THE USE OF NICKEL(II) SALEN MEDIATORS IN STEREOSELECTIVE
ELECTROHYDROCYCLIZATION REACTIONS
A Thesis
Presented to the faculty of the Department of Chemistry
California State University, Sacramento
Submitted in partial satisfaction of the requirements for the degree of
MASTER OF SCIENCE
in
Chemistry
by
Jessica Marney Yates
FALL 2012
© 2012
Jessica Marney Yates
ALL RIGHTS RESERVED
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THE USE OF NICKEL(II) SALEN MEDIATORS IN STEREOSELECTIVE
ELECTROHYDROCYCLIZATION REACTIONS
A Thesis
by
Jessica Marney Yates
Approved by:
______, Committee Chair James Miranda
______, Second Reader John Spence
______, Third Reader Benjamin Gherman
______Date
iii
Student: Jessica Marney Yates
I certify that this student has met the requirements for format contained in the University format manual, and that this thesis is suitable for shelving in the Library and credit is to be awarded for the thesis.
______, Graduate Coordinator ______Susan Crawford Date
Department of Chemistry
iv
Abstract
of
THE USE OF NICKEL(II) SALEN MEDIATORS IN STEREOSELECTIVE
ELECTROHYDROCYCLIZATION REACTIONS
by
Jessica Marney Yates
Electrohydrocyclization (EHC) reactions began in the 1960’s with Baizer and
Anderson and were eventually applied to mediated EHC reactions by Miranda, Wade, and Little in the early 2000’s. Mediated EHC reactions can lead to further advancements in organic synthesis in regards to conducting diastereoselective reactions. Currently, it is uncertain how exactly Ni(II) salen mediators are involved during EHC reactions.
Depending upon the reaction mechanism and how the electron is transferred, the mediator may or may not be able to affect the stereochemistry of the final electrolysis product. For this thesis, multiple bulk electrolysis (BE) reactions were carried out with various mediators. There was much evidence from the cyclic voltammetry experiments that a catalytic electrolysis and an inner sphere electron transfer occurred during the BE reactions. However, there was a solution color change during the BE reactions which was due to the metal being reduced, indicating an outer sphere electron transfer. It appears that a combination of the two mechanisms occurred. The cis/trans ratio results from the mediated BE reactions did not show any clear isomer selection. Each reaction resulted in about the same isomer ratio. The following results were obtained for the mediated BE v
reactions with the EHC substrate: Ni(II) salen c/t = 1/1.46, 1,2-ethylenediamine Ni(II) di- tert-butyl salen c/t = 1/1.36, 1,2-phenylenediamine Ni(II) di-tert-butyl salen c/t = 1/1.21,
(R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen c/t = 1/1.20, (S,S)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen c/t = 1/1.34. The bridge variations and the added tert-butyl groups on the mediators did not greatly change the cis/trans results when compared to the BE reaction with Ni(II) salen. The tert-butyl groups were too bulky to allow for the electron transfer and cyclization to occur concertedly on the mediator. This required an inner sphere electron transfer through a covalent linkage. More BE reactions are needed with mediators containing the same bridge variations without the tert-butyl groups.
______, Committee Chair James Miranda
______Date vi
ACKNOWLEDGMENTS
Dr. Miranda, my advisor and mentor, I can not thank you enough. Your guidance and support through out this entire process will never be forgotten. I will always remember your positive attitude and words of encouragement, even when the research was not going as planned. Most importantly you made me excited and proud about what I was doing. For all of that and more, I sincerely thank you.
Dr. Spence and Dr. Gherman, thank you both for not only agreeing to be on my thesis committee but for also giving me constructive and thoughtful feedback. I appreciate all of the time you both spent on helping me make this thesis better. Additional thanks to Dr.
Gherman for conducting the computational chemistry which became crucial in the NMR peak assignments.
To my fellow graduate lab buddies, Maddy McCrea-Hendrick and Tanya Hilger Estrada, for helping me further improve my lab skills and making research much more enjoyable.
To the National Science Foundation for funding this work through a Major Research
Instrumentation Grant (#0922676). Also to California State University, Sacramento,
College of Natural Science and Mathematics for their support of this research.
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DEDICATION
I dedicate this thesis to my parents, John and Patricia Yates, for their continual support in my education. They have always believed in my success and I would not be where I am today without them. Because of them, I know I can accomplish anything I set my mind to. They have both given me the world and I only hope that I have made them both proud.
I am truly lucky to have parents that would do anything for me. I love you both so much.
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TABLE OF CONTENTS
Pages Acknowledgments...... vii
Dedication… ...... viii
List of Tables ...... xii
List of Figures ...... xiii
List of Schemes ...... xvi
List of Abbreviations ...... xviii
Chapters
1. INTRODUCTION ...... 1
1.1 Electrochemistry Background ...... 1
1.2 Direct vs. Indirect Method ...... 3
1.3 General Experimental Set-up and Instruments ...... 9
1.4 Examples of Specific Electrochemical Reactions ...... 13
1.4.1 Cathodic Reduction Reactions ...... 14
1.4.2 Electroreductive (Cathodic) Cyclization Reactions ...... 17
1.4.3 Anodic Oxidation Reactions ...... 21
1.4.4 Electrooxidative (Anodic) Cyclization Reactions ...... 24
1.5 Background on Thesis Project ...... 26
1.6 Thesis Objective...... 33
1.6.1 Specific Aims ...... 34
2. RESULTS AND DISCUSSION ...... 37 ix
2.1 Synthesis of Mediators ...... 37
2.2 Synthesis of EHC Substrate ...... 41
2.3 Cyclic Voltammetry ...... 45
2.3.1 Redox Potentials ...... 45
2.3.2 Various Scan Rates ...... 53
2.3.3 Catalytic Current ...... 66
2.4 Bulk Electrolysis ...... 70
3. CONCLUSION ...... 93
3.1 Future Studies ...... 95
4. EXPERIMENTAL ...... 97
Appendicies
Appendix A. [N,N’-Bis(di-salicylidene)-1,2-ethylenediamine]Nickel(II) Spectra ...... 115
Appendix B. N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-ethylenediamine Spectra ...... 119
Appendix C. [N,N’-Bis(3,5-di-tert butylsalicylidene)-1,2-ethylenediamine]Nickel(II)
Spectra ...... 121
Appendix D. N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine Spectra ... 125
Appendix E. [N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine]Nickel(II)
Spectra ...... 127
Appendix F. [(R,R)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]
Nickel(II) Spectra ...... 131
Appendix G. [(S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]
Nickel(II) Spectra ...... 135 x
Appendix H. Hexanedial Spectra ...... 141
Appendix I. Deca-2,8-dienedioic acid diethyl ester Spectra ...... 146
Appendix J. Cyclohexane-1,2-diacetic acid diethyl ester Spectra ...... 154
References ...... 174
xi
LIST OF TABLES Table Page 1. Results of the reductive cyclizations of α,β-unsaturated esters ...... 18
2. Cyclic voltammogram summary ...... 52
3. Summary of Ni(II) salen ...... 55
4. Summary of 1,2-ethylenediamine Ni(II) di-tert-butyl salen ...... 57
5. Summary of 1,2-phenylenediamine Ni(II) di-tert-butyl salen ...... 59
6. Summary of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen ...... 62
7. Summary of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen ...... 64
8. Summary of the EHC substrate at various VSRs...... 66
9. 1H NMR experimental and calculated chemical shifts for the cis and trans
isomers of the BE product...... 81
10. 13C NMR experimental and calculated chemical shifts for the cis and trans
diastereomers of the BE product ...... 85
11. Summary of BE reaction results ...... 91
xii
LIST OF FIGURES
Figure Page 1. The two parts of a redox reaction ...... 1
2. A generic direct and indirect irreversible reduction reaction ...... 4
3. A general reversible cyclic voltammogram ...... 5
4. Cyclic voltammogram displaying a catalytic current; dashed line: mediator only,
solid line: mediator with substrate ...... 7
5. CV cell on cell stand and equipment ...... 10
6. BE cell on cell stand and equipment ...... 11
7. Half and overall reactions for a silver/silver chloride reference electrode ...... 13
8. General structure for inositol ...... 14
9. Products from various Kolbe electrolysis reactions (arrows indicate key bonds
formed) ...... 22
10. Reduced Ni(II) salen ...... 30
11. Ni(II) salen mediators ...... 34
12. EHC substrate ...... 35
13. Cis and trans BE product ...... 36
14. Nickel(II) salen ...... 37
15. Cyclic voltammogram of Ni(II) salen ...... 46
16. Cyclic voltammogram of 1,2-ethylenediamine Ni(II) di-tert-butyl salen ...... 47
17. Cyclic voltammogram of 1,2-phenylenediamine Ni(II) di-tert-butyl salen ...... 48
xiii
18. Cyclic voltammogram of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl
salen ...... 49
19. Cyclic voltammogram of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl
salen ...... 50
20. Cyclic voltammogram of the EHC substrate ...... 51
21. Cyclic voltammograms of Ni(II) salen ...... 54
22. Cyclic voltammograms of 1,2-ethylenediamine Ni(II) di-tert-butyl salen ...... 56
23. Cyclic voltammograms of 1,2-phenylenediamine Ni(II) di-tert-butyl salen ...... 58
24. Resonance structures of 1,2-phenylenediamine Ni(II) di-tert-butyl salen radical
anion ...... 60
25. Cyclic voltammograms of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl
salen ...... 61
26. Cyclic voltammograms of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl
salen ...... 63
27. Cyclic voltammograms of the EHC substrate ...... 65
28. Cyclic voltammogram of Ni(II) salen (dashed) and with the EHC substrate
(solid) ...... 67
29. Cyclic voltammogram of 1,2-ethylenediamine Ni(II) di-tert-butyl salen
(dashed) and with the EHC substrate (solid) ...... 68
30. Cyclic voltammogram of 1,2-phenylenediamine Ni(II) di-tert-butyl salen
(dashed) and with the EHC substrate (solid) ...... 68
xiv
31. Cyclic voltammogram (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
(dashed) and with the EHC substrate (solid) ...... 69
32. Cyclic voltammogram (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
(dashed) and with the EHC substrate (solid) ...... 69
33. By-products from BE reaction ...... 72
34. BE product ...... 77
35. 1H NMR 500 MHz of cyclohexane-1,2-diacetic acid diethyl ester ...... 78
36. 1H -1H COSY of cyclohexane-1,2-diacetic acid diethyl ester ...... 79
37. Zoomed in 1H -1H COSY of cyclohexane-1,2-diacetic acid diethyl ester ...... 80
38. 13C NMR 500 MHZ of cyclohexane-1,2-diacetic acid diethyl ester ...... 82
39. DEPT135 of cyclohexane-1,2-diacetic acid diethyl ester ...... 83
40. DEPT90 of cyclohexane-1,2-diacetic acid diethyl ester ...... 84
41. 1H -13C HSQC of cyclohexane-1,2-diacetic acid diethyl ester ...... 86
42. GC of BE reaction of the EHC substrate with (R,R)-1,2-cyclohexanediamine
Ni(II) di-tert-butyl salen ...... 87
43. MS of BE product at 11.272 min ...... 88
44. MS of BE product at 11.435 min ...... 89
45. Integration of BE product conducted with (R,R)-1,2-cyclohexanediamine Ni(II)
di-tert-butyl salen ...... 90
46. ERC substrate and Co(II) salen ...... 95
xv
LIST OF SCHEMES
Scheme Page 1. Cathodic reduction of vinyl bromide ...... 15
2. Electrochemical NHK coupling between aromatic aldehydes and aryl halides ... 16
3. Reductive cyclizations of α,β-unsaturated esters ...... 18
4. Retrosynthetic reaction plan for the synthesis of Ambliol-A ...... 19
5. ERC of keto enoate in the synthesis of Ambliol-A...... 19
6. Synthesis of quadrone utilizing two electroreductive cyclization reactions ...... 20
7. A Kolbe electrolysis reaction ...... 21
8. The direct Shono oxidation ...... 23
9. The indirect Shono oxidation ...... 23
10. Kolbe electrolysis used in the synthesis of perhydroazulenes ...... 24
11. The use of an anodic oxidation in the total synthesis of (+)-linalool oxide ...... 25
12. Electrohydrodimerization of acrylonitrile ...... 26
13. General EHC reaction ...... 27
14. One of the first EHC reactions ...... 27
15. One of the first electrochemically mediated reactions ...... 28
16. Nickel(II) salen mediated ERC (top) and EHC (bottom) reactions ...... 29
17. Modified Ni(II) salen in an ERC reaction...... 31
18. First possible pathway for EHC ring closure ...... 32
19. Second possible pathway for EHC ring closure ...... 32
20. Synthesis of 1,2-ethylenediamine di-tert-butyl ligand...... 38
xvi
21. Synthesis of 1,2-ethylenediamine Ni(II) di-tert-butyl salen ...... 38
22. Synthesis of 1,2-phenylenediamine di-tert-butyl ligand ...... 39
23. Synthesis of 1,2-phenylenediamine Ni(II) di-tert-butyl salen ...... 40
24. Synthesis of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen ...... 40
25. Synthesis of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen ...... 41
26. Synthesis of hexanedial (Procedure 1) ...... 42
27. Synthesis of deca-2,8-dienedioic acid diethyl ester (Procedure 1) ...... 43
28. Synthesis of hexanedial (Procedure 2) ...... 44
29. Synthesis of deca-2,8-dienedioic acid diethyl ester (Procedure 2) ...... 44
30. EHC reaction with Ni(II) salen ...... 71
31. EHC reaction with 1,2-ethylenediamine Ni(II) di-tert-butyl salen ...... 72
32. EHC reaction with 1,2-phenylenediamine Ni(II) di-tert-butyl salen ...... 73
33. EHC reaction with (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen ...... 74
34. EHC reaction with (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen ...... 75
35. Direct BE reaction (-2.600 V) of EHC substrate ...... 76
36. Direct BE reaction (-2.100 V) of EHC substrate ...... 76
xvii
LIST OF ABBREVIATIONS
(COCl)2 = oxalyl chloride abs. EtOH = absolute ethanol
BE = bulk electrolysis
CDCl3 = deuterated chloroform
CH2(CO2CH3)2 = dimethyl malonate
CH3CN = acetonitrile
CH3CO2H = acetic acid
CV = cyclic voltammetry
DCM = dichloromethane
DI H2O = deionized water
DMF = dimethylformamide
DMSO = dimethylsulfoxide
EHC = electrohydrocyclization
EOC = electrooxidative cyclization
ERC = electroreductive cyclization
Et4NOTs = tetraethylammonium tosylate
EtOAc = ethyl acetate
Hz = hertz
HWE = Horner-Wadsworth-Emmons
IR = infrared spectroscopy
MeOH = methanol xviii
nBu4NBF4 = tetra-n-butylammonium tetrafluoroborate nBu4NBr /TBAB = tetra-n-butylammonium bromide nBu4NPF6 = tetra-n-butylammonium hexafluorophosphate
NHK = Nozaki-Hiyama-Kishi
RBF = round bottom flask
Redox = reduction-oxidation
Rf = retention factor in chromatography r.t. = room temperature
RVC = reticulated vitreous carbon
Salen = bis(salicylidene)ethylenediamine
SCE = saturated calomel electrode
TBDPS = tert-butyldiphenylsilyl
TEA = triethylamine
THF = tetrahydrofuran
TMS = tetramethylsilane
VSR = voltage scan rate
xix 1
Chapter 1
INTRODUCTION
1.1 Electrochemistry Background
Electrochemical reactions involve an electron transfer between an electrode and a compound in solution.1 The electrode may be either anodic (causing oxidation of a compound), or cathodic (causing reduction). In some electrochemical techniques, such as cyclic voltammetry (CV), the electron transfer can be reversible causing reduction and then oxidation, or vice versa, to measure the reduction-oxidation (redox) potentials of a compound. For irreversible reactions, such as organic electrochemical reactions
(electrolysis), a technique called bulk electrolysis (BE) is commonly used. Starting from a neutral compound, radical anions (reduction) or radical cations (oxidation) are formed and can undergo a wide range of reactions which will be further discussed in section
1.4. Electrochemistry can be applied to many fields; however this thesis will focus on synthetic organic chemistry applications. The two parts of a general redox reaction can be seen in Figure 1.
Figure 1: The two parts of a redox reaction
There are many advantages with synthesizing organic molecules by an electrochemical method rather than by traditional organic chemistry. Electrochemistry
2 is often viewed as a green process due to its minimal amount of waste and raw material usage.2 By-product formation and hazardous or toxic reagents can be avoided. There is no need for stoichiometric reagents since electrons are used. Electrons are clean and among the reducing agents commonly used, they have the lowest cost per unit of charge. The instruments and equipment used for conducting electrochemical reactions are mechanically simple and low maintenance. The electrodes can be used for countless reactions, which gives the equipment large versatility. Electrochemical techniques do not normally require a high temperature or pressure, and as a result are relatively safer than other techniques like incineration, supercritical oxidation, wet oxidation, etc.
Electrochemistry has the potential for developing entirely new synthetic strategies for the production of complex molecules and can allow reactions to occur that would normally not be achievable by traditional organic chemistry. The reactions can also occur more rapidly and with comparable yields. Reversal of polarity for different functional groups offers a wealth of unexplored reactions and the possibility for structurally interesting products. An adequate combination of experimental conditions
(electrolyte composition, temperature, degree of convection, applied potential, current) and reaction characteristics (shape, size, construction materials, electrode materials) can be carefully selected for each electrochemical reaction to obtain the desired product.2 A mediator, such as a catalyst, can be used to transfer electrons from the electrode to an electroactive substance (substrate) rather than having the electrons transfer directly from the electrode to the substrate. Typically the mediator is easier to reduce than the substrate and creates an opportunity for chemoselectivity. Using a mediator can allow
3 for selectivity and control for the product in regards to stereochemistry, structure, and reaction mechanism. However, with all of these advantages and benefits related to electrochemistry there are some drawbacks.
