(2) C(13) 23(2) 17(2) 20(2) -2(2) -3(2) -2(2) C(14) 19(2) 17(2) 19(2) -3(2) 5(2) -2(2) C(15) 16(2) 18(2) 23(2) 0(2) -1(2) 1(2) C(16) 18(2) 16(2) 23(2) -2(2) -1(2) 0(2) C(17) 28(2) 22(2) 27(3) -6(2) 2(2) 1(2) ______

167 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for C17H28N2O2S3. ______x y z U(eq) ______

H(1A) 3207 7443 4356 25 H(1B) 3291 6536 5875 25 H(2A) 3022 6699 714 27 H(2B) 3274 5787 1723 27 H(3B) 2295 5825 1575 28 H(3A) 2317 6523 3820 28 H(4B) 2186 3670 4374 28 H(4A) 1960 4372 2403 28 H(5B) 2531 3368 401 26 H(5A) 2779 4351 241 26 H(6A) 3634 3971 -370 30 H(6B) 3494 2933 -535 30 H(7A) 4425 3218 221 33 H(7B) 4161 2564 2224 33 H(8A) 4721 3635 4208 25 H(8B) 4118 3722 5182 25 H(9B) 3854 5322 6325 22 H(9A) 4476 5216 6996 22 H(10B) 4214 6739 7284 23 H(10A) 4666 6617 5201 23 H(12) 4719 8263 6412 21 H(13) 4729 9576 8804 24 H(15) 3622 10668 4251 22 H(16) 3598 9367 1846 23 H(17A) 4351 10963 9929 39 H(17C) 3816 11291 8579 39 H(17B) 4387 11549 7445 39 H(2) 3318(17) 3920(30) 3620(90) 0(10) ______

168

Asymmetric Unit Molecule

Figure D.6. The crystal structure of 4,4-butylamino-bis-[11-(toluene-4-sulfonyl)-1,8- dithia-4,11-diazacyclotetradecane (87).

Table 1

Crystal Data and Structure Refinement for Bws

Identification code bws Empirical formula C19 H31 N2 O2 S3 Formula weight 415.64 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 7.874(3) Å α= 90°. b = 5.5648(18) Å β= 93.554(6)°. c = 46.458(15) Å γ = 90°. Volume 2031.8(11) Å3 Z 3 Density (calculated) 1.019 Mg/m3 Absorption coefficient 0.286 mm-1 F(000) 669 Crystal size 0.16 x 0.14 x 0.07 mm3 Theta range for data collection 1.76 to 28.37°. Index ranges -10<=h<=10, -7<=k<=7, -61<=l<=60 Reflections collected 16825 Independent reflections 4800 [R(int) = 0.0419] Completeness to theta = 28.37° 94.1 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9802 and 0.8355 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4800 / 0 / 236 Goodness-of-fit on F2 1.114 169 Table 1

Crystal Data and Structure Refinement for Bws

Final R indices [I>2sigma(I)] R1 = 0.0603, wR2 = 0.1395 R indices (all data) R1 = 0.0734, wR2 = 0.1463 Largest diff. peak and hole 0.871 and -0.342 e.Å-3

170 Table 2

Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for bws. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______S(1) 5656(1) 4966(1) 8267(1) 21(1) S(2) 7562(1) 3592(1) 9321(1) 25(1) S(3) -39(1) -2141(2) 8867(1) 33(1) O(1) 4202(2) 5433(4) 8071(1) 26(1) O(2) 6525(3) 6945(4) 8409(1) 26(1) N(1) 2444(3) -1572(4) 9677(1) 19(1) N(2) 5014(3) 3214(4) 8518(1) 20(1) C(1) 207(3) -3817(5) 9929(1) 20(1) C(2) 1985(3) -3822(5) 9820(1) 20(1) C(3) 4269(3) -1570(5) 9626(1) 20(1) C(4) 4865(3) 817(5) 9509(1) 21(1) C(5) 6766(3) 721(5) 9442(1) 17(1) C(6) 6130(3) 4265(5) 9011(1) 20(1) C(7) 6314(3) 2623(5) 8754(1) 21(1) C(8) 3751(4) 1330(6) 8441(1) 26(1) C(9) 2479(4) 1003(6) 8671(1) 28(1) C(10) 1306(4) -1140(6) 8592(1) 28(1) C(11) 1468(4) -2858(6) 9166(1) 26(1) C(12) 1353(3) -1083(5) 9416(1) 22(1) C(13) 7194(3) 3393(5) 8078(1) 20(1) C(14) 8850(4) 4266(6) 8085(1) 26(1) C(15) 10057(4) 3031(6) 7940(1) 26(1) C(16) 9661(4) 896(5) 7795(1) 24(1) C(17) 7987(4) 71(6) 7789(1) 25(1) C(18) 6758(4) 1298(5) 7928(1) 23(1) C(19) 11016(4) -502(6) 7653(1) 32(1) ______

