UC Santa Barbara Dissertation Template

UNIVERSITY OF CALIFORNIA

Santa Barbara

Umpolung - The “Flow” from Oxidation to Reduction.

A journey from cathodic carbon-carbon bond coupling reactions carried out in a flow reactor to the electrooxidative and photoreductive characteristics of phenanthroimidazole mediators.

A dissertation submitted in partial satisfaction of the

requirements for the degree Doctor of Philosophy

in Chemistry

Chiu Marco Lam

Committee in charge:

Professor R. Daniel Little, Chair

Professor Trevor W. Hayton

Professor Liming Zhang

Professor Javier Read de Alaniz

Professor Lior Sepunaru

June 2018 The dissertation of Chiu Marco Lam is approved.

______Professor Lior Sepunaru

______Professor Javier Read de Alaniz

______Professor Liming Zhang

______Professor Trevor W. Hayton

______Professor R. Daniel Little, Committee Chair

June 2018

Umpolung - The “Flow” from Oxidation to Reduction.

A journey from cathodic carbon-carbon bond coupling reactions carried out in a flow reactor to the electrooxidative and photoreductive characteristics of phenanthroimidazole mediators.

Chiu Marco Lam

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Acknowledgements

The research and writing of this dissertation took a long and tortuous path. Without the help and support of the people and institutions acknowledged here, I would not have been able to complete this study. While I bear sole responsibilities for the errors, omissions and imperfections in this dissertation, I am profoundly indebted to their guidance, generosity and forbearance.

Words cannot express my gratitude to members of my dissertation committee, especially my advisor Prof. R. Daniel Little. Being a caring and prudent mentor, Prof. Little has been shaping my intellectual development since our first meeting. He has had no hesitation reading numerous versions of the manuscripts, and managed to provide insightful comments and edits however impractical my ideas and writing might have been. My other committee member, Prof. Trevor W. Hayton, has also helped shape my graduate study in its initial stage. With his expertise in organometallic chemistry and knowledge of inorganic chemistry, Prof. Hayton’s invaluable advice helped me lay down a much more solid groundwork for inorganic chemistry. And Prof. Lior Sepunaru, despite a relatively late invitation, still agreed to serve as a member of my committee. His input proved to be instrumental for this study to have a genuinely interdisciplinary perspective. Prof. Javier

Read de Alaniz and Prof. Liming Zhang have also offered valuable opinions to my studies.

A special thank goes to Prof. Chengchu Zeng, for hosting me in Beijing and providing intellectual discussions.

My graduated study has been benefited greatly from researchers and institutions in the United States, China, and Germany. Beijing University of Technology, Johannes

Gutenberg-University Mainz, and University of Rostock. Prof. Kevin Moeller have always been the source of inspiration and encouragement. I have also benefited greatly from

discussion and working with Prof. Robert Francke, as well as Prof. Siegfried R. Waldvogel and his group.

I would like to express my gratitude toward my friends and colleagues in UCSB especially the Little group, the Hayton group, the Sepunaru group and the Dow lab. Thank you very much for giving me the opportunity to teach and be taught, sharing laughter and tears. I would like to thank Kunliang Wu, Yenping Lin, Gloria Mo and Siuhoi Lui for the encouragements and brought me into research. I would like to thank Sheng Sun, Kin-kei

Yim, James Chun-Pong Tam, and Stanley Fong for providing the consolation when I needed a break. I thank them for their close friendship and memories. I wish them all success.

Last but not least, I would like to express my deepest gratitude towards my parents

Chun-Kwong Lam and Siu-Yung Wong, my sister Yi, and my grandma Choi-Ying Cheng.

Without your unwavering support and love, I would not be where I am today. I owe all of my success to you.

VITA OF CHIU MARCO LAM June 2018

EDUCATION

University of California, Santa Barbara, CA Ph.D. in Chemistry (advisor: Prof. R. Daniel Little) 2018

University of California, Santa Barbara, CA B.S. in Biochemistry with a minor in History 2011

PROFESSIONAL TRAINING

Researcher Assistant 2009 - 2018 Advisor: Professor R. Daniel Little, University of California, Santa Barbara Principle research foci: 1) Development and use of a microflow reactor, especially for problematic electroreductive coupling reactions. 2) The disassembly of lignin-related structures; the dual role of electron transfer mediators in electrochemical and photoredox chemistry. 3) Research directed toward the development of a new class of electrochemical redox mediators. 4) Research directed toward the dual catalyst properties and photo-reduction potentials of an electro-oxidation triarylimidazole mediators.

Oversea graduate research in China Fall 2014 & Fall 2016 Mentor: Professor Cheng-Chu Zeng, Beijing University of Technology, China PIRE-ECCI Fellow; focus upon electron transfer chemistry achieved electrochemically.

Teaching Assistant (UCSB) 2012 - 2018 Lectured, supervised and demonstrated experiments with safety instruction to general, organic labs, and physical organic classes.