There is an initial cost for the instruments and materials required for conducting electrochemistry. The best electrode materials in terms of durability and inertness frequently involve precious metals and thus increases costs.2 There must always be a source of electricity, which can be from either a building or a battery. Electrochemical reactions take place at the electrode/electrolyte phase boundary, which means special care must be taken in optimizing the space-time yield.3 This can be done by using electrodes with a large surface area (carbon felt, reticulated vitreous carbon, packed bed, or fluidized bed electrodes) or through a mediator system. The lack of knowledge or understanding of electrochemistry however, is perhaps the greatest hindrance for its utilization.
1.2 Direct vs. Indirect Method
There are two different methods used for conducting electrochemical reactions.
First is the direct method which transfers electrons directly from an electrode to a substrate, and vice versa for reversible reactions. Second is the indirect method which uses a mediator to irreversibly transfer electrons to or from a substrate in solution. An example of a reduction reaction for both methods can be seen in Figure 2, where M stands for mediator.
4
Figure 2: A generic direct and indirect irreversible reduction reaction
In the direct method the substrate is in direct contact with the electrode, which will either gain an electron (reduction) or lose an electron (oxidation). The most effective and versatile electroanalytical technique associated with the direct method, available for redox reactions, is cyclic voltammetry (CV).3 The main purpose of CV is to determine the redox potentials of a substrate which is used to guide electrolysis parameters.4 In CV, the voltage potential applied across the electrode-solution interface is scanned linearly from an initial value to a final value at a constant rate and then back to the initial value, rapidly scanning for reducible or oxidizable species. The scan in which the potential becomes increasingly negative is termed a negative scan, and is when reduction occurs. The scan in which the potential becomes increasingly positive is termed a positive scan, and is when oxidation occurs. The results are plotted in a current vs. potential curve called a cyclic voltammogram. An example of a generic reversible cyclic voltammogram is shown in Figure 3.
5
Figure 3: A general reversible cyclic voltammogram
The resulting cyclic voltammogram contains information about the behavior of a substrate under an applied potential, such as whether oxidation or reduction is even possible and if the electron transfer is reversible or irreversible.4 In Figure 3, during the scan from -1.10 to -2.00 V the applied potential becomes increasingly negative, causing a cathodic peak potential (Epc) of the oxidant to occur at about -1.60 V. The current then decreases as the solution surrounding the electrode is depleted of the oxidant due to its conversion to the reductant. The direction of the potential is then switched, scanning from -2.00 to -1.10 V. The potential becomes increasingly positive causing a anodic peak potential (Epa) of the reductant to occur at about -1.45 V. The current then increases once the solution surrounding the electrode is depleted of the reductant. The
6 redox potentials can then be used to set reaction parameters, specifically for bulk electrolysis (BE).
To test for electrochemical reversibility the following equation can be used
o when the reaction is carried out at 25 C: Ep = Epa-Epc = 0.058/n; where n is the number of electrons transferred.3 When the previous equation is true, the rate of reduction and the rate of oxidation are equal. The difference in peak potentials ( Ep) is independent of scan rate for reversible reactions, the potentials occur at the same voltage. When the scan rate is increased the current passed at reduction (ipa) and the current passed at oxidation (ipc) both increase in proportion. The values of ipa and ipc are similar in magnitude for reversible reactions. For chemical reversibility the peak current ratio
(ipc/ipa) is equal, meaning the amount of substrate reduced equals the amount of substrate oxidized. If the ratio of ipa to ipc is greater than or less than 1, the reaction is semi-reversible and is dependent on the scan rate.
CV also provides an opportunity to obtain evidence for redox catalysis that an electron transfer between a mediator and a substrate actually occurs.5 The current will further increase due to the return of the mediator to the original redox couple after it has removed an electron from the substrate. This additional current is referred to as a
“catalytic current” and is extremely useful when planning on conducting indirect electrolysis reactions. An example of a catalytic current can be seen in Figure 4.6
7
Figure 4: Cyclic voltammogram displaying a catalytic current; dashed line: mediator only, solid line: mediator with substrate
The solid line cyclic voltammogram was conducted on a solution containing both a substrate and a mediator, while the dashed line cyclic voltammogram was conducted on a solution containing only the mediator. It is clear that the cathodic peak current increases when the substrate is added indicating that an electron transfer is occurring between the mediator and the substrate. The anodic peak disappears in the solid line cyclic voltammogram demonstrating that the reaction of the substrate with the mediator is fast on the voltammetry time scale.6
Another technique is bulk electrolysis (BE), also called controlled potential coulometry, which can be conducted using either the direct or indirect method. In a BE experiment, the working electrode is held at a constant potential, relative to the
8 reference electrode, and the current is monitored over time.7 As the experiment progresses, the substrate is converted from its original oxidation state to a new oxidation state, either being reduced or oxidized. As the substrate is consumed, the current decreases, approaching zero when the conversion nears completion. Once the BE reaction is complete, the product is extracted, purified, and analyzed by routine spectroscopic techniques such as NMR, GC-MS, and IR.
In the indirect electrolysis method, a mediator is used to transfer an electron from the electrode to a compound during a reduction reaction, or to transfer an electron from a compound to the electrode during an oxidation reaction. The heterogeneous reaction between the substrate and the electrode is therefore replaced by a homogeneous redox reaction in solution between the substrate and a regenerable, electrochemically active mediator.3 With a mediator the diffusion of the substrate towards the electrode is not the rate determining step of the overall process, and therefore the effect of low concentrations does not impair the whole reaction pathway.2
Compared to direct electrolysis, overvoltages may be reduced and corrosion of electrode surfaces may be avoided by using the indirect method since a lower voltage is used.3 A mediator allows for more control over the reaction pathway and the product since the structure of the mediator can vary greatly. Through chemoselectivity the mediator can potentially determine or favor the stereochemistry of the electrolysis product, which will be further investigated in this thesis.
The direct and indirect electrolysis methods can be performed two different ways, either by a constant current electrolysis or a controlled potential electrolysis.8 In a
9 constant current reaction the flow of current through the electrochemical cell is held at a constant value while the potentials of the electrodes are allowed to vary. The advantage of a constant current reaction is that the reaction setup is very simple and all electroactive species will be reduced or oxidized. The disadvantage is a decrease in chemoselectivity.
A controlled potential electrolysis is how BE reactions are conducted. During this reaction a reference electrode is added and the potential of the working electrode is held constant relative to the reference electrode. Therefore only substrates having a reduction/oxidation potential equal to or lower than that set will reduce/oxidize.
Reactions are highly selective and since the potential does not increase as the substrate is consumed selectivity is maintained throughout the reaction.8 A drawback to the controlled potential method is it can be time consuming to push the reaction to completion. Also, the setup is slightly more complex, one must use a third electrode and a potentiostat.
1.3 General Experimental Set-up and Instruments
The voltammetry (CV) and electrolysis (BE) reactions consist of an electrolytic substrate, multiple electrodes, an electrolyte, solvent, and various additives. Both techniques take place in an electrochemical reactor, commonly referred to as the cell.
The cell consists of a glass compartment and a Teflon stopper with multiple holes, one for each electrode (working, auxiliary, and reference), and an inert gas purge. Solutions for both CV and BE must be purged to remove any dissolved oxygen, since the reduction of oxygen can be observed in the CV plot and affect the BE reaction.
10
Common solvents include methanol, acetic acid, acetonitrile, dichloromethane, tetrahydrofuran, or water.8 The supporting electrolytes commonly used are tetraethylammonium tosylate (Et4NOTs), lithium perchlorate (LiClO4), tetra-n- butylammonium tetrafluoroborate (nBu4NBF4), or tetra-n-butylammonium hexafluorophosphate (nBu4NPF6). The supporting electrolyte contains free ions which distributes the electric current. Various additives may also be used, such as a proton donor in BE reactions. A common proton donor toward electrochemically generated carbonanion intermediates is malonic ester which is electroinactive even at fairly negative potentials.9 The cell is placed on a cell stand which has the electrode connections, nitrogen line, and a magnetic stirrer motor. A standard set-up of the cell and electrodes for conducting CV and BE on a cell stand and the equipment used throughout this thesis can be seen in Figure 5 (CV) and Figure 6 (BE).
Figure 5: CV cell on cell stand and equipment
11
Figure 6: BE cell on cell stand and equipment
The three electrode system consists of a working electrode, an auxiliary or counter electrode, and a reference electrode. There are a few differences among the electrodes depending upon whether conducting CV or BE. A larger working electrode is used for BE reactions than for CV, which allows for a more effective electrode to electrolyte solution ratio. For BE reactions the auxiliary electrode is typically separated from the working electrode and electrolyte solution by a semipermeable barrier (glass frit) to permit electrical current but not mass transport.3 This isolation prevents any by- products being formed which could contaminate or interfere with the reaction occurring at the working electrode.7 Separation of the auxiliary electrode is not necessary for CV since only redox potentials are being measured. The same reference electrode can be used for both CV and BE reactions.
12
The working electrode is where the electron transfer actually occurs. Depending upon whether the reaction is reduction or oxidation, the working electrode can be either cathodic or anodic. The potential of the working electrode is measured against a known reference electrode potential. Common types of working electrodes include inert materials such as gold, silver, platinum, carbon, or mercury. The applied current is passed between the working and auxiliary electrode.7 The potential of the auxiliary electrode is adjusted to balance the reaction occurring at the working electrode, which in turn keeps the reference electrode potential stable. The auxiliary electrode must be included to complete the electrical current and can be cathodic for oxidation reactions or anodic for reduction reactions. Auxiliary electrodes are usually made from inert materials such as platinum, gold, or carbon.
The reference electrode has a set known potential to which the working electrode is measured against, therefore allowing the potential of the working electrode to be determined. The high stability of the reference electrode potential is usually reached by a redox system with constant (buffered or saturated) concentrations of each species in the redox reaction.7 A silver/silver chloride electrode is commonly used as the reference electrode. There is a reaction occurring inside the electrode between the silver metal (Ag) and its salt, silver chloride (AgCl). The electrode contains a silver wire coated with silver chloride in a saturated potassium chloride and saturated silver chloride solution with a porous frit at the bottom. Figure 7 shows the redox reaction occurring inside a Ag/AgCl reference electrode.
13
Figure 7: Half and overall reactions for a silver/silver chloride reference electrode
In addition to the previously discussed materials and equipment, an electrochemical analyzer is used for electrochemical measurements and to control various parameters. The analyzer contains a fast digital function generator, high speed data acquisition circuitry, a potentiostat, and a galvanostat. The potentiostat is used to select any potential relative to a reference electrode and to control the current during a constant current experiment.10 A galvanostat can supply and measure a wide range of currents and keeps the current constant throughout the electrolysis.
1.4 Examples of Specific Electrochemical Reactions
There is a wide diversity in the use and applications of electrolysis in organic synthesis. The reactions can be grouped into following classifications: (1) cathodic reductions; (2) cathodic cyclizations; (3) anodic oxidations; (4) anodic cyclizations.4
There are many examples for each classification, however only a few examples will be discussed per classification to illustrate electrochemical reactions in general, practical applications, and recent advances.
14
1.4.1 Cathodic Reduction Reactions
Electrochemical reductions do not require stoichiometric metal or metal hydride sources which has strong economic and environmental implications.4 One example of how electrochemical methodology can be substituted for metal reagents, specifically tin, is from Hudlicky and coworkers in 1999.11 They demonstrated that the direct cathodic reduction of a vinyl bromide could be utilized in inositol synthons. First, their focus was to produce inositol intermediates, which could later be incorporated into the synthesis of inositols. Various structures of inositol are used in a number of biological pathways including insulin signal transduction and gene expression.12 A general structure for inositol 1 can be seen in Figure 8, which has 9 possible stereoisomers.
OH HO OH
HO OH OH
1
Figure 8: General structure for inositol
Scheme 1 displays the cathodic reduction of a vinyl bromide 2 used in an inositol intermediate 3 synthesis.4,11
15
-3.2 V Br Hg pool cathode H OH O Pt anode O HO OH
+ HO O Ag/Ag reference HO O HO OH OH OH nBu4NBF4/MeOH OH Divided cell 2 3 4 62% Scheme 1: Cathodic reduction of vinyl bromide
Starting with 2, a current potential of -3.2 V was applied for the synthesis of an inositol intermediate, 3. A mercury pool cathode was used which sat at the bottom of the cell and was connected to the potentiostat via a copper wire in a glass tube. A platinum foil anode in a fritted disk chamber was used, therefore making a divided cell. The reference
+ electrode was a Ag/Ag electrode, while nBu4NBF4 was used as the supporting electrolyte and methanol the solvent. The electroreduction of the brominated precursor
2 resulted in a 62% yield of the product 3, while an 80% yield was obtained from using
1.5 equivalents of tin. The product 3 can undergo further reactions to eventually produce an inositol, 4. This example from Hudlicky shows how it is possible to replace metal reagents entirely with comparable yields, although electrochemistry can also be used in conjunction with catalytic quantities of metal additives to retain desired reactivity profile of a particular metal.
Another cathodic reduction reaction can be seen from Durandetti and coworkers in 2001, who reported an electrochemical variant of the Nozaki-Hiyama-Kishi (NHK) reaction and is an excellent example of integrating electrochemical methods into preexisting reaction manifolds.4 A NHK coupling reaction is generally achieved by
CrCl2 and a catalytic amount of NiCl2 to mediate various insertion, transmetallation,
16 and addition steps. This reaction has been widely applied in organic synthesis and combines some rather unique features, such as high aldehyde chemoselectivity.13 Some reactions use up to 400 mol% of chromium, requiring large amounts of CrCl2, which is toxic, air and moisture sensitive, and expensive. Durandetti generated the ions CrII and
NiII electrochemically through oxidation of a commercially available sacrificial stainless steel anode rather than from CrCl2 and NiCl2. The NHK coupling reaction was performed on aromatic aldehydes and aryl halides containing various electron- withdrawing and electron-donating groups, shown in Scheme 2.
Fe/Cr/Ni anode Ni sponge cathode OH O X bipy: FG N N H + A A DMF, nBu4NBF4 FG 0.15-0.25 A 5 6 (constant current) 7 50-80% X = Br, Cl FG = OMe, CO2Me, CF3, etc. A = H, CF , CO Me 3 2
Scheme 2: Electrochemical NHK coupling between aromatic aldehydes and aryl halides
The amount of CrII and NiII generated during pre-electrolysis was determined by weighing the anode before and after the oxidation process, which resulted in 0.150 g of the anode being consumed.4 After the pre-electrolysis was completed, the stainless steel anode was replaced with an iron rod and a constant current density of 0.15 to 0.25 A was applied to keep the chromium content of the solution at a minimum. The reaction
17 had moderate to good yields and more importantly the catalytic amount of CrII required was only 7%. Thus, avoiding the use of CrCl2 and instead releasing chromium salts by oxidation of the anode.14 This inexpensive catalytic variant of NHK couplings could even have applications in industrial processes. For example, chromium catalysts are important in ethylene polymerization which make up plastics and would greatly benefit from using an electrochemistry method.15
1.4.2 Electroreductive (Cathodic) Cyclization Reactions
Electroreductive cyclization (ERC) reactions are becoming widely employed as a versatile means for intramolecular anionic cyclizations.4 For ERC reactions, cyclization occurs onto a carbonyl unit. One of the unique characteristics of cathodic reductions is that some can be classified as umpolung reactions; any transformation that effects a reversal of polarity in a functional group, changing a normally nucleophilic site into an electrophilic one, and vice versa. In 1988 Little reported the cathodic reduction of , -unsaturated esters to undergo an umpolung transformation that creates a nucleophilic -carbon.16 This nucleophilic -carbon was used to facilitate ring-closing reactions on various ketones and aldehydes. The direct reductive cyclization reactions of , -unsaturated esters can be seen in Scheme 3.
18
OH HO
CO2CH3 CO CH Hg pool cathode 2 3 Pt anode 9, 72% 10, 70% R O Et4NOTs (R = H, n = 2) CO2CH3 (R = CH3, n = 1) n SCE reference OH CO2CH3 10% aq. ACN HO 8 -2.1 to -2.2 V CO2CH3 R = H, CH3, cyclopentane n = 0, 1, 2 11, 76% 12, 79% (R = H, n = 1) (R = cyclopentane, n = 0)
Scheme 3: Reductive cyclizations of α,β-unsaturated esters
The electrolysis of 8 was carried out with a controlled potential in 10% aqueous acetonitrile and Et4NOTs as the supporting electrolyte. A mercury pool cathode, a platnium anode, and a saturated calomel electrode (SCE) as the reference electrode were used. The results of the electrolysis reactions are summarized in Table 1.16
Compound Yield (%) cis : trans 9 72 1 : 1.8 10 70 1 : 1.4 11 76 1 : 5.1 12 79 1 : 11.4 Table 1: Results of the reductive cyclizations of α,β-unsaturated esters
Good yields were obtained for each product (9, 10, 11, 12) (70-79%) and the degree of stereoselectivity varies from very poor (1 : 1.4) to being synthetically useful (1 : 11.4).
19
That same year Little applied the results from the ERC reactions toward the total synthesis of the marine natural product Ambliol-A.16 Scheme 4 displays the retrosynthetic plan Little and his coworkers attempted.