171 Table 3

Bond Lengths [Å] and Angles [°] for Bws. ______S(1)-O(2) 1.436(2) S(1)-O(1) 1.441(2) S(1)-N(2) 1.625(2) S(1)-C(13) 1.770(3) S(2)-C(6) 1.810(3) S(2)-C(5) 1.819(3) S(3)-C(10) 1.799(3) S(3)-C(11) 1.814(3) N(1)-C(12) 1.469(3) N(1)-C(3) 1.471(3) N(1)-C(2) 1.473(4) N(2)-C(8) 1.474(4) N(2)-C(7) 1.488(3) C(1)-C(1)#1 1.517(5) C(1)-C(2) 1.518(4) C(3)-C(4) 1.521(4) C(4)-C(5) 1.548(4) C(6)-C(7) 1.521(4) C(8)-C(9) 1.523(4) C(9)-C(10) 1.539(4) C(11)-C(12) 1.529(4) C(13)-C(14) 1.390(4) C(13)-C(18) 1.391(4) C(14)-C(15) 1.382(4) C(15)-C(16) 1.392(4) C(16)-C(17) 1.395(4) C(16)-C(19) 1.504(4) C(17)-C(18) 1.378(4)

O(2)-S(1)-O(1) 119.28(13) O(2)-S(1)-N(2) 106.86(12) O(1)-S(1)-N(2) 106.95(12) O(2)-S(1)-C(13) 106.62(13) O(1)-S(1)-C(13) 108.52(13) N(2)-S(1)-C(13) 108.20(13) C(6)-S(2)-C(5) 102.61(13) C(10)-S(3)-C(11) 103.07(15) C(12)-N(1)-C(3) 113.3(2) C(12)-N(1)-C(2) 112.6(2) C(3)-N(1)-C(2) 110.0(2) C(8)-N(2)-C(7) 116.4(2)

172 Table 3

Bond Lengths [Å] and Angles [°] for Bws. ______

C(8)-N(2)-S(1) 119.09(18) C(7)-N(2)-S(1) 115.48(18) C(1)#1-C(1)-C(2) 111.8(3) N(1)-C(2)-C(1) 114.0(2) N(1)-C(3)-C(4) 112.6(2) C(3)-C(4)-C(5) 111.4(2) C(4)-C(5)-S(2) 112.83(19) C(7)-C(6)-S(2) 114.60(19) N(2)-C(7)-C(6) 110.6(2) N(2)-C(8)-C(9) 112.1(2) C(8)-C(9)-C(10) 109.6(2) C(9)-C(10)-S(3) 116.2(2) C(12)-C(11)-S(3) 111.8(2) N(1)-C(12)-C(11) 116.6(2) C(14)-C(13)-C(18) 120.4(3) C(14)-C(13)-S(1) 119.1(2) C(18)-C(13)-S(1) 120.5(2) C(15)-C(14)-C(13) 119.2(3) C(14)-C(15)-C(16) 121.4(3) C(15)-C(16)-C(17) 118.3(3) C(15)-C(16)-C(19) 120.6(3) C(17)-C(16)-C(19) 121.1(3) C(18)-C(17)-C(16) 121.2(3) C(17)-C(18)-C(13) 119.5(3) ______Symmetry transformations used to generate equivalent atoms: #1 -x,-y-1,-z+2

173 Table 4

Anisotropic Displacement Parameters (Å2x 103) for bws. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______S(1) 21(1) 20(1) 21(1) 1(1) -3(1) 1(1) S(2) 23(1) 28(1) 22(1) 2(1) -2(1) -5(1) S(3) 23(1) 50(1) 26(1) 7(1) -4(1) -7(1) O(1) 25(1) 28(1) 23(1) 4(1) -6(1) 5(1) O(2) 32(1) 20(1) 26(1) -1(1) -2(1) -1(1) N(1) 15(1) 24(1) 18(1) 3(1) 2(1) 1(1) N(2) 20(1) 22(1) 19(1) 1(1) -3(1) -1(1) C(1) 20(1) 21(1) 20(1) 2(1) 1(1) 1(1) C(2) 19(1) 22(1) 19(1) 4(1) 2(1) 0(1) C(3) 16(1) 23(1) 21(1) -1(1) 0(1) 0(1) C(4) 18(1) 24(1) 22(1) 3(1) 1(1) 1(1) C(5) 10(1) 20(1) 21(1) 9(1) -4(1) -2(1) C(6) 20(1) 21(1) 20(1) 1(1) 0(1) 1(1) C(7) 20(1) 23(1) 18(1) -1(1) -2(1) 3(1) C(8) 26(1) 29(2) 22(1) -1(1) -3(1) -5(1) C(9) 27(2) 33(2) 24(1) -1(1) 0(1) -6(1) C(10) 39(2) 26(2) 20(1) 0(1) 4(1) -12(1) C(11) 21(1) 33(2) 22(1) 3(1) -6(1) 0(1) C(12) 18(1) 25(2) 24(1) 6(1) 0(1) 1(1) C(13) 22(1) 21(1) 18(1) 2(1) -2(1) 2(1) C(14) 25(1) 25(2) 26(1) 1(1) -6(1) -3(1) C(15) 19(1) 30(2) 30(2) 6(1) -3(1) -1(1) C(16) 26(1) 28(2) 18(1) 8(1) 1(1) 4(1) C(17) 27(1) 26(2) 21(1) 0(1) 0(1) -1(1) C(18) 24(1) 24(2) 20(1) 1(1) 0(1) -5(1) C(19) 31(2) 38(2) 28(2) 5(1) 7(1) 8(1) ______

174 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for Bws ______x y z U(eq) ______

H(21A) 113 -2497 10070 24 H(21B) -631 -3514 9765 24 H(22A) 2816 -4116 9985 24 H(22B) 2077 -5168 9683 24 H(13A) 4504 -2860 9488 24 H(13B) 4928 -1927 9810 24 H(14A) 4697 2098 9653 25 H(14B) 4169 1222 9331 25 H(15A) 6916 -503 9291 20 H(15B) 7448 215 9618 20 H(12A) 4945 4158 9070 24 H(12B) 6327 5943 8951 24 H(11A) 7466 2808 8682 25 H(11B) 6177 929 8813 25 H(9A) 1791 2481 8687 34 H(9B) 3093 710 8861 34 H(10A) 2024 -2508 8538 33 H(10B) 573 -699 8419 33 H(16A) 1241 -4502 9236 31 H(16B) 2635 -2830 9099 31 H(17A) 1636 538 9345 27 H(17B) 157 -1036 9470 27 H(1) 9149 5694 8188 31 H(6) 11180 3653 7939 32 H(4) 7688 -1363 7687 30 H(3) 5621 718 7921 27 H(7A) 12079 -433 7774 48 H(7B) 11196 195 7464 48 H(7C) 10656 -2180 7629 48 H(8B) 3119 1790 8257 38 ______

175

C7H10NO3S

Molecule

Figure D.7. The Crystal structure of 5-Oxo-[1,4]-thiazapane-3-carboxylic acid methyl ester 100.

Table 1

Crystal Data and Structure Refinement for C7H10NO3S

Identification code C7H10NO3S Empirical formula C7H10NO3S Formula weight 188.22 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 4.889(2) Å α= 96.513(7)°. b = 8.545(4) Å β= 92.864(7)°. c = 10.148(4) Å γ = 97.198(7)°. Volume 417.0(3) Å3 Z 2 Density (calculated) 1.499 Mg/m3 Absorption coefficient 0.353 mm-1 F(000) 198 Crystal size 0.47 x 0.40 x 0.20 mm3 Theta range for data collection 2.02 to 28.31°. Index ranges -6 ≤ h ≤ 6, -10 ≤ k ≤ 10, -13 ≤ l ≤ 13 Reflections collected 3515 Independent reflections 1862 [R(int) = 0.0329] Completeness to theta = 28.31° 89.1 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9328 and 0.8517 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1862 / 0 / 110