OH ERC OH COCH3 CO CH CO2CH3 2 3
O 13 14a 15 Ambliol-A
Scheme 4: Retrosynthetic reaction plan for the synthesis of Ambliol-A
Unfortunately the reaction was unsuccessful at the time. Rather than forming predominately the trans product 14a, the reaction favored the ester and hydroxyl groups cis to each other 14b at a ratio of 2.9:1, Scheme 5.16
COCH OH OH 3 +e- CO2CH3 CO2CH3 + CO2CH3 70% c/t = 2.9:1 15 14a 14b
Scheme 5: ERC of keto enoate in the synthesis of Ambliol-A
There appeared to be a kinetic preference for the formation of 14b over 14a, however the reaction may still be possible with additional studies.16 This example of an ERC reaction shows the uniqueness of electrochemical reactions in regards to the ability of umpolung reactions and selectivity. If one could find a set of conditions which would
20 lead to products selectivity (stereo, regio) efficiently and in a predictable manner, then the results may be very useful in the application to organic synthesis.
Soon after Little and coworkers published their work on ERC reactions, they published the formal total synthesis of quadrone 21 in 1990, which can be seen in
Scheme 6.4
O O CO2CH3 Cathodic reduction OH CO CH O H Hg pool cathode 2 3 + SCE reference nBu4NBr, CH3CN 89% 17 16 major 18 minor
5 steps
NC H O CN Hg pool cathode OTBDPS O HO OTBDPS -2.4 V vs. SCE O 7 steps H CH (CO CH ) H 2 2 3 2 nBu NBr, CH CN 20 4 3 90% CHO 21 19 quadrone
Scheme 6: Synthesis of quadrone utilizing two electroreductive cyclization reactions
Quadrone is an antitumor agent originally produced by a type of mold, Aspergillus terreus.17 The approach from Little uses two ERCs in the synthesis of quadrone. The first ERC is the reduction of the -unsaturated ester 16 to yield a mixture of 17 and 18 in an 89% yield.4 In this step a mercury pool cathode and a SCE as the reference electrode were used. The supporting electrolyte was nBu4NBr and acetonitrile was the
21 solvent. After 5 steps, 19 was produced and underwent an ERC, utilizing the - unsaturated nitrile, resulting in 20 with a 90% yield. The reaction was carried out in the same manner as the previous ERC step, except dimethyl malonate (CH2(CO2CH3)2) was used as a proton donor. After 7 additional steps, quadrone 21 was obtained. This is an excellent example of how ERCs can be applied toward total synthesis and demonstrates the synthetic utility of electrochemical key steps.
1.4.3 Anodic Oxidation Reactions
The anodic oxidation of organic molecules has been developed significantly over the past few decades. The advantages of this technique lie in its utility for selectively oxidizing functional groups, generating highly reactive intermediates, and reversing the polarity of nucleophiles.8 One of the best known anodic oxidation reactions is the Kolbe electrolysis. The Kolbe electrolysis is the electrochemical decarboxylation of an organic acid to generate a carbon-centered radical, which can undergo dimerization, addition to alkenes, or facilitate radical chain reactions.4 A general Kolbe electrolysis reaction can be seen in Scheme 7.
Scheme 7: A Kolbe electrolysis reaction
22
Both intermolecular and intramolecular coupling reactions are known.8 More recent examples using the Kolbe electrolysis include the synthesis of heterocycles, perhydroazulenes, and fatty acids, and in key steps for the synthesis of bicyclic -lactam
(+)-PS-5 and L-xylonolactone. Structures of the specific products synthesized using the
Kolbe electrolysis previously mentioned can be seen in Figure 9. The bond produced by the Kolbe electrolysis for compound 32 is not evident after the additional steps.
Heterocycles Perhydroazulenes Bicyclic -lactam (+)-PS-5 (produced after 4 additional steps) R O 2 H CH3 R N N O CO2H R1OC 32 27 29
R1 = H, CH3 Fatty Acids L-xylonolactone R2 = CH3, C5H11, (CH ) CO CH 2 4 2 3 OH O O MeO2C O H3C(H2C)7 CO2Me O O OMe OEt 30 33 AcO O O 28 MeO 13
31
Figure 9: Products from various Kolbe electrolysis reactions (arrows indicate key bonds formed)
Another well-known anodic electrochemical reaction is the Shono oxidation.
The Shono oxidation generates N-acyliminum ions from the oxidation of amides and
23 has been applied to the total synthesis of natural products, asymmetric building blocks for organic synthesis, and many other applications in medicinal chemistry.4 The oxidation of amides to N-acyliminum ions can be performed in two ways: direct oxidation and indirect oxidation.
The direct oxidation is the true Shono oxidation and can be seen in Scheme 8.4
O O O Anodic O R R -e-, -H+ R MeOH R N Oxidation N N N
- MeOH, -e H3CO 34 35 36 37
Scheme 8: The direct Shono oxidation
The N-acyliminum ion 36 is generated by the electrochemical oxidation of the amide
34, followed by nucleophilic trapping, which is generally a protic solvent, resulting in
37. The Shono oxidation via oxidation of an electrolyte can be seen in Scheme 9.4
O O O Anodic H O H Oxidation X H H N N -HX N Nu-H N
- R4NX, -2 e Nu "X+" 38 39 40 41
Scheme 9: The indirect Shono oxidation
The indirect Shono oxidation generates N-acyliminum ions 40 electrochemically through the oxidation of a halogenated electrolyte (R4NX) to form the highly reactive
24
“X+” species. This species in turn reacts with the amide nitrogen forming intermediate
39 and then through loss of HX forms 40.
1.4.4 Electrooxidative (Anodic) Cyclization Reactions
Electrooxidative cyclization (EOC) reactions have been applied to the synthesis of complex natural products and are capable of being incorporated into everyday synthetic transformations.4 EOCs are all based on the same general principle: electrooxidation to form a radical-cation, followed by intramolecular trapping of a nucleophile. These reactions are unique in that they take place in highly nucleophilic solvents, such as isopropanol and methanol. Common functional groups involved in
EOCs include electron-rich alkyl enol ethers, silyl enol ethers, ketene dithioacetals, and phenols. Nucleophiles can be electron-rich aryl- or hetero-aryl rings, enol ethers, or hydroxyls.
In 1995 Schafer and coworkers applied the Kolbe electrolysis to the synthesis of complex organic molecules notoriously difficult to make, perhydroazulenes.4 Scheme
10 displays the reaction conditions used to initiate radical cyclization.
Pt anode O Steel cathode O O 5 eq. CH3CO2H
CO2H MeOH 5% neutralization - + 42 -2e , -2H , -2CO2 43 44 72% overall yield
Scheme 10: Kolbe electrolysis used in the synthesis of perhydroazulenes
25
Electrochemical oxidation took place in methanol with a platinum anode and steel cathode which initiated the radical decarboxylation of 42 that led to the cyclized perhydroazulenes 43 and 44. Five equivalents of acetic acid were used which also underwent radical decarboxylation to form a methyl radical that coupled to the radical from the cyclization. The electrolysis resulted in a 72% overall yield and produced a
1:1.4 cis to trans mixture of the final product.
In 2001, Moeller applied a previously reported methodology for forming tetrahydrofuran (THF) containing molecules in the synthesis of the natural product (+)- linalool oxide 47.4,8 Linalool has a pine or woody scent and is commonly used as a fragrant or flavoring agent. The synthesis of (+)-linalool oxide 47 can been seen in
Scheme 11.
MeO RVC anode Pt cathode MeO OMe H 30% MeOH/THF 2,6-lutidine Two Steps OH O O H 0.03M Et4NOTs undivided cell H OH H OH OH 8mA; 2F/mol 80% c/t = 1/7 45 46 47 (+)-linalool oxide
Scheme 11: The use of an anodic oxidation in the total synthesis of (+)-linalool oxide
The methoxy enol ether 45 was electrochemically oxidized to generate the dimethoxy cyclized acetal 46. The electrolysis was carried out in methanol with an RVC anode and a Pt cathode using Et4NOTs as the supporting electrolyte. 2,6-lutidine was necessary to
26 neutralize the generated acid. 2 F/mol was consumed to produce the desired trans orientation of the THF containing molecule 46 as the major isomer. (+)-linalool oxide
47 was produced after two additional steps.
1.5 Background on Thesis Project
Baizer and his coworkers pioneered the exploration, development, and use of electrohydrodimerization reactions.14 The process is initiated electrochemically and leads to dimerization of electron deficient alkenes. The initial reduction leads to an umpolung, or charge reversal, where the polarity of the -carbon changes from electrophilic to nucleophilic. In the mid 1960s Baizer was successful in the electrohydrodimerization of acrylonitrile 48 helping produce one of the most commonly used nylons in the textile and plastic industries, nylon 6,6 50, Scheme 12.
O 2 e-, 2 HA H 2 CN NC N CN N H n 48 49 O 50 Nylon 6,6
Scheme 12: Electrohydrodimerization of acrylonitrile
The reaction resulted in a new sigma bond between two -carbons. After a few more steps nylon 6,6 50 is produced. This electrolytic reductive coupling was then extended to intramolecular reactions or electrohydrocyclization (EHC) reactions.18 The
-carbons are bonded to an electron acceptor (aldehyde, ketone, ester) which leads to cyclization. EHC is very similar to ERC reactions except cyclization occurs between
27 two -carbons rather than between a carbonyl group and a -carbon. Potentially, EHC reactions can be applied to existing organic chemistry reactions or create a completely new synthetic route for cyclized compounds. Scheme 13 displays a general EHC reaction.
Z +2e- , +2HA Z Z Z 51 52
Scheme 13: General EHC reaction
The first EHC reactions were conducted by Anderson, Baizer, Petrovich.18 They successfully synthesized three-, four-, five-, six-membered carbocyclic rings by - coupling from bisactivated olefins. Scheme 14 shows one of the many EHC reactions they performed.
Hg cathode Pt anode CO Et CO2Et CO2Et 2 Et NOTs + 4 CO Et CO Et CO2Et 2 2 SCE reference 53 12% aq. ACN 54 55 -1.9 V
Scheme 14: One of the first EHC reactions
The EHC substrate 53 (40 g) was electrolyzed at -1.91 to -1.96 V (vs. SCE) using
19 aqueous acetonitrile and the supporting electrolyte Et4NOTs. The catholyte was diluted with water and extracted with ether. Distillation of the ether residue followed by
28 vapor phase chromatography showed the presence of 5.3 g of cis BE product 54 and
13.4 g of trans BE product 55, which is a 1:2.5 c/t ratio. While there was slight stereoselectivity for the trans isomer, this reaction was eventually applied to mediated electrolysis reactions to try increase the stereoselectivity.5
Mediated EHC reactions can lead to further advancements in organic synthesis in regards to isomeric compounds by possibly favoring one isomer over another. The first electrochemically mediated reactions were conducted by Utley and published in
1995.20 Utley and his coworkers generated Diels-Alder adducts of o-quinodimethanes by the cathodic reduction of dibromides in the presence of maleic anhydride, Scheme
15.
O O R1 R1 DMF, Et NBr Br 4 + O O Br 2 Faraday R2 O R2 O 56 58 57
Scheme 15: One of the first electrochemically mediated reactions
The process was initiated at the potential for the anhydride 57, which was about 400 mV easier to reduce than the dibromide 56. This is most likely due to redox catalysis, with the anhydride having a dual role as a mediator and a dienophile.
The findings from Utley were eventually applied to EHC reactions in 2005 by
Miranda.5 Miranda, Wade, and Little investigated cyclization reactions using nickel(II) salen as a mediator. Ni(II) salen was chosen as the mediator since its redox behavior is
29 well defined and its utility in organic synthesis is well established. After redox catalysis was confirmed, an ERC and an EHC reaction was performed, Scheme 16.
N N O Ni O 60 6 mol % Ni(II)[salen] OH O nBu NBr, CH CN 4 3 CO2CH3 CO2CH3 2 eq. CH2(CO2CH3)2 59 -2.1 V (Ag/AgNO3) 61 72% c/t = 1/1.26 Epc = -2.6 V RVC cathode
6 mol % Ni(II)[salen] 60 CO CH CO2CH3 2 3 nBu NBr, CH CN 4 3 CO2CH3 CO2CH3 2 eq. CH2(CO2CH3)2 62 -2.1 V (Ag/AgNO3) 63 73% c/t = 1/3.1 E = -2.9 V RVC cathode pc
Scheme 16: Nickel(II) salen mediated ERC (top) and EHC (bottom) reactions
Both ERC and EHC reactions proved to be successful with fairly good yields and favored the trans isomer.5 The reactions used 6 mol % of Ni(II) salen 60, with a
RVC cathode, a platinum anode, and dimethyl malonate as a proton donor. Acetonitrile was the solvent and nBu4NBr was used as the supporting electrolyte. The reactions were conducted at -2.1 V which is a lower potential than the potential required for direct electrolysis. The ERC substrate reduces directly at -2.6 V and the EHC substrate reduces directly at -2.9 V. While cyclization occurred, it was uncertain from these reactions how the electron was transferred between the mediator and the substrate.
30
The reduced mediator can be either a metal-centered ion 64 or a ligand-centered ion 65, Figure 10. The electron transfer from the mediator can then occur as an outer sphere or inner sphere electron transfer.
N N N N Ni Ni O (I) O O (II) O 64 65
Figure 10: Reduced Ni(II) salen
For an outer sphere electron transfer, the electron transfers from the working electrode to the mediator forming either a metal-centered ion or a ligand-centered ion. The electron then travels through space to the substrate. The other method is an inner sphere electron transfer, where the electron is transferred through a covalent linkage between a ligand-centered ion and the substrate. This mechanism is less entropically favorable than the outer sphere electron transfer since the two compounds must come together.
Miranda, Wade, and Little conducted another ERC reaction with a slightly modified
Ni(II) salen 66 to further examine the electron transfer method. Scheme 17 shows the
ERC electrolysis with the modified mediator.5
31
N N Ni O O O CHO 66 CO2CH3 starting 6 mol % + CO2CH3 material, 59
59 nBu4NBr, CH3CN 67 2 eq. CH2(CO2CH3)2 -2.1 V (Ag/AgNO3) 95% mass balance
Scheme 17: Modified Ni(II) salen in an ERC reaction
With the modified mediator 66, no original ERC products were formed. Only the starting material 59 and a five-membered ring 67 were produced at a 1.56:1 ratio with a 95% mass balance yield.5 These results made it clear that the mediator is facilitating cyclization and supports an inner sphere electron transfer mechanism.
Therefore, the site of reactivity between the substrate and the mediator is most likely the imine carbon. The modified mediator was too crowded to allow conjugated addition to occur but was still able to allow an acid-base reaction. Due to the results from the reaction in Scheme 17 two inner sphere electron transfer pathways for an electrolysis reaction with Ni(II) salen were proposed.
The first possible pathway has the substrate cyclizing on its own, after it breaks free from the mediator, Scheme 18.
32
H3CO2C
O H3CO2C CO2CH3 OCH3 O CO2CH3 N N OCH3 Ni O O 69 70 N N Ni 68 O O 60
Scheme 18: First possible pathway for EHC ring closure
In the first pathway, the substrate is reduced by the Ni(II) salen mediator forming a complex together 68. The substrate then breaks off of the mediator forming a radical anion 69. The negative charge shifts between the oxygen and the -carbon which gains a proton from the solution. The -carbon then becomes a carbanion through the addition of another electron and attacks the other -carbon cyclizing on its own to form the final product 70. If this is indeed the favored pathway then it appears that the mediator would not play a role in the stereochemistry of the final product.
The second possible pathway has the electron transfer and cyclization occurring concertedly, Scheme 19.
H3CO2C
O CHCO2CH3 OCH CO2CH3 3 (a) HA CO CH CH2CO2CH3 2 3 N N N N Ni (b) +e- Ni 70 O O O O N N 68 71 Ni O O 60
Scheme 19: Second possible pathway for EHC ring closure
33
The pathway begins in the same way as the first pathway, however once the complex 68 is formed the electron transfer and cyclization occur at the same time. If this is the actual pathway, then the mediator can possibly affect the stereochemistry of the BE product. This is where Miranda, Wade, and Little stopped in their investigation in mediated stereoselective electrolysis reactions and is where this thesis project begins.
1.6 Thesis Objective
Currently it is uncertain how exactly Ni(II) salen mediators are involved during
EHC reactions. Depending upon the reaction mechanism and how the electron is transferred, the mediator may or may not be able to affect the stereochemistry of the final product. My project will therefore examine various Ni(II) salen mediators during
EHC reactions of an , -unsaturated diethyl ester, focusing on controlling and selecting the stereochemistry of the final product. The results may offer a more efficient and effective way to select for cis or trans products through using electrochemistry and can then be applied to other diastereoselective organic chemistry reactions.
Electrolysis reactions will be carried out with multiple slightly varied mediators.
To see what has the largest influence on stereochemistry, mediators will vary in both bridge sterics and chirality. The BE product will be analyzed through NMR and GC to determine the cis to trans ratio. After a ratio is calculated for each electrolysis reaction, an overall conclusion will be made on the effects each mediator had on the stereochemistry of the final product and what is the most plausible electron transfer
34 pathway. Computational chemistry will be used to support and confirm identification of the cis and trans BE product.
1.6.1 Specific Aims
A. Synthesize multiple Ni(II) salen mediators, Figure 11.
N N N N Ni Ni O O O O 60 72
N N N N N N Ni Ni Ni O O O O O O
73 74 75
Figure 11: Ni(II) salen mediators
These mediators were chosen based on background research and scientific reasoning.