176 Table 1

Crystal Data and Structure Refinement for C7H10NO3S (continued) Goodness-of-fit on F2 1.056 Final R indices [I>2sigma(I)] R1 = 0.0520, wR2 = 0.1345 R indices (all data) R1 = 0.0612, wR2 = 0.1399 Largest diff. peak and hole 0.808 and -0.422 e.Å-3

177 Table 2

Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (Å2x

103) for C7H10NO3S. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______S(1) 4732(1) 3523(1) 6908(1) 17(1) O(1) 1354(4) -1451(2) 6536(2) 19(1) O(2) 4950(4) -2308(2) 7596(2) 21(1) O(3) 10016(4) 1901(2) 10365(2) 19(1) N(1) 6927(4) 614(2) 8752(2) 15(1) C(1) 7249(5) 4199(3) 8286(2) 16(1) C(2) 6660(5) 3426(3) 9557(2) 15(1) C(3) 7975(5) 1914(3) 9595(2) 14(1) C(4) 4523(5) 500(3) 7823(2) 14(1) C(5) 5077(5) 1432(3) 6626(2) 17(1) C(6) 3686(5) -1257(3) 7329(2) 15(1) C(7) 339(5) -3095(3) 6036(3) 21(1) ______

178 Table 3

Bond Lengths [Å] and Angles [°] for C7H10NO3S ______S(1)-C(5) 1.808(3) S(1)-C(1) 1.808(3) O(1)-C(6) 1.343(3) O(1)-C(7) 1.455(3) O(2)-C(6) 1.200(3) O(3)-C(3) 1.238(3) N(1)-C(3) 1.351(3) N(1)-C(4) 1.455(3) C(1)-C(2) 1.537(3) C(1)-H(1A) 0.9900 C(1)-H(1B) 0.9900 C(2)-C(3) 1.517(3) C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900 C(4)-C(6) 1.526(3) C(4)-C(5) 1.542(3) C(4)-H(4) 1.0000 C(5)-H(5A) 0.9900 C(5)-H(5B) 0.9900 C(7)-H(7A) 0.9800 C(7)-H(7B) 0.9800 C(7)-H(7C) 0.9800

C(5)-S(1)-C(1) 101.51(11) C(6)-O(1)-C(7) 114.51(19) C(3)-N(1)-C(4) 125.58(19) C(2)-C(1)-S(1) 114.47(17) C(2)-C(1)-H(1A) 108.6 S(1)-C(1)-H(1A) 108.6 C(2)-C(1)-H(1B) 108.6 S(1)-C(1)-H(1B) 108.6 H(1A)-C(1)-H(1B) 107.6 C(3)-C(2)-C(1) 112.04(19) C(3)-C(2)-H(2A) 109.2 C(1)-C(2)-H(2A) 109.2 C(3)-C(2)-H(2B) 109.2 C(1)-C(2)-H(2B) 109.2 H(2A)-C(2)-H(2B) 107.9 O(3)-C(3)-N(1) 121.3(2) O(3)-C(3)-C(2) 119.9(2) N(1)-C(3)-C(2) 118.8(2)

179 Table 3

Bond Lengths [Å] and Angles [°] for C7H10NO3S (continued)

N(1)-C(4)-C(6) 107.28(18) N(1)-C(4)-C(5) 113.14(19) C(6)-C(4)-C(5) 109.47(19) N(1)-C(4)-H(4) 109.0 C(6)-C(4)-H(4) 109.0 C(5)-C(4)-H(4) 109.0 C(4)-C(5)-S(1) 115.30(17) C(4)-C(5)-H(5A) 108.5 S(1)-C(5)-H(5A) 108.5 C(4)-C(5)-H(5B) 108.5 S(1)-C(5)-H(5B) 108.5 H(5A)-C(5)-H(5B) 107.5 O(2)-C(6)-O(1) 125.0(2) O(2)-C(6)-C(4) 124.8(2) O(1)-C(6)-C(4) 110.13(19) O(1)-C(7)-H(7A) 109.5 O(1)-C(7)-H(7B) 109.5 H(7A)-C(7)-H(7B) 109.5 O(1)-C(7)-H(7C) 109.5 H(7A)-C(7)-H(7C) 109.5 H(7B)-C(7)-H(7C) 109.5 ______Symmetry transformations used to generate equivalent atoms:

180 Table 4

Anisotropic Displacement Parameters (Å2x 103) for C7H10NO3S. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______S(1) 17(1) 12(1) 23(1) 2(1) -1(1) 5(1) O(1) 15(1) 13(1) 28(1) 1(1) -7(1) 1(1) O(2) 16(1) 13(1) 35(1) 1(1) -3(1) 6(1) O(3) 14(1) 14(1) 30(1) 0(1) -6(1) 6(1) N(1) 9(1) 12(1) 23(1) 1(1) -2(1) 4(1) C(1) 12(1) 10(1) 25(1) -1(1) 1(1) 3(1) C(2) 12(1) 11(1) 23(1) 0(1) 0(1) 5(1) C(3) 10(1) 12(1) 22(1) 2(1) 2(1) 4(1) C(4) 10(1) 10(1) 22(1) 0(1) -1(1) 4(1) C(5) 17(1) 12(1) 22(1) 0(1) -1(1) 3(1) C(6) 13(1) 13(1) 19(1) 0(1) 2(1) 3(1) C(7) 18(1) 14(1) 29(1) -2(1) -3(1) -1(1) ______

181 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for C7H10NO3S ______x y z U(eq) ______

H(1A) 9090 3979 8009 19 H(1B) 7326 5364 8494 19 H(2A) 7380 4190 10341 18 H(2B) 4638 3179 9607 18 H(4) 2977 914 8304 17 H(5A) 3782 935 5870 21 H(5B) 6973 1323 6363 21 H(7A) 1613 -3508 5410 31 H(7B) -1494 -3151 5582 31 H(7C) 212 -3734 6779 31

182

Asymmetric Unit

Figure D.8. The Crystal structure of the ligand 3,6,9-trithiadecanol 113 complexed with Rhodium 117.

Table 1

Crystal Data and Structure Refinement for C7H16Cl3O2RhS3

Identification code C7H16Cl3O2RhS3 Empirical formula C7 H14 Cl3 O Rh S3, H2 O Formula weight 437.64 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 14.7924(9) Å α= 90°. b = 7.3684(5) Å β= 115.2210(10)°. c = 14.0502(9) Å γ = 90°. Volume 1385.43(15) Å3 Z 4 Density (calculated) 2.098 Mg/m3 Absorption coefficient 2.245 mm-1 F(000) 872 Crystal size 0.54 x 0.33 x 0.17 mm3 Theta range for data collection 1.52 to 28.27°. 183 Table 1

Crystal Data and Structure Refinement for C7H16Cl3O2RhS3 (continued)

Index ranges -19 ≤ h ≤ 19, -9 ≤ k ≤ 9, -18 ≤ l ≤ 18 Reflections collected 11808 Independent reflections 3314 [R(int) = 0.0231] Completeness to theta = 28.27° 96.8 % Absorption correction Semi-empirical from equivalents Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3314 / 0 / 154 Goodness-of-fit on F2 1.148 Final R indices [I>2sigma(I)] R1 = 0.0318, wR2 = 0.0745 R indices (all data) R1 = 0.0323, wR2 = 0.0747 Largest diff. peak and hole 1.940 and -0.681 e.Å-3

184 Table 2

Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (Å2x

103) for C7H16Cl3O2RhS3. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______Rh(1) 2817(1) 9679(1) 2186(1) 13(1) Cl(1) 3483(1) 11191(1) 1126(1) 20(1) Cl(2) 1417(1) 11637(1) 1637(1) 20(1) Cl(3) 3775(1) 11582(1) 3647(1) 23(1) S(1) 4152(1) 7807(1) 2698(1) 22(1) S(2) 2289(1) 8241(1) 3294(1) 17(1) S(3) 1980(1) 7886(1) 763(1) 18(1) O(1) -211(2) 5535(4) 1335(2) 31(1) O(2) 1601(2) 1960(4) 8923(2) 29(1) C(1) 4099(3) 6596(6) 3790(3) 33(1) C(2) 3049(3) 6174(5) 3656(3) 26(1) C(3) 1032(2) 7325(5) 2632(3) 22(1) C(4) 752(3) 6263(6) 1642(3) 34(1) C(5) 766(3) 7196(5) 710(3) 28(1) C(6) 2662(3) 5782(5) 1037(3) 31(1) C(7) 3776(3) 6148(5) 1620(4) 38(1)