Ni(II) salen 60 was used as a control, since it has been used before and is the basic structure for the remaining mediators.5 Next, tert-butyl groups were added 72 to the aromatic rings which would heavily favor an interaction between the EHC substrate and the proposed site of reactivity on the mediator, the carbon in the imine. The bulkiness of the tert-butyl groups influences the redox reactivity and overall catalytic properties.21 A phenyl group was used as the bridge 73 to increase conjugation and stabilize a ligand- centered radical anion. Last, two chiral mediators 74, 75 were used to determine whether the chirality of the mediator can favor one isomer over the other. They are
35 enantiomers and can have different electrochemical properties in regards to redox behavior and the electron transfer mechanism.
B. Synthesize the EHC substrate 53 for electrolysis reactions, Figure 12.
CO2Et CO2Et
53
Figure 12: EHC substrate
This substrate was chosen based on literature data. A very similar compound has already been reported to cyclize into a 6-membered ring through direct and mediated electrolysis.5, 19 The compound 53 contains alkenes bonded to electron acceptors which is crucial for successful EHC reactions.
C. Run CV on all mediators and EHC substrate 53.
Conducting CV on all of the mediators and the EHC substrate is essential to determine the redox behavior and potentials. The voltage found to reduce each mediator will be used to set the potential for the BE reactions. Other CV experiments will be conducted to investigate electron transfer reversibility and redox catalysis.
D. Run BE reactions with EHC substrate and each mediator.
E. Analyze the product, Figure 13, from BE reactions through NMR and GC to determine cis to trans ratios. Confirm NMR assignments of the cis 54 and trans 55 BE product with calculated chemical shifts.
36
CO2Et CO2Et CO2Et CO2Et
54 55
Figure 13: Cis and trans BE product
Once the tertiary carbons are identified, one can roughly determine which isomer is the major and minor based on relative peak height. Then through GC analysis the exact ratio of the two diastereomers can be determined.
37
Chapter 2
RESULTS AND DISCUSSION
2.1 Synthesis of Mediators
Five mediators were synthesized for the use in bulk electrolysis (BE) reactions.
The mediators were chosen based on favoring either the cis or trans cyclized BE product. The five mediators synthesized were Ni(II) salen, 1,2-ethylenediamine Ni(II) di-tert-butyl salen, 1,2-phenylenediamine Ni(II) di-tert-butyl salen, (R,R)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen, and (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen. For both 1,2-ethylenediamine Ni(II) di-tert-butyl salen and 1,2- phenylenediamine Ni(II) di-tert-butyl salen the ligand had to be synthesized, while for
(R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen and (S,S)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen the ligand was able to be purchased.
Ni(II) salen 60 was synthesized previously by other students, Figure 14.22
N N Ni O O
60
Figure 14: Nickel(II) salen
38
Ni(II) salen is the parent compound for the remaining mediators and has already been successful in EHC reactions.5 The mediator was analyzed by 1H NMR and IR to ensure purity (see Appendix A).
The 1,2-ethylenediamine di-tert-butyl ligand 78 was synthesized by refluxing ethylenediamine 76 and 3,5-di-tert-butylsalicylaldehyde 77 in 95% ethanol, Scheme 20.
O
H N N K2CO3, 95% EtOH H N NH 2 2 + 2 OH OH HO 76 reflux, 2 h 87% yield 78 77
Scheme 20: Synthesis of 1,2-ethylenediamine di-tert-butyl ligand
Ethylenediamine 76 was dissolved in water and added to it potassium carbonate and ethanol. The solution was heated to reflux, where 77 in 95% ethanol was added dropwise. After 2 hours the solution was cooled to 0oC where bright yellow crystals formed. The crystals were isolated by vacuum filtration to yield 78 at an 87% yield. The ligand was then metallated with nickel by refluxing with Ni(II) acetate in absolute ethanol, Scheme 21.
N N N N Ni(II) Acetate, abs. EtOH Ni OH HO O O reflux, 1 h 78 100% yield 72
Scheme 21: Synthesis of 1,2-ethylenediamine Ni(II) di-tert-butyl salen
39
After refluxing for 1 hour the solution was cooled to room temperature where dark yellow crystals formed. The crystals were isolated by vacuum filtration to yield 72 at an
100% yield. 1,2-ethylenediamine Ni(II) di-tert-butyl salen 72 has added tert-butyl groups which will hopefully favor a reaction at the proposed site of reactivity, the imine carbon.
The 1,2-phenylenediamine di-tert-butyl ligand 80 was synthesized by refluxing o-phenylenediamine 79 and 77 in 95% ethanol, Scheme 22.
O
H K2CO3, 95% EtOH N N + 2 OH H2N NH2 reflux, 2 h OH HO 79 69% yield 80 77
Scheme 22: Synthesis of 1,2-phenylenediamine di-tert-butyl ligand
O-phenylenediamine 79 was dissolved in water and added to it potassium carbonate and ethanol. The solution was heated to reflux, where 77 in 95% ethanol was added dropwise. After 2 hours the solution was cooled to 0oC where bright yellow crystals formed. The crystals were isolated by vacuum filtration to yield 80 at a 69% yield. The ligand was then metallated with nickel by refluxing with Ni(II) acetate in absolute ethanol, Scheme 23.
40
N N Ni(II) Acetate, abs. EtOH N N Ni OH HO reflux, 1 h O O 43% yield 80 73
Scheme 23: Synthesis of 1,2-phenylenediamine Ni(II) di-tert-butyl salen
After refluxing for 1 hour the solution was cooled to room temperature where brown- red crystals formed. The crystals were isolated by vacuum filtration to yield 1,2- phenylenediamine Ni(II) di-tert-butyl salen 73 at a 43% yield. In addition to the tert- butyl groups, the phenyl bridge can stabilize a ligand-centered radical anion.
(R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen 74 was synthesized by refluxing (R,R)-(-)-N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine 81 with Ni(II) acetate in absolute ethanol, Scheme 24.
N N Ni(II) Acetate, abs. EtOH N N Ni OH HO reflux, 1 h O O 100% yield 81 74
Scheme 24: Synthesis of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
After refluxing for 1 hour the solution was cooled to room temperature where dark yellow crystals formed. The crystals were isolated by vacuum filtration to yield 74 at an
100% yield. 74 is chiral and will help determine whether or not the stereochemistry of the mediator influences the stereochemistry of the BE product.
41
(S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen 75 was synthesized by refluxing (S,S)-(+)-N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine 82 with Ni(II) acetate in abs. ethanol, Scheme 25.
N N Ni(II) Acetate, abs. EtOH N N Ni OH HO reflux, 1 h O O 93% yield 82 75
Scheme 25: Synthesis of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
After refluxing for 1 hour the solution was cooled to room temperature where dark yellow crystals formed. The crystals were isolated by vacuum filtration to yield 75 at a
93% yield. 75 is the enantiomer of the previous mediator 74 and may have different effects on the BE reaction.
All of the mediators, except (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen, have been synthesized previously and spectra data matched literature values.
(S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen was fully characterized. Spectra for all of the mediators is shown in the appendices.
2.2 Synthesis of EHC Substrate
The EHC substrate, deca-2,8-dienedioic acid diethyl ester, was synthesized by two different procedures. The first procedure used the Swern oxidation followed by the
Horner-Wadsworth-Emmons (HWE) olefination.23, 24 This method worked well a few
42 times, but usually yields were either very low or none. On most occasions the excess
DMSO used in the Swern reaction was unable to be completely removed which seemed to inhibit the HWE reaction to occur properly, therefore a new procedure was devised.
The second procedure used the Parikh-Doering oxidation and in situ a stabilized Wittig reaction.25, 26 This method worked consistently and resulted in much higher yields than the first procedure.
The Swern oxidation produced hexanedial 84 from 1,6-hexanediol 83 using oxalyl chloride, DMSO, and TEA in DCM, Scheme 26.
oxalyl chloride DMSO O HO TEA H OH H O 83 DCM, -78oC 84 19-22 h 80% yield
Scheme 26: Synthesis of hexanedial (Procedure 1)
Oxalyl chloride was added to anhydrous DCM at -78oC, followed by the addition of
DMSO, 1,6-hexanediol 83 dissolved in DCM, and TEA. The solution stirred overnight.
The reaction was quenched and the organic layer was washed and dried. The solvent was removed by rotary evaporation to yield the crude product 84 at an 80% yield. One of the by-products from the Swern oxidation is dimethyl sulfide which has an unpleasant odor and special care must be taken to minimize inhalation. Hexanedial 84 was used crude in the next step; the HWE olefination. Multiple attempts were made to
43 further purify the aldehyde and remove the excess DMSO by flash chromatography, however yields were very low and the DMSO was still not removed. There was one occasion without DMSO in the crude product and the HWE reaction was a success. It is uncertain what was done differently that allowed for the removal of DMSO.
The HWE olefination started with crude hexanedial 84 and yielded deca-2,8- dienedioic acid diethyl ester 53 using sodium hydride and diethylphosphonoacetic acid ethyl ester 85 in THF, Scheme 27.
O O O O H NaH EtO H + 2 EtO P OEt OEt O OEt THF, 0oC O 84 85 2.5 h 53 26% yield
Scheme 27: Synthesis of deca-2,8-dienedioic acid diethyl ester (Procedure 1)
NaH was washed with hexane to remove the mineral oil. Anhydrous THF was added and the solution cooled to 0oC. 85 was slowly added and the solution stirred for 15 minutes. Hexanedial 84 was dissolved in THF and slowly added. The solution stirred for 2.5 hours at room temperature. The reaction was quenched with water and the product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent removed by rotary evaporation. The product
53 was isolated by flash chromatography and resulted in a 26% yield (0.5902 g).
The EHC substrate was also synthesized by the Parikh-Doering oxidation and in situ a stabilized Wittig reaction. The Parikh-Doering oxidation is similar to the Swern
44
Oxidation except sulfur-trioxide-pyridine complex 86 is used in place of oxalyl chloride, Scheme 28.
O O N DCM S O HO O OH TEA 86 H H 83 DMSO, 0oC O 84 overnight
Scheme 28: Synthesis of hexanedial (Procedure 2)
DMSO was cooled to 0oC and hexanediol dissolved in anhydrous DCM was added.
After 2 minutes TEA was added. Next 86 was added in one portion and the reaction stirred overnight. Rather than working-up the reaction, the next step was conducted in situ to try and increase yield. The solution was cooled to 0oC and the stabilized Wittig
87 was added, Scheme 29.
O O O H P OEt EtO H OEt + 2 r.t., 4 h O 71% yield O 84 53
87
Scheme 29: Synthesis of deca-2,8-dienedioic acid diethyl ester (Procedure 2)
The stabilized Wittig 87 was added in one portion and the reaction stirred for 4 hours at room temperature. The solution was cooled to 0oC, diluted with DCM, and quenched with water. The product was extracted with ether. The combined organic layers were
45
washed with brine, dried over Na2SO4, and the solvent removed by rotary evaporation.
The product 53 was isolated by flash chromatography and resulted in a 71% yield
(1.6400 g). Conducting the oxidation and olefination steps in situ proved to be much more successful with greater yields in less time than the first procedure.
2.3 Cyclic Voltammetry
2.3.1 Redox Potentials
Cyclic voltammograms were recorded to establish the redox behavior of the five mediators and the EHC substrate. Each cyclic voltammogram was conducted in a quiet
(unstirred) solution of DMF using a carbon cathode, a platinum anode, and a Ag/AgCl,
NaCl sat., reference electrode. The supporting electrolyte was nBu4NPF6 and the scan rate was 0.1 V/s. Either a 1 mM or 5 mM concentration of each mediator was used depending upon solubility.
46
Figure 15 displays the cyclic voltammogram of 5 mM Ni(II) salen 60.
Figure 15: Cyclic voltammogram of Ni(II) salen
The cyclic voltammogram of Ni(II) salen in Figure 15 is almost completely reversible with a cathodic peak potential (Epc) of -1.603 V and an anodic peak potential (Epa) of
-1.434 V. The change in peak potentials ( Ep) is 0.169 V, while the current ratio (ipc/ipa) is 1.066 A.
47
Figure 16 displays the cyclic voltammogram of 1 mM 1,2-ethylenediamine
Ni(II) di-tert-butyl salen 72.
Figure 16: Cyclic voltammogram of 1,2-ethylenediamine Ni(II) di-tert-butyl salen
The cyclic voltammogram of 1,2-ethylenediamine Ni(II) di-tert-butyl salen in Figure
16 displays a cathodic peak potential at -1.750 V and an anodic peak potential at -1.650
V. The change in peak potentials is 0.100 V, while the current ratio is 2.263 A. The cyclic voltammogram was conducted using only 1 mM of 1,2-ethylenediamine Ni(II) di-tert-butyl salen due to solubility issues. The mediator was unable to completely dissolve in DMF at a 5 mM concentration for unknown reasons.
48
Figure 17 displays the cyclic voltammogram of 5 mM 1,2-phenylenediamine
Ni(II) di-tert-butyl salen 73.
Figure 17: Cyclic voltammogram of 1,2-phenylenediamine Ni(II) di-tert-butyl salen
The cyclic voltammogram of 1,2-phenylenediamine Ni(II) di-tert-butyl salen in Figure
17 displays an almost irreversible redox reaction, with a cathodic peak potential of
-1.491 V and an anodic peak potential of -1.395 V. The change in peak potentials is
0.096 V, while the current ratio is 3.861 A. Due to the increased conjugation, the ligand-centered radical anion is more stable which is why the oxidation peak is almost nonexistent.
49
Figure 18 displays the cyclic voltammogram of 5 mM (R,R)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen 74.
Figure 18: Cyclic voltammogram of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert- butyl salen
The cyclic voltammogram of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen in
Figure 18 displays a redox process, with a cathodic peak potential of -1.827 V and an anodic peak potential of -1.661 V. The change in peak potentials is 0.166 V, while the current ratio is 1.805 A.
50
Figure 19 displays the cyclic voltammogram of 5 mM (S,S)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen 75.
Figure 19: Cyclic voltammogram of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert- butyl salen
The cyclic voltammogram of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen in
Figure 19 displays a redox process with a cathodic peak potential of -1.847 V and an anodic peak potential of -1.657 V. These peak potentials are extremely similar to the peak potentials of the (R,R) enantiomer, meaning they have similar electrochemical behaviors. The change in peak potentials is 0.190 V, while the current ratio is 2.194 A.
51
Figure 20 displays the cyclic voltammogram of 5 mM EHC substrate 53.
Figure 20: Cyclic voltammogram of the EHC substrate
The cyclic voltammogram of the EHC substrate in Figure 20 shows an irreversible reduction peak potential at -2.375 V. An irreversible cyclic voltammogram occurs when the product of the electrode reaction is either very short lived or very stable. The product could have also diffused away from the electrode surface by the time the reverse potential is reached. In this case the radical anion formed is very unstable and most likely the electron is lost before the working electrode reverses its scan.
52
A summary of the cyclic voltammograms can be seen in Table 2.
Compound Epc (V) Epa (V) Ep (V) ipc/ipa
Ni(II) salen 60 -1.603 -1.434 0.169 1.066
1,2-ethylenediamine Ni(II) di-tert- -1.750 -1.650 0.100 2.263 butyl salen 72 1,2-phenylenediamine Ni(II) di-tert- -1.491 -1.395 0.096 3.861 butyl salen 73 (R,R)-1,2-cyclohexanediamine Ni(II) -1.827 -1.661 0.166 1.805 di-tert-butyl salen 74 (S,S)-1,2-cyclohexanediamine Ni(II) -1.847 -1.657 0.190 2.194 di-tert-butyl salen 75
EHC substrate 53 -2.375 ------Table 2: Cyclic voltammogram summary
The cathodic peak potentials (Epc) for each mediator and the EHC substrate were used to set the voltage potentials for the BE reactions. In order to ensure reduction occurred during the BE reactions, the reduction potential is set to 0.200 V more negative than the reduction potential from the cyclic voltammograms. Overall the mediators require less voltage than the EHC substrate which is beneficial in reducing overvoltages and the amount of electricity required. The values of Ep and ipc/ipa shed light onto the reversibility of the electron transfer. None of the compounds above are electrochemically reversible ( Ep doesn’t equal 0.058) meaning the rate of reduction does not equal the rate of oxidation. This implies structural reorganization which can be due to the geometry shape change from the metal being reduced.27 For a chemical
53
reversible reaction the peak current ratio (ipc/ipa) should be about one, meaning the amount of substrate reduced equals the amount oxidized. Ni(II) salen is chemically reversible reaction having a current ratio close to one. Since the curve of the cyclic voltammograms is highly dependent upon the scan rate, more CV was needed to better understand the redox reaction occurring for the remaining mediators.
2.3.2 Various Scan Rates
To further investigate the chemical reversibility of each mediator and the EHC substrate, CV of each compound was conducted at various voltage scan rates (VSR);
0.02 V/s, 0.05 V/s, 0.1 V/s, 0.2 V/s, 0.3 V/s, 0.4 V/s, 0.5 V/s, 1.0 V/s. The standard
VSR used for CV is 0.1 V/s. The slower and faster VSRs were chosen based on the range used in other studies.6 This large range of VSRs will help show any reversibility trends. Each cyclic voltammogram was conducted in a quiet solution of DMF using a carbon cathode, a platinum anode, and a Ag/AgCl, NaCl sat., reference electrode. The supporting electrolyte was nBu4NPF6. 1 mM for each mediator was used while 10 mM for the EHC substrate was used.
54
Figure 21 displays the cyclic voltammograms of 1 mM Ni(II) salen 60 at various scan rates.
N N Ni O O 60
Figure 21: Cyclic voltammograms of Ni(II) salen
55
Table 3 summarizes the results of the cyclic voltammograms of Ni(II) salen 60 at various scan rates.