185 Table 3

Bond Lengths [Å] and Angles [°] for C7H16Cl3O2RhS3 ______Rh(1)-S(1) 2.2606(8) Rh(1)-S(3) 2.2731(8) Rh(1)-S(2) 2.2786(8) Rh(1)-Cl(2) 2.3678(8) Rh(1)-Cl(1) 2.3819(8) Rh(1)-Cl(3) 2.3899(8) S(1)-C(1) 1.806(4) S(1)-C(7) 1.838(4) S(2)-C(3) 1.818(3) S(2)-C(2) 1.831(4) S(3)-C(6) 1.800(4) S(3)-C(5) 1.838(4) O(1)-C(4) 1.407(4) C(1)-C(2) 1.514(5) C(3)-C(4) 1.492(5) C(4)-C(5) 1.486(6) C(6)-C(7) 1.519(6)

S(1)-Rh(1)-S(3) 90.01(3) S(1)-Rh(1)-S(2) 90.34(3) S(3)-Rh(1)-S(2) 96.53(3) S(1)-Rh(1)-Cl(2) 179.61(3) S(3)-Rh(1)-Cl(2) 89.70(3) S(2)-Rh(1)-Cl(2) 89.94(3) S(1)-Rh(1)-Cl(1) 86.95(3) S(3)-Rh(1)-Cl(1) 86.43(3) S(2)-Rh(1)-Cl(1) 176.00(3) Cl(2)-Rh(1)-Cl(1) 92.79(3) S(1)-Rh(1)-Cl(3) 88.11(3) S(3)-Rh(1)-Cl(3) 176.60(3) S(2)-Rh(1)-Cl(3) 86.33(3) Cl(2)-Rh(1)-Cl(3) 92.17(3) Cl(1)-Rh(1)-Cl(3) 90.64(3) C(1)-S(1)-C(7) 105.3(2) C(1)-S(1)-Rh(1) 102.89(13) C(7)-S(1)-Rh(1) 103.09(14) C(3)-S(2)-C(2) 101.92(17) C(3)-S(2)-Rh(1) 113.38(12) C(2)-S(2)-Rh(1) 103.18(12) C(6)-S(3)-C(5) 102.71(18) C(6)-S(3)-Rh(1) 105.45(14)

186 Table 3

Bond Lengths [Å] and Angles [°] for C7H16Cl3O2RhS3 (continued) ______

C(5)-S(3)-Rh(1) 110.68(13) C(2)-C(1)-S(1) 114.2(3) C(1)-C(2)-S(2) 109.8(3) C(4)-C(3)-S(2) 119.3(2) O(1)-C(4)-C(5) 107.4(3) O(1)-C(4)-C(3) 109.2(3) C(5)-C(4)-C(3) 118.4(4) C(4)-C(5)-S(3) 118.2(3) C(7)-C(6)-S(3) 110.1(3) C(6)-C(7)-S(1) 116.1(3) ______Symmetry transformations used to generate equivalent atoms:

187 Table 4

Anisotropic Displacement Parameters (Å2x 103) for C7H16Cl3O2RhS3. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______Rh(1) 12(1) 8(1) 17(1) 0(1) 6(1) 0(1) Cl(1) 21(1) 15(1) 25(1) 0(1) 12(1) -5(1) Cl(2) 17(1) 12(1) 28(1) 2(1) 7(1) 3(1) Cl(3) 21(1) 19(1) 24(1) -6(1) 5(1) -4(1) S(1) 14(1) 13(1) 38(1) 4(1) 12(1) 2(1) S(2) 18(1) 15(1) 18(1) 1(1) 8(1) 0(1) S(3) 24(1) 11(1) 19(1) -2(1) 9(1) -4(1) O(1) 16(1) 24(1) 51(2) -8(1) 12(1) -2(1) O(2) 29(1) 29(1) 33(2) 9(1) 15(1) 11(1) C(1) 17(2) 32(2) 46(2) 22(2) 10(2) 6(1) C(2) 22(2) 22(2) 34(2) 13(1) 12(1) 4(1) C(3) 19(2) 22(2) 28(2) 0(1) 12(1) -1(1) C(4) 22(2) 42(2) 39(2) -11(2) 15(2) -7(2) C(5) 25(2) 25(2) 33(2) -4(2) 10(2) -3(1) C(6) 37(2) 20(2) 38(2) -2(2) 19(2) 4(2) C(7) 30(2) 20(2) 74(3) -16(2) 32(2) -2(2)

188 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for C7H16Cl3O2RhS3 ______x y z U(eq) ______

H(1) -626 6383 1207 47 H(1A) 4471 5442 3889 40 H(1B) 4440 7328 4436 40 H(2A) 3072 5682 4321 31 H(2B) 2745 5245 3101 31 H(3A) 917 6537 3141 27 H(3B) 560 8354 2471 27 H(4) 1225 5217 1811 40 H(5A) 345 8296 574 34 H(5B) 441 6385 95 34 H(6A) 2443 4994 1470 37 H(6B) 2523 5141 369 37 H(7A) 4021 6577 1104 46 H(7B) 4116 4984 1911 46 H(2A') 1870(50) 2270(90) 8550(50) 64(19) H(2B') 2050(40) 1760(70) 9490(40)

189

Asymmetric Unit

Cation

Figure D.9. The Crystal structure of N,N’-Bis-[1-Aza-4,7-dithiacyclonanyl]-butane 110.

Table 1

Crystal Data and Structure Refinement for C16H34Cl2N2O8S4

Identification code C16H34Cl2N2O8S4 Empirical formula C16 H34 Cl2 N2 O8 S4 Formula weight 581.59 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 9.250(6) Å α= 90°. b = 6.686(4) Å β= 102.585(11)°. c = 20.151(12) Å γ = 90°.

190 Table 1

Crystal Data and Structure Refinement for C16H34Cl2N2O8S4 (continued)

Volume 1216.3(13) Å3 Z 2 Density (calculated) 1.588 Mg/m3 Absorption coefficient 0.656 mm-1 F(000) 612 Crystal size 0.40 x 0.10 x 0.02 mm3 Theta range for data collection 2.07 to 26.30°. Index ranges -11 ≤ h ≤ 11, -8 ≤ k ≤ 8, -24 ≤ l ≤ 25 Reflections collected 9237 Independent reflections 2473 [R(int) = 0.0693] Completeness to theta = 26.30° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9870 and 0.7794 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2473 / 0 / 149 Goodness-of-fit on F2 1.016 Final R indices [I>2sigma(I)] R1 = 0.0444, wR2 = 0.0988 R indices (all data) R1 = 0.0681, wR2 = 0.1048 Largest diff. peak and hole 0.433 and -0.315 e.Å-3

191 Table 2

Atomic Coordinates ( x 104) and Equivalent Isotropic Displacement Parameters (Å2x

103) for C16H34Cl2N2O8S4. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______Cl(1) 2695(1) 6131(1) 752(1) 21(1) S(1) 6399(1) 1573(1) 2456(1) 20(1) S(2) 4705(1) 5761(1) 2925(1) 22(1) O(1) 3445(3) 7649(3) 1198(1) 41(1) O(2) 3764(2) 4785(3) 594(1) 36(1) O(3) 1694(2) 5084(3) 1082(1) 27(1) O(4) 1884(2) 7034(4) 138(1) 45(1) N(1) 7255(2) 3610(3) 3866(1) 17(1) C(1) 7684(3) 1454(4) 3823(1) 20(1) C(2) 6563(3) 380(4) 3276(1) 20(1) C(3) 4454(3) 2165(4) 2179(2) 22(1) C(4) 3744(3) 3437(4) 2650(1) 22(1) C(5) 4963(3) 5614(4) 3844(1) 23(1) C(6) 5929(3) 3879(4) 4172(1) 19(1) C(7) 8539(3) 4921(4) 4173(1) 18(1) C(8) 9351(3) 4292(4) 4879(1) 19(1)