Scan Rate (V/s) Epc (V) Epa (V) Ep (V) ipc/ipa 0.02 -1.587 -1.505 0.082 1.292
0.05 -1.587 -1.507 0.080 1.089
0.1 -1.588 -1.510 0.078 1.028
0.2 -1.591 -1.507 0.084 1.001
0.3 -1.591 -1.507 0.084 0.9928
0.4 -1.591 -1.505 0.086 0.9833
0.5 -1.592 -1.500 0.092 1.011
1.0 -1.603 -1.494 0.109 1.053 Table 3: Summary of Ni(II) salen
The change in peak potentials ( Ep) remains larger than 0.058 V confirming electrochemical irreversibility. As the scan rate increases the current ratio (ipc/ipa) for each cyclic voltammogram remains close to one, further confirming chemical reversibility.
56
Figure 22 displays the cyclic voltammograms of 1 mM 1,2-ethylenediamine
Ni(II) di-tert-butyl salen 72 at various scan rates.
N N Ni O O
72
Figure 22: Cyclic voltammograms of 1,2-ethylenediamine Ni(II) di-tert-butyl salen
57
Table 4 summarizes the results of the cyclic voltammograms of 1,2-ethylenediamine
Ni(II) di-tert-butyl salen 72 at various scan rates.
Scan Rate (V/s) Epc (V) Epa (V) Ep (V) ipc/ipa 0.02 -1.729 ------
0.05 -1.739 ------
0.1 -1.750 -1.650 0.100 2.263
0.2 -1.763 -1.656 0.107 2.516
0.3 -1.766 -1.653 0.113 2.283
0.4 -1.777 -1.660 0.117 2.182
0.5 -1.777 -1.653 0.124 1.664
1.0 -1.784 -1.653 0.131 1.714 Table 4: Summary of 1,2-ethylenediamine Ni(II) di-tert-butyl salen
At the slowest scan rates the mediator is completely irreversible, an anodic peak was not detected. As the scan rate increases the current ratio decreases, indicating a semi- reversible redox process.
58
Figure 23 displays the cyclic voltammograms of 1 mM 1,2-phenylenediamine
Ni(II) di-tert-butyl salen 73 at various scan rates.
N N Ni O O
73
Figure 23: Cyclic voltammograms of 1,2-phenylenediamine Ni(II) di-tert-butyl salen
59
Table 5 summarizes the results of the cyclic voltammograms of 1,2-phenylenediamine
Ni(II) di-tert-butyl salen 73 at various scan rates.
Scan Rate (V/s) Epc (V) Epa (V) Ep (V) ipc/ipa 0.02 -1.495 ------
0.05 -1.516 ------
0.1 -1.534 -1.431 0.103 4.185
0.2 -1.513 -1.432 0.081 4.143
0.3 -1.516 -1.444 0.072 3.290
0.4 -1.512 -1.444 0.068 2.938
0.5 -1.501 -1.438 0.063 3.153
1.0 -1.495 -1.426 0.069 2.447 Table 5: Summary of 1,2-phenylenediamine Ni(II) di-tert-butyl salen
At the slowest scan rates the mediator is completely irreversible, an anodic peak was not detected. As the scan rate increases the current ratio decreases getting closer to one but still remains above two even at the fastest scan rate. This indicates that the mediator is very stable as a radical anion due to the resonance structures from the phenyl bridge,
Figure 24.
60
N N N N Ni Ni O O O O
73a 73b
N N N N Ni Ni O O O O
73d 73c
Figure 24: Resonance structures of 1,2-phenylenediamine Ni(II) di-tert-butyl salen radical anion
61
Figure 25 displays the cyclic voltammograms of 1 mM (R,R)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen 74 at various scan rates.
N N Ni O O
74
Figure 25: Cyclic voltammograms of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert- butyl salen
62
Table 6 summarizes the results of the cyclic voltammograms of (R,R)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen 74 at various scan rates.
Scan Rate (V/s) Epc (V) Epa (V) Ep (V) ipc/ipa 0.02 -1.787 ------
0.05 -1.796 ------
0.1 -1.806 -1.699 0.107 2.096
0.2 -1.817 -1.699 0.188 1.623
0.3 -1.822 -1.693 0.129 1.565
0.4 -1.829 -1.687 0.142 1.505
0.5 -1.831 -1.684 0.147 1.469
1.0 -1.854 -1.671 0.183 1.528 Table 6: Summary of (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
At slow scan rates there is not any measurable anodic current which resembles an irreversible cyclic voltammogram. At faster scan rates the anodic peak increases becoming more like a reversible cyclic voltammogram. This type of behavior is associated with an electron transfer followed by a chemical reaction, which is called an
EC process.1
63
Figure 26 displays the cyclic voltammograms of 1 mM (S,S)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen 75 at various scan rates.
N N Ni O O
75
Figure 26: Cyclic voltammograms of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert- butyl salen
64
Table 7 summarizes the results of the cyclic voltammograms of (S,S)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen 75 at various scan rates.
Scan Rate (V/s) Epc (V) Epa (V) Ep (V) ipc/ipa 0.02 -1.793 ------
0.05 -1.802 -1.699 0.103 2.105
0.1 -1.809 -1.703 0.106 1.673
0.2 -1.814 -1.697 0.117 1.349
0.3 -1.818 -1.690 0.128 1.209
0.4 -1.821 -1.685 0.136 1.184
0.5 -1.822 -1.679 0.143 1.172
1.0 -1.831 -1.667 0.164 1.307 Table 7: Summary of (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
The results of the cyclic voltammograms for (S,S)-1,2-cyclohexanediamine Ni(II) di- tert-butyl salen at various scan rates are very similar to the results of the cyclic voltammograms for (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen. At slow scan rates the process resembles an irreversible electron transfer while at faster scan rates the process resembles a reversible electron transfer. Most likely an EC process is occurring.
65
Figure 27 displays the cyclic voltammograms of 10 mM EHC substrate 53 at various scan rates.
CO2Et CO2Et
53
Figure 27: Cyclic voltammograms of the EHC substrate
66
Table 8 summarizes the results of the cyclic voltammograms of the EHC substrate 53 at various scan rates.
Scan Rate (V/s) Epc (V) Epa (V) Ep (V) ipc/ipa 0.02 -2.265 ------
0.05 -2.318 ------
0.1 -2.342 ------
0.2 -2.392 ------
0.3 -2.415 ------
0.4 -2.442 ------
0.5 -2.460 ------
1.0 -2.514 ------Table 8: Summary of the EHC substrate at various VSRs
Regardless of the scan rate there is complete absence of any measurable anodic current, therefore the process is irreversible. This confirms the observations from the previous cyclic voltammogram.
2.3.3 Catalytic Current
To determine whether redox catalysis was possible, CV was conducted for each mediator in the presence of the EHC substrate 53. Each cyclic voltammogram was conducted in a quiet solution of DMF using a carbon cathode, a platinum anode, and a
Ag/AgCl, NaCl sat., reference electrode. The supporting electrolyte was nBu4NPF6 and
67 the scan rate was 0.1 V/s. A 1mM concentration of each mediator and a 10 mM of the
EHC substrate was used. A catalytic current is seen in the following figures of the cyclic voltammogram of each mediator with the cyclic voltammogram of the mediator with the EHC substrate.
N N Ni O O 60
Figure 28: Cyclic voltammogram of Ni(II) salen (dashed) and with the EHC substrate (solid)
68
N N Ni O O
72
Figure 29: Cyclic voltammogram of 1,2-ethylenediamine Ni(II) di-tert-butyl salen (dashed) and with the EHC substrate (solid)
N N Ni O O
73
Figure 30: Cyclic voltammogram of 1,2-phenylenediamine Ni(II) di-tert-butyl salen (dashed) and with the EHC substrate (solid)
69
N N Ni O O
74
Figure 31: Cyclic voltammogram (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen (dashed) and with the EHC substrate (solid)
N N Ni O O
75
Figure 32: Cyclic voltammogram (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen (dashed) and with the EHC substrate (solid)
70
A catalytic current is observed for each mediator in the presence of the EHC substrate which ensures that redox catalysis is possible. There is clearly an increase in the cathodic peak current when compared to the cyclic voltammogram of only the mediator. An anodic peak is not observed on the return scan indicating the electron- transfer agent is being consumed faster than the rate at which it is oxidized to reform the mediator.6 However, the catalyst is being regenerated after delivering an electron to the
EHC substrate at a rate that is large enough to observe a catalytic current.
2.4 Bulk Electrolysis
Bulk electrolysis (BE) reactions were carried out on the EHC substrate directly and indirectly with various mediators. Each BE reaction was conducted in a stirred solution of DMF using a reticulated vitreous carbon (RVC) cathode, a platinum wire anode, and a Ag/AgCl, NaCl sat., reference electrode. 0.1 M of the supporting electrolyte nBu4NPF6 and 2 equivalents of the proton donor dimethyl malonate
(CH2(CO2Me)2) were used. The potential used to conduct each reaction depended upon the reduction potential of the mediator and the EHC substrate from the previous cyclic voltammograms (see section 2.3.1 Redox Potentials). The reactions took place at room temperature. The mediated reactions started with 6.55 mM of the EHC substrate and 1 mM of the mediator. The direct BE reactions started with 6.55 mM of the EHC substrate and no mediator.
71
The BE reaction for the EHC substrate 53 with Ni(II) salen 60 is shown in
Scheme 30.
N N Ni O O 60 1 mM mediator CO Et CO Et CO Et 2 2 + 2 CO2Et CO2Et CO2Et 0.1 M nBu4NPF6, DMF 53 2 eq. CH2(CO2Me)2 54 55 -1.800 V (vs. Ag/AgCl) RVC cathode, Pt anode
Scheme 30: EHC reaction with Ni(II) salen
The reduction potential for Ni(II) salen 60 is -1.603 V, therefore the potential for the BE reaction was set to -1.800 V. The orange solution slowly turned dark blue as the nickel(II) was reduced. After 4.6 hours the current had leveled off and a GC sample showed only starting material and no cyclized product. The potential was then increased more negatively to -2.100 V for 20.3 hours. After a total of 24.9 hours and 300.82 C of charge had passed the reaction was complete. Once the reaction was worked up a small amount of the EHC substrate was still present and the BE reaction should have ran longer. A 137.5% crude yield was obtained. The percent yield was over 100% due to the remaining excess proton donor, supporting electrolyte, and DMF. The by-products decanedioic acid diethyl ester 88 and 2-decenedioic acid diethyl ester 89 were produced in small amounts, Figure 33.
72
O O EtO EtO OEt OEt O O 88 89
Figure 33: By-products from BE reaction
The BE reaction for the EHC substrate 53 with 1,2-ethylenediamine Ni(II) di- tert-butyl salen 72 is shown in Scheme 31.
N N Ni O O 72 1 mM mediator CO Et CO Et CO Et 2 2 + 2 CO Et CO Et CO Et 2 0.1 M nBu NPF , DMF 2 2 53 4 6 54 55 2 eq. CH2(CO2Me)2 -2.100 V (vs. Ag/AgCl) RVC cathode, Pt anode
Scheme 31: EHC reaction with 1,2-ethylenediamine Ni(II) di-tert-butyl salen
The reduction potential for 72 is -1.750 V, therefore the potential for the BE reaction was set to -2.100 V. The cloudy green-yellow solution slowly turned dark blue as the nickel(II) was reduced. The reaction was monitored by GC and after 9.5 hours and
216.91 C of charge had passed the reaction was complete. A 114.3% crude yield was obtained. A major by-product was decanedioic acid diethyl ester 88 which was produced at a percent ratio of 46.86% to 53.18% of cyclized product. The large amount of by-product formation was a result of having a mixture of EE, EZ, and ZZ EHC
73 substrate isomers. The different isomers were identified by analyzing the EHC substrate closer using the 1H NMR 500 MHz and GC-MS. The Z double bond results in a different chemical shift and coupling constants compared to the E double bond. The EE
EHC substrate has a different retention time than the EZ and/or ZZ EHC substrate. The
EZ and ZZ EHC substrate could not be identified separately. It appeared that having one or more cis double bonds did not allow cyclization to occur and the double bonds were simply reduced. The EHC substrate for this reaction was synthesized by the second procedure.
The BE reaction for the EHC substrate 53 with 1,2-phenylenediamine Ni(II) di- tert-butyl salen 73 is shown in Scheme 32.
N N Ni O O 73
CO Et 1 mM mediator CO Et CO Et 2 2 + 2 CO2Et CO2Et CO2Et 53 0.1 M nBu4NPF6, DMF 54 55 2 eq. CH2(CO2Me)2 -1.700 V (vs. Ag/AgCl) RVC cathode, Pt anode
Scheme 32: EHC reaction with 1,2-phenylenediamine Ni(II) di-tert-butyl salen
The reduction potential for 73 is -1.491 V, therefore the potential for the BE reaction was set to -1.700 V. The red-orange solution slowly turned dark blue as the Ni(II) was reduced. After 10.4 hours the current had leveled off and a GC sample showed only
74 starting material and no cyclized product. The potential was then set to -2.100 V and after 6.6 hours the GC showed only cyclized product. After a total of 17.0 hours and
236.37 C of charge had passed the reaction was complete. A 184.5% crude yield was obtained. A major by-product was decanedioic acid diethyl ester 88 which was produced at a percent ratio of 24.88% to 75.12% of cyclized product. This was due to having a slight mixture of EHC substrate isomers. The EHC substrate for this reaction was synthesized using the second procedure.
The BE reaction for the EHC substrate 53 with (R,R)-1,2-cyclohexanediamine
Ni(II) di-tert-butyl salen 74 is shown in Scheme 33.
N N Ni O O 74 CO Et 1 mM mediator CO Et CO Et 2 2 + 2 CO2Et CO2Et CO2Et 53 0.1 M nBu NPF , DMF 4 6 54 55 2 eq. CH2(CO2Me)2 -2.100 V (vs. Ag/AgCl) RVC cathode, Pt anode
Scheme 33: EHC reaction with (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
The reduction potential for 74 is -1.827 V, therefore the potential for the BE reaction was set to -2.100 V. The orange solution slowly turned dark blue as the nickel(II) was reduced. After 8.8 hours and 171.62 C of charge had passed the reaction was complete.
The product was purified through flash chromatography, a 73.77% yield was obtained.
75
Less than a 0.5% ratio of decanedioic acid diethyl ester was produced compared to the cyclized product. The EHC substrate was synthesized using the first procedure. An attempt was made to separate the cis and trans diastereomers through silica flash chromatography (30% diethyl ether, 70% pet. ether), however it was unsuccessful. It appears the diastereomers have extremely close if not the same retention factors. Since the diastereomers were unable to be separated the crude product was used to analyze all of the BE reactions.
The BE reaction for the EHC substrate 53 with (S,S)-1,2-cyclohexanediamine
Ni(II) di-tert-butyl salen 75 is shown in Scheme 34.
N N Ni O O 75 CO Et 1 mM mediator CO Et CO Et 2 2 + 2 CO2Et CO2Et CO2Et 53 0.1 M nBu4NPF6, DMF 54 55 2 eq. CH2(CO2Me)2 -2.100 V (vs. Ag/AgCl) RVC cathode, Pt anode
Scheme 34: EHC reaction with (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
The reduction potential for 75 is -1.847 V, therefore the potential for the BE reaction was set to -2.100 V. The orange solution slowly turned dark blue as the nickel(II) was reduced. After 11.0 hours and 156.01 C of charge had passed the reaction was complete.
A 51.8% crude yield was obtained. A small amount of the by-product decanedioic acid
76 diethyl ester 88 was produced, at a percent ratio of 3.57% to 96.43% of cyclized product. The EHC substrate used was from the first procedure.
The direct BE reaction for the EHC substrate 53 is shown in Scheme 35.
0.1 M nBu4NPF6, DMF 2 eq. CH2(CO2Me)2 CO Et CO Et CO Et 2 2 + 2 CO Et CO Et CO Et 2 -2.600 V (vs. Ag/AgCl) 2 2 53 RVC cathode, Pt anode 54 55
Scheme 35: Direct BE reaction (-2.600 V) of EHC substrate
The reduction potential for the EHC substrate is -2.375 V, therefore the potential for the
BE reaction was set to -2.600 V. The solution remained clear throughout the reaction.
After 27.7 hours and 452.12 C of charge had passed the reaction was complete. A
165.0% crude yield was obtained. Less than a 1% ratio of decanedioic acid diethyl ester was produced compared to the cyclized product. A direct electrolysis was also ran at
-2.100 V, Scheme 36, since the mediated BE reactions had to be at this voltage for cyclization to occur.
0.1 M nBu4NPF6, DMF 2 eq. CH2(CO2Me)2 CO Et CO Et CO Et 2 2 + 2 CO Et CO Et CO Et 2 -2.100 V (vs. Ag/AgCl) 2 2 RVC cathode, Pt anode 53 54 55
Scheme 36: Direct BE reaction (-2.100 V) of EHC substrate
77
After 9.5 hours and 138.28 C of charge had passed a very small amount of the EHC substrate had cyclized. The reaction ran overnight and after 23.6 hours it appeared most of the substrate had cyclized. Once the reaction was worked up there was actually a good amount of starting material still present; a percent ratio of 30.9% EHC substrate compared to 69.1% BE product. A 124.8% crude yield was obtained. A small amount of decanedioic acid diethyl ester 88 was produced.
Since the diastereomers of the BE product were unable to be separated, the spectra shows a mixture of isomers therefore the non-isomeric form of the BE product
90, Figure 34, will be used for data assignments.
CO2Et CO2Et 90
Figure 34: BE product
All of the following data shown is of crude BE product, therefore the spectra does show extra peaks due to excess proton donor and by-products. The cis and trans
1H NMR and 13C NMR peaks were identified by comparing literature data and calculated chemical shifts with further NMR experiments.28 Based on the relative peak heights in the 13C NMR of the cis and trans tertiary carbon it will be clear which isomer is in greater abundance. This is assuming that the relaxation times of the cis and trans tertiary carbons are the same. An exact cis to trans ratio was calculated from the two identified BE product peaks in the GC.
78
Figure 35 displays the 1H NMR of the BE product cyclohexane-1,2-diacetic acid diethyl ester 90.
Figure 35: 1H NMR 500 MHz of cyclohexane-1,2-diacetic acid diethyl ester
H1 and H2 have the same chemical shifts for each diastereomer. These protons are far enough removed from the stereocenters to be virtually undifferentiated. Both
29 appear at an expected chemical shift based on known values for an ethyl ester. H1 is at about 1.25 ppm and is split into a triplet (J = 7.124) from H2. H2 is at about 4.13 ppm
1 and is split into a quartet (J = 7.152) from H1. The H NMR also displays a doublet of doublets for the trans H4 protons which indicates each proton has geminal coupling and
79
1 1 coupling to trans H5. The H - H COSY, Figure 36, confirms the coupling between H1 and H2, while also showing the coupling between the remaining protons.
H1 H2
Figure 36: 1H -1H COSY of cyclohexane-1,2-diacetic acid diethyl ester
1 1 It is clear that H1 and H2 are coupled together. The H - H COSY also shows coupling between the H4trans protons indicating that they are diastereotopic hydrogens.
This means the two protons associated with each H4trans peak are not on the same carbon. It is virtually impossible for H4AB to be coupled with H4CD since they are five bond lengths away. Therefore one of the H4trans peaks is comprised of H4A and H4C and
1 1 the other is of H4B and H4D. A zoomed in H - H COSY, which better shows the coupling between these protons, can be seen in Figure 37.
80
H4AC H5t H4BD H5t
H4A H4B H4C H4D
H4B H4A H4D H4C
Figure 37: Zoomed in 1H -1H COSY of cyclohexane-1,2-diacetic acid diethyl ester
In regards to the trans isomer, H4A has geminal coupling with H4B and is coupled to H5 creating a doublets of doublets just as H4C has geminal coupling with H4D and is coupled to H5 which both (H4A and H4C) appear at the exact same chemical shift making only one set of doublet of doublets at about 2.47 ppm. The same coupling pattern occurs for H4B and H4D which make a doublet of doublets at about 2.10 ppm.
The H4cis protons are also diastereotopic but they overlap and appear at the same chemical shift.
1 Looking back at the H NMR (Figure 35), the remaining protons (H4, H5, H6, and H7) are affected by the stereocenters and appear at different chemical shifts for the
81 cis and trans isomers. The protons were identified based on literature data and then confirmed with a 1H -13C HSQC (Figure 41) and supported by calculated chemical shifts.28
The calculated 1H NMR chemical shifts compared to the experimental 1H NMR chemical shifts are fairly close, Table 9 displays both the cis and trans values.30, 31
Table 9: 1H NMR experimental and calculated chemical shifts for the cis and trans isomers of the BE product
The experimental and calculated chemical shifts for H1, H2, H4, and H5 for both cis and trans isomers agree with each other. H6 and H7 are calculated to appear in the reverse order than found experimentally, however the 1H -13C HSQC confirms that the experimental values are identified correctly. H7cis and H5trans are calculated to have the same chemical shift and the 1H -13C HSQC shows these two protons basically in-line with each other. Before running the 1H -13C HSQC, all carbons had to be identified, which was done from a DEPT135, a DEPT90, and literature data.
82
Figure 38 displays the 13C NMR for the BE product 90.
Figure 38: 13C NMR 500 MHz of cyclohexane-1,2-diacetic acid diethyl ester
C1, C2, and C3 were identified based on literature values and confirmed with known chemical shifts for those functional groups.28, 29 The difference in the cis and trans corresponding carbon peaks was small, however, usually the trans-diastereomer carbons appear at higher chemical shifts than the cis-diastereomer carbons.28 This was later confirmed after identifying the cis and trans tertiary carbon C5. The remaining carbons were identified through a DEPT135 and a DEPT90. The unassigned peaks are from either the excess proton donor or by-products.
83
C4, C6, and C7 (all secondary carbons) were identified through a DEPT135,
Figure 39.
Figure 39: DEPT135 of cyclohexane-1,2-diacetic acid diethyl ester The DEPT135 confirmed C1 as a tertiary carbon, C2 as a secondary carbon, and
C3 as a quaternary carbon since there were no peaks around 173 ppm present (see full spectrum in Appendix J). C4 are closest to the ester group making them more downfield than C6 and C7 due to more deshielding. C7 are the farthest from the ester group and more shielded, consequently appear further upfield. C6 are located between C4 and C7 on the structure and therefore also on the NMR, which agrees with the calculated chemical shifts (Table 10). Carbon peaks were determined to be cis or trans based on literature data.28
84
C5 was identified through a DEPT90, Figure 40.
Figure 40: DEPT90 of cyclohexane-1,2-diacetic acid diethyl ester The DEPT90 clearly displays only two peaks as tertiary carbons (see full spectrum in Appendix J). To determine the cis and trans peak, calculated chemical shifts were first examined. The calculated 13C NMR chemical shifts compared to the experimental 13C NMR chemical shifts are fairly similar to each other and follow the same downfield to upfield order. Table 10 displays both the cis and trans values.30, 31
85
Table 10: 13C NMR experimental and calculated chemical shifts for the cis and trans diastereomers of the BE product
The calculated chemical shifts have C5trans (42.27 ppm) further downfield than
1 13 C5cis (40.80 ppm). A H - C HSQC (Figure 41) was conducted to confirm this assignment since the chemical shifts of the protons bonded to C5 have already been determined.
86
Figure 41: 1H -13C HSQC of cyclohexane-1,2-diacetic acid diethyl ester
1 13 The H - C HSQC results coincide with the calculated values, C5trans appears
1 13 further downfield than C5cis. The H - C HSQC is phase sensitive and displays positive peaks (CH2 groups) as red and negative peaks (CH and CH3 groups) as blue. In Figure
41 the blue colored peaks have a circle around them. Looking back at the DEPT90
(Figure 40), it is clear that C5trans has a larger peak intensity than C5cis and it is safe to assume that the trans diastereomer is in greater abundance.
To determine the exact amount of cis to trans, GC-MS was conducted. The GC for the BE reaction of the EHC substrate with (R,R)-1,2-cyclohexanediamine Ni(II) di- tert-butyl salen 74 is shown in Figure 42.
87
BE Product
CO2Et CO2Et 90
Proton Donor
DMF
Decanedioic Acid Diethyl Ester
Figure 42: GC of BE reaction of the EHC substrate with (R,R)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen
DMF, the proton donor dimethyl malonate, and decanedioic acid diethyl ester were identified based on the GC-MS data analysis NIST08 library and further confirmed by mass spectrometry (MS). Decanedioic acid diethyl ester was a minor or major side product for some of the BE reactions. Upon further investigation, it turned out that the EHC substrate used in those BE reactions contained a mixture of isomers with a majority of 2E,8E-decadienedioc acid diethyl ester but also some of the EZ and
ZZ isomers. When at least one Z double bond was present it appears that cyclization was unable to occur and the double bonds simply reduced. The two larger peaks
88 between 11.20-11.50 min were confirmed by MS to be the BE product. The MS for the peak at 11.272 min and at 11.435 is shown in Figure 43 and Figure 44, respectively.
CO2Et CO2Et 90
C14H24O4 Molar Mass: 256.3379
Figure 43: MS of BE product at 11.272 min
89
CO2Et CO2Et 90
C14H24O4 Molar Mass: 256.3379
Figure 44: MS of BE product at 11.435 min
The MS for both peaks on the GC clearly have the same fragmentation pattern, which matches literature values for the BE product.28 The molecular ion as a radical cation is unstable, therefore there is no molecular ion peak (M+) at 255 m/z. Instead, a peak at 211 m/z is seen due to the loss of -OCH2CH3. The peak at 169 m/z is due to the loss of one –CH2CO2CH2CH3 group and the peak at 81 m/z is due to the loss of both –
CH2CO2CH2CH3 groups. From the DEPT90 it was concluded that there is more trans isomer than cis, therefore the peak at 11.272 min must be trans since it has a larger abundance and the smaller peak at 11.435 min must be cis. This is assuming that the response factor for both diastereomers is the same, which is most likely true and was the
90 reason behind not using an internal standard. Using the integration values, Figure 45, for each peak there is 45.5% of the cis isomer and 54.5% of the trans isomer or a 1:1.20 cis/trans ratio.
CO2Et Trans CO2Et Area: 11,240,142 90 11.272 min Cis Area: 9,386,767 11.435 min
Figure 45: Integration of BE product conducted with (R,R)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen
91
The remaining BE reactions had the cis and trans isomers identified based on retention times. The results for each BE reaction is summarized in Table 11.
Mediator % cis, % trans c/t ratio
Ni(II) salen 60 40.6%, 59.4% 1:1.46
1,2-ethylenediamine Ni(II) di-tert-butyl 42.3%, 57.7% 1:1.36 salen 72 1,2-phenylenediamine Ni(II) di-tert-butyl 45.2%, 54.8% 1:1.21 salen 73 (R,R)-1,2-cyclohexanediamine Ni(II) di- 45.5%, 54.5% 1:1.20 tert-butyl salen 74 (S,S)-1,2-cyclohexanediamine Ni(II) di- 42.7%, 57.3% 1:1.34 tert-butyl salen 75
None (direct BE at -2.600 V) 43.1%, 56.9% 1:1.33
None (direct BE at -2.100 V) 39.7%, 60.3% 1:1.51 Table 11: Summary of BE reaction results
There is no clear trend with the BE reactions and the cis/trans ratio. Each reaction resulted in favoring the trans isomer at around the same selectivity. The Ni(II) salen had the highest degree of stereoselectivity, favoring the trans isomer over the cis about 1.5 to 1. The tert-butyl groups may have been too bulky to allow the various mediator bridges to fully effect the EHC substrate during cyclization. Even though the EHC substrate was able to cyclize directly at -2.100 V there is evidence to support that the mediated reactions did go through a catalytic process rather than a direct electrolysis.
First is the cyclic voltammograms (section 2.3.3 Catalytic Current) which clearly
92 display a catalytic current. This supports the mechanism that the mediator is transferring the electron from the working electrode to the substrate. Second is the BE reaction times. The average time for the BE reactions at -2.100 V with a mediator is 11 hours while the direct electrolysis takes well over 24 hours for completion. However there is no way to dispute that a small amount of the EHC substrate did cyclize directly during the mediated BE reactions.
It is still unclear how the electron is transferred for mediated BE reactions; whether an inner sphere electron transfer or an outer sphere electron transfer is occurring. There is evidence in the cyclic voltammograms that an inner sphere electron transfer occurred in the BE reactions. If that is true, then the substrate can cyclize while either bonded to the mediator or after it breaks free. The cis/trans ratios are similar for each mediated reaction which supports cyclization happening after the substrate has detached from the mediator. However if the electron transfer was completely ligand centered than there would not be a solution color change during the BE reactions. The color change is due to the metal being reduced and occurred during each BE reaction. It appears that a combination of an inner sphere and outer sphere electron transfer is occurring. From these results it is uncertain which one is the more dominant process.
93
Chapter 3
CONCLUSION
All five mediators were successfully synthesized with moderate to excellent yields. The five mediators were Ni(II) salen (previously synthesized), 1,2- ethylenediamine Ni(II) di-tert-butyl salen (100% yield), 1,2-phenylenediamine Ni(II) di- tert-butyl salen (43% yield), (R,R)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen
(100% yield), and (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen (93% yield).
The EHC substrate, deca-2,8-dienedioic acid diethyl ester, was synthesized from two different procedures. The first started with hexanediol and through a Swern oxidation produced hexanedial (80% yield) which then underwent a HWE reaction to produce the
EHC substrate (26% yield). This method gave low yields and was usually unsuccessful.
The favored procedure was a Parikh-Doering oxidation and in situ a stabilized Wittig reaction (71% yield). Not only was the percent yield of the EHC substrate much higher but performing the reactions in situ saved time and chemicals.
From the CV experiments the redox potentials of the mediators and EHC substrate were determined along with information about the reversibility and process of the electron transfer and redox catalysis. Ni(II) salen has a cathodic peak potential (Epc) of -1.603 V and an anodic peak potential (Epa) of -1.434 V and has chemical reversibility with a current ratio close to one. 1,2-ethylenediamine Ni(II) di-tert-butyl salen has an Epc at -1.750 V and an Epa at -1.650 V and showed chemical irreversibility with a current
94
ratio far from one. 1,2-phenylenediamine Ni(II) di-tert-butyl salen has an Epc at -1.491 V and an Epa at -1.395 V and also showed chemical irreversibility. (R,R)-1,2- cyclohexanediamine Ni(II) di-tert-butyl salen has an Epc at -1827 V and an Epa at -1.661
V. At slower scan rates this mediator showed chemical irreversibility and at faster scan rates showed chemical reversibility which means most likely an EC process was occurring. (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen has an Epc at -1.847 V and an Epa at -1.657 V and also showed an EC process. The EHC substrate has a Epc at
-2.375 V and was electrochemically and chemically irreversible.
All of the mediators were shown to be electrochemically irreversible with Ep values greater than 0.059 V. This supports an inner sphere or ligand centered electron transfer. All of the mediators also displayed a catalytic current when comparing the cyclic voltammogram of the mediator to the cyclic voltammogram of the mediator plus the EHC substrate. This is evidence that an electron transfer between the mediator and the EHC substrate occurred.
The BE reactions carried out on the EHC substrate directly and indirectly resulted in similar cis/trans ratios of the cyclized product. The following results were obtained:
Ni(II) salen c/t = 1/1.46, 1,2-ethylenediamine Ni(II) di-tert-butyl salen c/t = 1/1.36, 1,2- phenylenediamine Ni(II) di-tert-butyl salen c/t = 1/1.21, (R,R)-1,2-cyclohexanediamine
Ni(II) di-tert-butyl salen c/t = 1/1.20, (S,S)-1,2-cyclohexanediamine Ni(II) di-tert-butyl salen c/t = 1/1.34, direct at -2.600 V c/t = 1/1.33, and direct at -2.100 V c/t = 1/1.51.
95
There does not appear to be any stereoselectivity occurring between the various mediators.
3.1 Future Studies
Rather than having nickel(II) based mediators other metals may be more suitable due the coordination chemistry of transition metal complexes with salen-type ligands and the differences in orbital shells. The electrochemical behavior of cobalt(II) salen as a mediator has already been investigated.5 Co(II) salen 91 has been proven to be unsuccessful at promoting cyclization of the ERC substrate 59 in Figure 46, which is very similar in structure to the EHC substrate used in this thesis.
O N N Co CO2CH3 O O 59 91
Figure 46: ERC substrate and Co(II) salen
The difference in the cathodic peak potentials for Co(II) salen and the ERC substrate was too large to allow the electron transfer to occur from the reduced form of Co(II) salen to the compound. Studies have also suggested that in electrocatalytic reduction reactions the electron transfer for Co(II) salen is metal centered.9 Looking toward the right of nickel on the periodic table is zinc, which has a full d10 electron configuration and should favor a ligand centered electron transfer. Some research has been done on the optical and
96 electrical properties of zinc salen, yet nothing was found on the electrochemical behavior.32
A graduate student, Jason Fell, at CSUS is currently conducting computational studies that showed that Ni(II) and Zn(II) were the best metals for electron transfer, while
Co(II) and Cu(II) would most likely not result in an effective electron transfer. The most thermodynamically favored electron transfer from the metal salens to both methyl acrylate and acrylonitrile occurred with the Ni(II) and Zn(II) salens. Reduced Ni(II) salen and Zn(II) salen also had lower activation energies for electron transfer along both the inner sphere and outer sphere electron transfer pathways. Currently the redox behavior of
Zn(II) salen in mediated ERC and EHC reactions is being investigated.
Another possibility is to reduce the amount of steric hinderance by removing the tert-butyl groups completely and try the same bridge variations. The tert-butyl groups may have been too bulky to allow diastereomer selection to occur. With less steric hinderance the effect of the bridge might be more evident in the cis/trans results. Another option is to replace the tert-butyls with a less bulky group such as methyls which may still favor a reaction at the carbon imine.
97
Chapter 4
EXPERIMENTAL
General: 1,6-hexanediol, sodium hydride (NaH) (60% oil immersion), (R,R)-(-)-N,N’-
Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine, and dimethyl malonate
(CH2(CO2Me)2) were purchased from Aldrich Chemical Company, Inc. Oxalyl chloride
((COCl)2), (ethoxycarbonylmethylene)triphenylphosphorane, and sulfur trioxide-pyridine complex were purchased from Alfa Aesar. Deuterated chloroform (CDCl3) was purchased from Cambridge Isotope Laboratories, Inc. Anhydrous dimethyl sulfoxide
(DMSO), triethylamine (TEA), anhydrous tetrahydrofuran (THF), ether, hexane, absolute ethanol (abs. EtOH), and anhydrous dimethylformamide (DMF) were purchased from
EMD. Potassium carbonate (K2CO3) and magnesium sulfate (MgSO4) were purchased from Fisher Chemical. Sodium sulfate (Na2SO4) was purchased from J.T. Baker
Chemical Co. Dichloromethane (DCM) and ethyl acetate (EtOAc) were purchased from
Mallinckrodt. DCM was distilled over calcium hydride prior to use. Nickel (II) acetate and o-phenylenediamine were purchased from Matheson Coleman & Bell. (S,S)-(+)-
N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine was purchased from
Strem Chemicals. 3,5-di-tert-butylsalicylaldehyde, ethylenediamine, tetra-n- butylammonium hexafluorophosphate (nBu4NPF6), and diethylphosphonoacetic acid ethyl ester were purchased from TCI Co. Unless otherwise stated, all reagents were used
98 unpurified from the supplier. Air sensitive reactions were performed under nitrogen atmosphere and used oven-dried glassware with standard syringe/septa techniques.