192 Table 3

Bond Lengths [Å] and Angles [°] for C16H34Cl2N2O8S4 ______Cl(1)-O(2) 1.423(2) Cl(1)-O(1) 1.431(2) Cl(1)-O(4) 1.434(2) Cl(1)-O(3) 1.434(2) S(1)-C(3) 1.808(3) S(1)-C(2) 1.813(3) S(2)-C(4) 1.815(3) S(2)-C(5) 1.818(3) N(1)-C(6) 1.498(3) N(1)-C(7) 1.497(3) N(1)-C(1) 1.503(3) C(1)-C(2) 1.519(4) C(3)-C(4) 1.525(4) C(5)-C(6) 1.524(4) C(7)-C(8) 1.517(4) C(8)-C(8)#1 1.524(5)

O(2)-Cl(1)-O(1) 108.85(14) O(2)-Cl(1)-O(4) 109.38(15) O(1)-Cl(1)-O(4) 109.55(15) O(2)-Cl(1)-O(3) 110.20(13) O(1)-Cl(1)-O(3) 109.18(13) O(4)-Cl(1)-O(3) 109.67(13) C(3)-S(1)-C(2) 104.95(13) C(4)-S(2)-C(5) 102.20(14) C(6)-N(1)-C(7) 114.0(2) C(6)-N(1)-C(1) 112.9(2) C(7)-N(1)-C(1) 113.0(2) N(1)-C(1)-C(2) 110.4(2) C(1)-C(2)-S(1) 111.19(19) C(4)-C(3)-S(1) 117.6(2) C(3)-C(4)-S(2) 114.8(2) C(6)-C(5)-S(2) 114.65(19) N(1)-C(6)-C(5) 111.6(2) N(1)-C(7)-C(8) 114.3(2) C(7)-C(8)-C(8)#1 108.8(3) ______Symmetry transformations used to generate equivalent atoms: #1 -x+2,-y+1,-z+1

193 Table 4

Anisotropic Displacement Parameters (Å2x 103) for C16H34Cl2N2O8S4. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______Cl(1) 26(1) 18(1) 20(1) 2(1) 6(1) 2(1) S(1) 23(1) 21(1) 16(1) -2(1) 4(1) 0(1) S(2) 25(1) 17(1) 22(1) -1(1) -1(1) 1(1) O(1) 49(2) 38(1) 40(1) -21(1) 20(1) -20(1) O(2) 42(1) 28(1) 44(1) -3(1) 22(1) 9(1) O(3) 28(1) 23(1) 33(1) 4(1) 12(1) -4(1) O(4) 39(1) 59(2) 35(1) 28(1) 1(1) 4(1) N(1) 19(1) 14(1) 15(1) -1(1) -1(1) 0(1) C(1) 25(2) 14(1) 19(2) 0(1) 2(1) 3(1) C(2) 28(2) 13(1) 17(2) -2(1) 4(1) 2(1) C(3) 20(2) 23(2) 19(2) -3(1) -2(1) -1(1) C(4) 20(2) 22(2) 21(2) -2(1) -2(1) -5(1) C(5) 25(2) 21(2) 20(2) -5(1) 0(1) 2(1) C(6) 22(2) 17(1) 18(2) -3(1) 3(1) 0(1) C(7) 19(2) 16(1) 17(2) 2(1) 0(1) -2(1) C(8) 20(2) 18(1) 17(2) 1(1) 2(1) 0(1) ______

194 Table 5

Hydrogen Coordinates ( x 104) and Isotropic Displacement Parameters (Å2x 10 3) for C16H34Cl2N2O8S4 ______x y z U(eq) ______

H' 6990(30) 4010(40) 3415(16) 26(8) H(1A) 7733 795 4267 23 H(1B) 8677 1372 3715 23 H(2A) 5585 382 3401 23 H(2B) 6873 -1029 3247 23 H(3A) 4314 2866 1736 26 H(3B) 3899 890 2096 26 H(4A) 3694 2636 3057 26 H(4B) 2716 3755 2413 26 H(5A) 5414 6880 4044 28 H(5B) 3979 5493 3958 28 H(6A) 6262 4131 4665 23 H(6B) 5337 2633 4112 23 H(7A) 8176 6308 4195 22 H(7B) 9250 4925 3870 22 H(8A) 9716 2903 4868 22 H(8B) 8670 4343 5196 22

195