NMR: 1H NMR spectra were recorded using either a Bruker Avance 300 or Avance III
500 NMR at ambient temperature. 13C NMR spectra were recorded using a Bruker III
Avance spectrometer at 125 MHz at ambient temperature. All chemical shifts are reported in ppm relative to TMS (0.00 ppm) or CDCl3 (7.27 ppm) on the scale.
Multiplicity (br: broad, s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, m: multiplet) and coupling constants are in hertz (Hz). The 1H NMR, COSY, 13C NMR,
DEPT135, DEPT90, and HSQC spectra were analyzed using either Spinworks or
Topspin.
Electrochemistry: A BASi C-3 Cell Stand and an Electrochemical
Analyzer/Workstation, model 600D, from CH Instruments were used for all electrochemical experiments.
General Procedure for Cyclic Voltammetry (CV): A standard single compartment glass cell vial was used for CV experiments. The working electrode was a glassy carbon electrode (surface area: 7 mm2) and a platinum electrode was used as the auxiliary electrode (surface area: 2 mm2). The potentials were recorded against the reference of Ag/AgCl, NaCl sat., which was separated from the medium by a porous
Vycor membrane (surface area: 28 mm2). This electrode has a potential of -0.045 V versus the saturated calomel electrode (SCE) at 25oC.33 The voltage scan rate (VSR) was
99 varied between 0.2 V/s and 1.0 V/s. The electrodes were immersed in a quiet solution of
Ni(II) salen mediators and 0.1 M nBu4NPF6 in 5 mL of anhydrous DMF. The concentration of the mediator was either 1 mM or 5 mM depending upon the CV experiment. The solution was deoxygenated for at least 10 min by bubbling nitrogen in the solution and the cell contents were maintained under a nitrogen atmosphere during the experiment. CV was performed using a computer-controlled potentiostat electroanalytical system. The data was collected and exported to a spreadsheet program.
General Procedure for Bulk Electrolysis (BE): All reactions were carried out in a two compartment BE glass cell. The working electrode was a reticulated vitreous carbon (RVC) electrode (area: 31 cm3). A coiled platinum wire (length: 23 cm) within a fritted glass isolation chamber was used as the auxiliary electrode. The reference electrode was a Ag/AgCl, NaCl sat., that was separated from the medium by a porous
Vycor membrane (surface area: 28 mm2). This electrode has a potential of -0.045 V versus the SCE at 25oC.33
A 0.1 M solution of nBu4NPF6 in 85 mL of anhydrous DMF was poured into the cell containing all three electrodes. The solution was deoxygenated for 20 min by bubbling nitrogen in the solution and the cell contents were maintained under a nitrogen atmosphere during the experiment. The solution was stirred with a stirbar throughout the entire experiment. A pre-electrolysis potential, depending upon the mediator used, was applied and the current was monitored until it leveled off. In a separate vial, a 6.55 mM solution of the EHC substrate was prepared in a solution containing 0.1 M solution of
100
nBu4NPF6 in 5 mL of anhydrous DMF. To this solution 1 mM of the mediator and 2 equivalents of the proton donor dimethyl malonate were added.
After the pre-electrolysis, the current was stopped and the solution containing the
EHC substrate was added to the cell. The current flow was resumed by applying the same potential applied during the pre-electrolysis step. The reaction was monitored by GC.
Once complete, the solution was transferred to a RBF and cooled to 0oC. The reaction was quenched with 60 mL of H2O and extracted with diethyl ether (60 mL x 3). The combined organic layers were washed with brine (60 mL x 3) and dried over Na2SO4.
The solvent was removed by rotary evaporation to give the crude BE product.
IR: A Perkin Elmer System 200 FT-IR Spectrometer was used for all IR measurements.
GC-MS: An Agilent Technologies 7890A GC System containing an Agilent J&W GC
Column (stationary phase: HP-5MS, 30 m x 0.250 mm x 0.25 m) with a 5975C inert XL
EI/CI MSD with Triple-Axis Detector was used to obtain all GC-MS data. The method used for all runs was: 40oC for 1 min, 5oC/min to 110oC, 20oC/min to 280oC, hold for 2 min.
Computational Chemistry: Spartan ’08 version 1.1.1 was used to draw the cis-trans isomers of the BE product, cyclohexane-1,2-diacetic acid diethyl ester. Gaussian 03 revision C.01 carried out the electronic structure calculations and calculations of the 1H
NMR and 13C NMR absolute chemical shifts.30 The compounds’ geometries were optimized using PCM(chloroform)/B3LYP/6-31G(d) and the chemical shifts were
101 calculated using PCM(chloroform)/B3LYP/6-311+G(2d,p).31 The NMR relative chemical shifts were calculated by subtracting the absolute chemical shifts from the absolute chemical shift of TMS (31.8166 ppm for 1H NMR and 182.9875 ppm for 13C
NMR). Linear regression of the relative chemical shifts was used to improve accuracy.
For 1H NMR the regression corrected chemical shifts were calculated using m (slope) =
0.9333 and b (y-intercept) = 0.1203, where R (Pearson correlation coefficient) = 0.9974.
For 13C NMR the regression corrected chemical shifts were calculated using m = 0.9488 and b = -2.1134, where R = 0.9973.
102
N N Ni O O 60
[N,N’-Bis(di-salicylidene)-1,2-ethylenediamine]Nickel(II) 60: Previously synthesized by other students.22
1 H NMR (CDCl3, 500 MHz): 7.4650 (s, 2H), 7.2004 (m, 2H), 7.0363 (m, 4H), 6.5265
(m, 2H), 3.4374 (s, 4H).
CV: Epc = -1.603 V, Epa = -1.434 V.
IR (KBr): 2800, 1625.45, 1537.17, 1451.92, 1348.78, 1200.10,
1127.57 cm-1.
1H NMR and IR data matched literature values.22
N N
OH HO
78
N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-ethylenediamine 78: A 3-neck 100 mL RBF was filled with DI H2O (3.0 mL) and ethylenediamine (0.1282 g, 2.134 mmoles).
Potassium carbonate (K2CO3) (0.5897 g, 4.267 mmoles) and 12.0 mL of EtOH were added. The solution was heated to reflux. 3,5-di-tert-butylsalicylaldehyde (1.000 g, 4.267 mmoles) was dissolved in 10.0 mL of EtOH and added dropwise over 5 min. The solution refluxed for 2 h and then cooled to 0oC for 3 h. The crystals were isolated by
103 vacuum filtration and washed with cold EtOH. The product 78 (0.9303 g, 1.888 mmoles,
88.66% yield) was bright yellow crystals.
1 H NMR (CDCl3, 300 MHz): 13.6384 (s, 2H), 8.3839 (s, 2H), 7.3580 (d, J = 2.459 Hz,
2H), 7.0606 (d, J = 2.361 Hz, 2H), 3.9188 (s, 4H), 1.4284 (s, 18H), 1.2792 (s, 18H).
1H NMR data matched literature values.34
N N Ni O O
72
[N,N’-Bis(3,5-di-tert butylsalicylidene)-1,2-ethylenediamine]Nickel(II) 72: A 100 mL
RBF was filled with 78 (0.8248 g, 1.674 mmoles) and 35.0 mL of abs. EtOH. Ni(II) acetate (0.4166 g, 1.674 mmoles) was added to the mixture. The solution was heated to reflux for 1 h and then cooled to r.t. The solution was vacuum filtered and washed with cold EtOH. The product 72 (0.9209 g, 1.676 moles, 100.1% yield) was dark yellow crystals.
1 H NMR (CDCl3, 300 MHz): 7.4878 (s, 2H), 7.3045 (d, J = 2.606 Hz, 2H), 6.8673 (d,
J = 2.618 Hz, 2H), 3.3002 (s, 4H), 1.4059 (s, 18H), 1.2552 (s, 18H).
CV: Epc = -1.924 V, Epa = -1.537 V, Epa = -1.817 V.
IR (KBr): 2952.28, 1623.12, 1532.55, 1442.08, 1318.19, 1257.90, 1173.42,
1090.11 cm-1.
1H NMR and IR data matched literature values.34
104
N N
OH HO
80
N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine 80: A 3-neck 100 mL
RBF was filled with DI H2O (3.0 mL) and o-phenylenediamine (0.2300 g, 2.127 mmoles). K2CO3 (0.5879 g, 4.254 mmoles) and 12.0 mL of EtOH were added. The solution was heated to reflux. 3,5-di-tert-butylsalicylaldehyde (0.9968 g, 4.254 mmoles) was dissolved in 10.0 mL of EtOH and added dropwise over 5 min. The solution refluxed for 2 h and then was cooled to 0oC for 3 h. The solution was vacuum filtered and washed with cold EtOH. The product 80 (0.7899 g, 1.461 mmoles, 68.69% yield) was bright yellow crystals.
1 3 H NMR (CDCl3, 300 MHz): 13.4637 (s, 2H), 8.6476 (s, 2H), 7.4460 (dd, J = 5.555
Hz, 4J = 2.431 Hz, 2H), 7.3199 (m, 2H), 7.2237 (dd, 3J = 8.046 Hz, 4J = 2.372 Hz, 2H),
7.0760 (m, 2H), 1.4527 (s, 18H), 1.3269 (s, 18H).
1H NMR data matched literature values.35
N N Ni O O
73
105
[N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine]Nickel(II) 73: A 100 mL RBF was filled with 80 (0.7300 g, 1.350 mmoles) and 35.0 mL of abs. EtOH. Ni(II) acetate (0.3360 g, 1.350 mmoles) was added to the mixture. The solution was heated to reflux for 1 h and then cooled to r.t. The solution was vacuum filtered and washed with cold EtOH. The product 73 (0.3500 g, 0.5859 mmoles, 43.40% yield) was brown-red crystals.
1 3 4 H NMR (CDCl3, 300 MHz): 8.2275 (s, 2H), 7.6926 (dd, J = 6.150 Hz, J = 3.385
Hz, 2H), 7.4122 (d, J = 2.536 Hz, 2H), 7.1793 (dd, 3J = 6.233 Hz, 4J = 3.263 Hz, 2H),
7.0898 (d, J = 2.581 Hz, 2H), 1.4702 (s, 18H), 1.3122 (s, 18H).
CV: Epc = -1.491 V, Epa = -1.395 V.
IR (KBr): 2956.85, 1606.74, 1580.32, 1525.36, 1464.09, 1358.71, 1198.86,
1179.20 cm-1.
1H NMR and IR data matched literature values.36
N N Ni O O
74
[(R,R)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 74:
A 100 mL RBF was filled with (R,R)-(-)-N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2- cyclohexanediamine (1.000 g, 1.829 mmoles) and 45.0 mL of abs. EtOH. Ni(II) acetate
106
(0.4552 g, 1.829 mmoles) was added to the mixture. The solution was heated to reflux for
1 h and then cooled to r.t. The solution was vacuum filtered and washed with cold EtOH.
The product 74 (1.100 g, 1.825 mmoles, 99.78% yield) was dark yellow crystals.
1 H NMR (CDCl3, 300 MHz): 7.3945 (s, 2H), 7.2966 (d, J = 2.624 Hz, 2H), 6.8784 (d,
J = 2.597 Hz, 2H), 2.9664 (m, 2H), 2.4741 (m, 4H), 1.9317 (m, 4H), 1.4102 (s, 18H),
1.2587 (s, 18H).
CV: Epc = -1.827 V, Epa = -1.661 V.
IR (KBr): 2952.16, 2866.99, 1617.36, 1529.58, 1435.36, 1324.29, 1256.54,
1174.08 cm-1.
1H NMR data matched literature values.37
N N Ni O O
75
[(S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 75:
A 100 mL RBF was filled with (S,S)-(+)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2- cyclohexanediamine (0.6082 g, 1.112 mmoles) and 45.0 mL of abs. EtOH. Ni(II) acetate
(0.2731 g, 1.097 mmoles) was added to the mixture. The solution was heated to reflux for
1 h and then cooled to r.t. The solution was vacuum filtered and washed with cold EtOH.
The product 75 (0.6205 g, 1.029 mmoles, 92.54% yield) was dark yellow crystals.
107
1 H NMR (CDCl3, 300 MHz): 7.3919 (s, 2H), 7.2985 (d, J = 2.640 Hz, 2H), 6.8834 (d,
J = 2.584 Hz, 2H), 2.9560 (m, 2H), 2.4394 (m, 4H), 1.9108 (m, 4H), 1.4101 (s, 18H),
1.2588 (s, 18H).
13 C NMR (CDCl3, 125 MHz): 162.6970 (2CH), 157.6941 (2C), 140.2122 (2C),
135.8141 (2C), 128.9585 (2CH), 126.1950 (2CH), 119.4404 (2C), 69.7934 (2CH),
35.8120 (2C), 33.7757 (2C), 31.3542 (6CH3), 29.6532 (6CH3), 28.8553 (2CH2), 24.4789
(2CH2).
CV: Epc = -1.847 V, Epa = -1.657 V.
IR (KBr): 2952.52, 2866.54, 1615.93, 1529.74, 1435.54, 1324.71, 1256.48,
1173.90 cm-1.
O H H O 84
Hexanedial 84: The general oxidation procedure of Swern was followed.23 A 3-neck
1000 mL RBF was cooled to -78oC and filled with 700.0 mL of anhydrous DCM. The entire reaction was kept under nitrogen atmosphere. Oxalyl chloride (10.00 mL, 0.1143 moles) was added to the solution and stirred for 20 min. DMSO (15.72 mL, 0.2032 moles) was added dropwise and stirred for 30 min. 1,6-hexanediol (3.000 g, 0.02539 moles) was dissolved in 5.0 mL of anhydrous DCM and added slowly. The solution was stirred for 1 h. TEA (35.39 mL, 0.2539 moles) was added and the reaction was stirred overnight. The RBF was then placed in an ice bath and the solution diluted with DCM
108
and the reaction quenched with DI H2O. The solution was transferred to a separatory funnel and the aqueous layer removed. The organic layer was washed with 1M HCl (500 mL x 1), DI H2O (500 mL x 1), sat. NaHCO3 (500 mL x 1), and brine (500 mL x 1). The organic layer was dried over MgSO4, filtered through celite and silica, and the solvent removed by rotary evaporation. The product 84 (2.413 g, 0.02114 moles, 79.54% yield) was a clear yellow oil and used crude in the following reaction.
1 H NMR (CDCl3, 300 MHz): 9.7807 (t, J = 1.456 Hz, 2H), 2.4892 (m, 4H), 1.6732
(m, 4H).
13 C NMR (CDCl3, 125 MHz): 201.8402 (2CH), 43.5749 (2CH2), 21.4894 (2CH2).
IR (neat): 2940.40, 1719.92, 1595.76, 1439.74, 1251.89, 1053.11 cm-1.
MS: m/z 114.9, 96.1, 81.0, 72.1.
Rf: 0.095 (20:80 EtOAc-hexane, visualized with vanillin stain).
1H NMR, 13C NMR, IR, and MS data matched literature values.38
O EtO OEt O 53
Deca-2,8-dienedioic acid diethyl ester 53: Synthesized by two different procedures.
1) The general olefination procedure of Horner, Wadsworth, and Emmons was followed.24 Sodium hydride (60% oil immersion) (1.576 g, 0.03941 moles) was washed with hexane (10 mL x 3) in a 3-neck 100 mL RBF. The RBF was cooled to 0oC, placed under nitrogen gas, and 30.0 mL of anhydrous THF was added. Diethylphoshonoacetic
109 acid ethyl ester (5.213 mL, 0.02627 moles) was slowly added and the solution stirred for
15 minutes. Hexanedial 84 (1.000 g, 0.008758 moles) was dissolved in 2.0 mL of anhydrous THF and slowly added to the solution. The solution stirred for 2.5 hours at r.t.
The reaction was quenched with DI H2O (25 mL) and extracted with ethyl acetate (25 mL x 6). The combined organic layers were washed with brine, dried over Na2SO4, and the solvent removed by rotary evaporation. The product was isolated by flash chromatography on silica gel using 20:80 ethyl acetate-hexane as eluant. The product 53
(0.5902 g, 2.324 mmoles, 26.49%) was a clear yellow oil.
2) The general oxidation procedure of Parikh and Doering was followed in situ with the general procedure of Wittig.25, 26 DMSO (33.0 mL, 465.3 mmoles) was added to a 3-neck
250 mL RBF under nitrogen gas and cooled to 0oC. A 0.3 M solution of DCM and hexanediol 83 (1.0747 g, 9.1076 mmoles) was added to the RBF. After 2 minutes, TEA
(11.8 mL, 84.6 mmoles) was added. Next, sulfur trioxide-pyridine complex (11.8 g, 84.6 mmoles) was added in one portion and the RBF flushed with nitrogen gas. The reaction stirred overnight. To ensure completion, a TLC and GC were done the next day. Once complete, the RBF was cooled to 0oC and the stabilized Wittig,
(ethoxycarbonylmethylene)triphenylphosphorane, (18.3 g, 52.5 mmoles) was added in one portion. The RBF was flushed with nitrogen gas. The reaction was allowed to slowly come to r.t. and monitored by TLC. After 4 h the reaction was complete. The RBF was
o cooled to 0 C and diluted with DCM. The reaction was quenched with DI H2O (80 mL) and extracted with ether (60 mL x 4). The combined organic layers were washed with
110
brine (120 mL x 2), dried over Na2SO4, and the solvent removed by rotary evaporation.
The product was isolated by flash chromatography on silica gel using 20:80 ethyl acetate- hexane as eluant. The product 53 (1.6400 g, 6.4567 mmoles, 70.89%) was a clear yellow oil.
1 3 4 H NMR (CDCl3, 500 MHz): 6.9388 (m, J = 15.769 Hz, J = 6.944 Hz, 2H), 5.8161
(m, 3J = 15.713 Hz, 4J = 1.577 Hz, 2H), 4.1858 (q, J = 7.170 Hz, 4H), 2.2162 (m, 4H),
1.4981 (m, 4H), 1.2893 (t, J = 7.026 Hz, 6H).
13 C NMR (CDCl3, 125 MHz): 166.6375 (2C), 148.5898 (2CH), 121.6753 (2CH),
60.1926 (2CH2), 31.8754 (2CH2), 27.4842 (2CH2), 14.2732 (2CH3).
CV: Epc = -2.375 V.
IR (neat): 2981.71, 2935.79, 2861.47, 1721.36, 1655.01, 1368.23, 1267.23, 1182.52,
1044.85 cm-1.
MS: m/z 254.2, 180.2, 135.1, 107.1, 81.1, 67.1, 55.1.
Rf: 0.31 (20:80 EtOAc-hexane, visualized with KMnO4 stain).
CO2Et CO2Et 90
Cyclohexane-1,2-diacetic acid diethyl ester 90: Synthesized from the following seven electrolysis reactions.
111
N N Ni O O 60 1 mM mediator CO Et CO Et CO Et 2 2 + 2 CO2Et CO2Et CO2Et 0.1 M nBu4NPF6, DMF 53 2 eq. CH2(CO2Me)2 54 55 -1.800 V (vs. Ag/AgCl) RVC cathode, Pt anode
1. Deca-2,8-dienedioic acid diethyl ester 53 (161.3 mg, 0.6350 mmoles) with [N,N’-
Bis(di-salicylidene)-1,2-ethylenediamine]Nickel(II) 60 (19.17 mg, 0.05899 mmoles) afforded a mixture of diastereomers 54, 55 (223.5 mg crude, 0.8730 mmoles, 137.5% crude yield, c/t = 1:1.46) as an orange oil after 24.9 h and 300.82 C of charge had passed following the general electrolysis procedure described above.
N N Ni O O 72 1 mM mediator CO Et CO Et CO Et 2 2 + 2 CO Et CO Et CO Et 2 0.1 M nBu NPF , DMF 2 2 53 4 6 54 55 2 eq. CH2(CO2Me)2 -2.100 V (vs. Ag/AgCl) RVC cathode, Pt anode
2. Deca-2,8-dienedioic acid diethyl ester 53 (159.7 mg, 0.6287 mmoles) with [N,N’-
Bis(3,5-di-tert butylsalicylidene)-1,2-ethylenediamine]Nickel(II) 72 (49.41 mg, 0.09001 mmoles) afforded a mixture of diastereomers 54, 55 (158.7 mg crude, 0.6199 mmoles,
114.3% crude yield, c/t = 1:1.36) as a dark red oil after 9.5 h and 216.91 C of charge had passed following the general electrolysis procedure described above.
112
N N Ni O O 73
CO Et 1 mM mediator CO Et CO Et 2 2 + 2 CO2Et CO2Et CO2Et 53 0.1 M nBu4NPF6, DMF 54 55 2 eq. CH2(CO2Me)2 -1.700 V (vs. Ag/AgCl) RVC cathode, Pt anode
3. Deca-2,8-dienedioic acid diethyl ester 53 (127.6 mg, 0.5024 mmoles) with [N,N’-
Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine]Nickel(II) 73 (53.7 mg, 0.0900 mmoles) afforded a mixture of diastereomers 54, 55 (237.3 mg, 0.9270 mmoles, 184.5% crude yield, c/t = 1:1.21) as a dark red oil after 17.0 h and 236.37 C of charge had passed following the general electrolysis procedure described above.
N N Ni O O 74 CO Et 1 mM mediator CO Et CO Et 2 2 + 2 CO2Et CO2Et CO2Et 53 0.1 M nBu NPF , DMF 4 6 54 55 2 eq. CH2(CO2Me)2 -2.100 V (vs. Ag/AgCl) RVC cathode, Pt anode
4. Deca-2,8-dienedioic acid diethyl ester 53 (150 mg, 0.5898 mmoles) with [(R,R)-N,N'-
Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 74 (54.3 mg,
0.0900 mmoles) afforded a mixture of diastereomers 54, 55 (111.4 mg crude, 0.4352
113 mmoles, 73.77% crude yield, c/t = 1:1.20) as an orange oil after 8.8 h and 232.54 C of charge had passed following the general electrolysis procedure described above.
N N Ni O O 75 CO Et 1 mM mediator CO Et CO Et 2 2 + 2 CO2Et CO2Et CO2Et 53 0.1 M nBu4NPF6, DMF 54 55 2 eq. CH2(CO2Me)2 -2.100 V (vs. Ag/AgCl) RVC cathode, Pt anode
5. Deca-2,8-dienedioic acid diethyl ester 53 (140 mg, 0.5505 mmoles) with [(S,S)-N,N'-
Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 75 (54.3 mg,
0.0900 mmoles) afforded a mixture of diastereomers 54, 55 (76.1 mg crude, 0.297 mmoles, 51.8% crude yield, c/t = 1:1.34) as an orange oil after 11.0 h and 156.01 C of charge had passed following the general electrolysis procedure described above.
0.1 M nBu4NPF6, DMF 2 eq. CH2(CO2Me)2 CO Et CO Et CO Et 2 2 + 2 CO Et CO Et CO Et 2 -2.600 V (vs. Ag/AgCl) 2 2 53 RVC cathode, Pt anode 54 55
6. Direct electrolysis (no catalyst) at -2.600 V with 1,10-diethyl ester-2,8-decadienedioic acid 53 (100 mg, 0.3932 mmoles) afforded a mixture of diastereomers 54, 55 (165.0 mg crude, 0.6445 mmoles, 165.0% crude yield, c/t = 1:1.33) as a yellow oil after 27.7 h and
452.12 C of charge had passed following the general electrolysis procedure described above.
114
0.1 M nBu4NPF6, DMF 2 eq. CH2(CO2Me)2 CO Et CO Et CO Et 2 2 + 2 CO Et CO Et CO Et 2 -2.100 V (vs. Ag/AgCl) 2 2
53 RVC cathode, Pt anode 54 55
7. Direct electrolysis (no catalyst) at -2.100 V with 1,10-diethyl ester-2,8-decadienedioic acid 53 (150.8 mg, 0.5937 mmoles) afforded a mixture of diastereomers 54, 55 (189.7 mg crude, 0.7410 mmoles, 124.8% crude yield, c/t = 1:1.51) as a yellow oil after 23.6 h and
138.28 C of charge had passed following the general electrolysis procedure described above.
1 H NMR (CDCl3, 500 MHz): (mixture of cis and trans) 4.1277 (q, J = 7.152 Hz, 8H),
2.4835 (dd, 2J = 14.804 Hz, 3J = 3.835 Hz, 2H, trans), 2.2420 (m, 3H, cis), 2.1988 (m,
2H, cis), 2.0961 (dd, 2J = 14.865 Hz, 3J = 8.402, 2H, trans), 1.7525 (m, 3H, trans),
1.6854 (m, 3H, trans), 1.5770 (m, 11H), 1.2543 (t, 3J = 7.124, 13H).
13 C NMR (CDCl3, 125 MHz): (cis isomer): 173.2191 (2C), 60.2978 (2CH2), 35.7571
(2CH), 35.5549 (2CH2), 28.8163 (2CH2), 23.8481 (2CH2), 13.5582 (2CH3). (trans isomer): 173.1759 (2C), 60.2643 (2CH2), 39.2826 (2CH), 39.0935 (2CH2), 32.3679
(2CH2), 25.8034 (2CH2), 14.2625 (2CH3).
IR (neat): 2981.33, 2929.77, 2856.46, 1733.16, 1439.25, 1340.52 cm-1.
MS: m/z 211.2, 169.2, 165.1, 123.1, 95.1, 81.1.
1H NMR, 13C NMR, IR, and MS data matched literature values for the cis and trans isomers.28
115
APPENDIX A.
[N,N’-BIS(DI-SALICYLIDENE)-1,2-ETHYLENEDIAMINE]NICKEL(II) SPECTRA
116
1 [N,N’-Bis(di-salicylidene)-1,2-ethylenediamine]Nickel(II) 60, H NMR (CDCl3, 500
MHz)
117
[N,N’-Bis(di-salicylidene)-1,2-ethylenediamine]Nickel(II) 60, CV (5 mM in DMF, C cathode, Pt anode, 0.1 M nBu4NPF6, potential vs Ag/AgCl, VSR = 0.1 V/s)
118
[N,N’-Bis(di-salicylidene)-1,2-ethylenediamine]Nickel(II) 60, IR (KBr)
119
APPENDIX B.
N,N’-BIS(3,5-DI-TERT-BUTYLSALICYLIDENE)-1,2-ETHYLENEDIAMINE
SPECTRA
120
1 N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-ethylenediamine 78, H NMR (CDCl3, 300
MHz)
121
APPENDIX C.
[N,N’-BIS(3,5-DI-TERT BUTYLSALICYLIDENE)-1,2-
ETHYLENEDIAMINE]NICKEL(II) SPECTRA
122
[N,N’-Bis(3,5-di-tert butylsalicylidene)-1,2-ethylenediamine]Nickel(II) 72, 1H NMR
(CDCl3, 500 MHz)
123
[N,N’-Bis(3,5-di-tert butylsalicylidene)-1,2-ethylenediamine]Nickel(II) 72, CV (1 mM in
DMF, C cathode, Pt anode, 0.1 M nBu4NPF6, potential vs Ag/AgCl, VSR = 0.1 V/s)
124
[N,N’-Bis(3,5-di-tert butylsalicylidene)-1,2-ethylenediamine]Nickel(II) 72, IR (KBr)
125
APPENDIX D.
N,N’-BIS(3,5-DI-TERT-BUTYLSALICYLIDENE)-1,2-PHENYLENEDIAMINE
SPECTRA
126
1 N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine 80, H NMR (CDCl3, 300
MHz)
127
APPENDIX E.
[N,N’-BIS(3,5-DI-TERT-BUTYLSALICYLIDENE)-1,2-
PHENYLENEDIAMINE]NICKEL(II) SPECTRA
128
[N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine]Nickel(II) 73, 1H NMR
(CDCl3, 300 MHz)
129
[N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine]Nickel(II) 73, CV (5 mM in DMF, C cathode, Pt anode, 0.1 M nBu4NPF6, potential vs Ag/AgCl, VSR = 0.1 V/s)
130
[N,N’-Bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediamine]Nickel(II) 73, IR (KBr)
131
APPENDIX F.
[(R,R)-N,N'-BIS(3,5-DI-TERT-BUTYLSALICYLIDENE)-1,2-
CYCLOHEXANEDIAMINE]NICKEL(II) SPECTRA
132
[(R,R)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 74,
1 H NMR (CDCl3, 300 MHz)
133
[(R,R)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 74, CV
(5 mM in DMF, C cathode, Pt anode, 0.1 M nBu4NPF6, potential vs Ag/AgCl, VSR = 0.1
V/s)
134
[(R,R)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 74, IR
(KBr)
135
APPENDIX G.
[(S,S)-N,N'-BIS(3,5-DI-TERT-BUTYLSALICYLIDENE)-1,2-
CYCLOHEXANEDIAMINE]NICKEL(II) SPECTRA
136
[(S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 75,
1 H NMR (CDCl3, 300 MHz)
137
[(S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 75,
13 C NMR (CDCl3, 125 MHz)
138
[(S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 75,1H
13 NMR- C NMR HSQC (CDCl3, F1: 125 MHz, F2: 500 MHz)
139
[(S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 75, CV
(5 mM in DMF, C cathode, Pt anode, 0.1 M nBu4NPF6, potential vs Ag/AgCl, VSR = 0.1
V/s)
140
[(S,S)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 75, IR
(KBr)
141
APPENDIX H.
HEXANEDIAL SPECTRA
142
1 Hexanedial 84, H NMR, CDCl3, 300 MHz
143
13 Hexanedial 84, C NMR, CDCl3, 125 MHz
144
Hexanedial 84, IR (neat)
145
Hexanedial 84, MS
146
APPENDIX I.
DECA-2,8-DIENEDIOIC ACID DIETHYL ESTER SPECTRA
147
1 Deca-2,8-dienedioic acid diethyl ester 53, H NMR (CDCl3, 500 MHz)
148
1 1 Deca-2,8-dienedioic acid diethyl ester 53, H NMR- H NMR COSY (CDCl3, 500 MHz)
149
13 Deca-2,8-dienedioic acid diethyl ester 53, C NMR (CDCl3, 125 MHz)
150
1 13 Deca-2,8-dienedioic acid diethyl ester 53, H NMR- C NMR HSQC (CDCl3, F1: 125
MHz, F2: 500 MHz)
151
Deca-2,8-dienedioic acid diethyl ester 53, CV (5 mM in DMF, C cathode, Pt anode, 0.1
M nBu4NPF6, potential vs Ag/AgCl, VSR = 0.1 V/s)
152
Deca-2,8-dienedioic acid diethyl ester 53, IR (neat)
153
Deca-2,8-dienedioic acid diethyl ester 53, MS
154
APPENDIX J.
CYCLOHEXANE-1,2-DIACETIC ACID DIETHYL ESTER SPECTRA
155
1 Cyclohexane-1,2-diacetic acid diethyl ester 90, H NMR, CDCl3, 500 MHz
156
1 1 Cyclohexane-1,2-diacetic acid diethyl ester 90, H NMR- H NMR COSY (CDCl3, 500
MHz)
157
13 Cyclohexane-1,2-diacetic acid diethyl ester 90, C NMR, CDCl3, 125 MHz
158
1 13 Cyclohexane-1,2-diacetic acid diethyl ester 90, H NMR- C NMR HSQC (CDCl3, F1:
125 MHz, F2: 500 MHz)
159
13 Cyclohexane-1,2-diacetic acid diethyl ester 90, C NMR DEPT135, CDCl3, 125 MHz
160
13 Cyclohexane-1,2-diacetic acid diethyl ester 90, C NMR DEPT90, CDCl3, 125 MHz
161
Cyclohexane-1,2-diacetic acid diethyl ester 90, IR (neat)
162
Cyclohexane-1,2-diacetic acid diethyl ester 90, MS
163
Cyclohexane-1,2-diacetic acid diethyl ester 90, (with [N,N’-Bis(di-salicylidene)-1,2- ethylenediamine]Nickel(II) 60), GC
164
Cyclohexane-1,2-diacetic acid diethyl ester 90 (with [N,N’-Bis(3,5-di-tert butylsalicylidene)-1,2-ethylenediamine]Nickel(II) 72), GC
165
Cyclohexane-1,2-diacetic acid diethyl ester 90, (with [N,N’-Bis(3,5-di-tert- butylsalicylidene)-1,2-phenylenediamine]Nickel(II) 73), GC
166
Cyclohexane-1,2-diacetic acid diethyl ester 90, (with [(R,R)-N,N'-Bis(3,5-di-tert- butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 74), GC
167
Cyclohexane-1,2-diacetic acid diethyl ester 90, (with [(S,S)-N,N'-Bis(3,5-di-tert- butylsalicylidene)-1,2-cyclohexanediamine]Nickel(II) 75), GC
168
Cyclohexane-1,2-diacetic acid diethyl ester 90, (direct electrolysis at -2.600 V), GC
169
Cyclohexane-1,2-diacetic acid diethyl ester 90, (direct electrolysis at -2.100 V), GC
170
Cis-cyclohexane-1,2-diacetic acid diethyl ester 54, 1H NMR calculated chemical shifts
(PCM(chloroform)/B3LYP/6-311+G(2d,p))
H11 H31 O H40 H15 H32 H37 H41 H29 O H38 H1 H42 H12
H10 H26 H14 H9 H23 O H27 H8 H17 H24 H28 H13 H18 O
171
Cis-cyclohexane-1,2-diacetic acid diethyl ester 54,13C NMR calculated chemical shifts
(PCM(chloroform)/B3LYP/6-311+G(2d,p))
O C7 C30 C39 C3 O C36 C2 C33
C19 C6 C5 O C22 C4 C16 C25 O
172
Trans-cyclohexane-1,2-diacetic acid diethyl ester 55,1H NMR calculated chemical shifts
(PCM(chloroform)/B3LYP/6-311+G(2d,p))
H12 H31 O H40 H16 H32 H37 H41 H8 O H38 H1 H42 H13
H11 H27 H15 H24 H10 O H28 H9 H18 H25 H29 H14 H19 O
173
Trans-cyclohexane-1,2-diacetic acid diethyl ester 55,13C NMR calculated chemical shifts
(PCM(chloroform)/B3LYP/6-311+G(2d,p))
O C7 C30 C39 C3 O C36 C2 C33
C20 C6 C5 O C23 C4 C17 C26 O
174
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