PRESENTATIONS AND CONFERENCES

 Electrode surface modification by electrografting using diazonium salts Indirect electrolysis of a lignin model, 1st Annual Meeting of Center for Sustainable Use of Renewable Feedstocks (CenSURF), UCSB. (Oral Presentation, 09/14/2013)  TEMPO-scandium triflate oxidation of benzylic alcohols Two stage cleavage of lignin model systems, 2nd Annual Meeting of Center for Sustainable Use of Renewable Feedstocks (CenSURF), UCSB. (Oral Presentation and Poster, 08/21/2014)

 Electrochemical character and application of halide mediators using CF3CH2OH as solvent, 227th National Meeting of the Electrochemical Society, Chicago, IL. (Oral presentation, 5/28/2015)  Selective and mild oxidation with TEMPO and scandium triflate, SoCal Organometallics Meeting, UC Riverside. (Poster, 12/05/2015)  Electroreductive coupling reactions using a microflow reactor, 229th National Meeting of the Electrochemical Society, San Diego, CA. (Oral presentation, 5/30/2016)  Electroreductive carbon-carbon bond coupling carried out in a flow reactor, Renewable Carbon Workshop, The Mellichamp Academic Initiative in Sustainability, UC Santa Barbara. (Poster, 9/6/2016)  Photoredox Catalyst Based on a Triarylimidazole Oxidative Electrochemical Mediator, 231th National Meeting of the Electrochemical Society, New Orleans, LA. (Oral presentation, 5/29/2017)  Photoredox Catalyst Based on a Triarylimidazole Oxidative Electrochemical Mediator, 50th Heyrovský Discussion, Třešť, Czech Republic. (Invited, Oral presentation, 6/18- 22/2017)  Photoredox Catalyst Based on a Triarylimidazole Oxidative Electrochemical Mediator, 67th Annual Meeting of The International Society of Electrochemistry, Providence, RI. (Oral presentation, 8/31/2017)

PUBLICATIONS

1. Zeng, C. C.; Zhang, N. T.; Lam, C. M.; Little, R. D. Novel triarylimidazole redox catalysts: synthesis, electrochemical properties and applicability to electrooxidative C-H activation, Org. Lett. 2012, 14, 1314-1317. 2. Zhang, N. T.; Zeng, C. C.; Lam, C. M.; Gbur, R. K.; Little, R. D. Triarylimidazole Redox Catalysts: Electrochemical Analysis and Empirical Correlations, J. Org. Chem. 2013, 78, 2104–2110. 3. Chen, J.; Yan, W. Q.; Lam, C. M.; Zeng, C. C.; Hu, L. M.; Little, R. D. Electrocatalytic Aziridination of alkenes mediated by n-Bu4NI: A Radical Pathway, Org. Lett. 2015, 4, 986-989. 4. Li, L. J.; Jiang, Y.Y.; Lam, C. M.; Zeng, C.C.; Hu, L. M.; Little, R. D. Aromatic C-H bond functionalization induced by electrochemically in situ generated tris(P- bromophenyl)aminium (TBPA) radical cation: cationic chain reactions of electron-rich aromatics with enamides, J. Org. Chem. 2015, 21, 11021-11030. 5. Kang, L. S.; Luo, M. H.; Lam, C. M.; Zeng, C. C.; Hu, L. M.; Little, R. D. Electrochemical C-H functionalization and subsequent C-S and C-N bond formation: paired electrosynthesis of 3-amino-2-thiocyanato-α,β-unsaturated carbonyl derivatives mediated by bromide ion, Green Chemistry, 2016, 18, 3767-3774. 6. Gao, W. J.; Lam, C. M.; Zeng, C. C.; Sun, B. G.; Little, R. D. Selective electrochemical C-O bond cleavage of -O-4 lignin model compounds mediated by iodide ion, Tetrahedron, 2017, 73, 2447-2454. 7. Lam, C. M.; Little, R. D.; Hayton, T. W.; Francke, R. On the Reactivity of TEMPO in the Presence of Lewis Acids: Tuning the Selectivity by Using Scandium Triflate, manuscript in preparation.

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8. Lam, C. M.; Little, R. D.; Electroreductive carbon-carbon bond coupling carried out in a flow reactor, manuscript in preparation. 9. Lam, C. M.; Little, R. D.; Photoredox Catalyst Based on an Arylimidazole Oxidative Electrochemical Mediator, manuscript in preparation.

FELLOWSHIPS AND AWARDS

 Center for Sustainable Use of Renewable Feedstocks (CENSURF) Fellowship. (2013- 2014)  The Partnership in International Research and Education in Electron Chemistry and Catalysis at Interfaces (PIRE-ECCI) Fellowship & travel grants. (2014-2015)  Roche Bioscience Distinguished Teaching Fellowship. (2015-2016)  Mellichamp Sustainability Fellowship (2016)  IRES-Research in China on Electron Chemistry and Catalysis at Interfaces Fellowship & travel grants. (2016)  The Electrochemical Society (ECS) Travel Grant for the 231st ECS Meeting, New Orleans, LA. (2017)  Doctoral Student Travel Grant (2017)  Overseas Exchange (sponsored by a PIRE-ECCI Fellowship), study with Professor Cheng-Chu Zeng of the Beijing University of Technology, Beijing, China. (Nov. 2014- Feb. 2015)  Overseas Exchange (sponsored by IRES-ECCI Fellowship), study with Professor Cheng-Chu Zeng of the Beijing University of Technology, Beijing, China. (Nov. 2016 – Jan. 2017)

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Abstract

Umpolung - The “Flow” from Oxidation to Reduction.

A journey from cathodic carbon-carbon bond coupling reactions carried out in a flow reactor to the electrooxidative and photoreductive characteristics of phenanthroimidazole mediators.

Chiu Marco Lam

Electroorganic synthesis has become an established, useful, and environmentally benign alternative to classic organic synthesis for the oxidation and the reduction of organic compounds. Electric current replaces toxic redox reagents, and the overall energy consumption may be reduced.1,2 Electroorganic chemistry provides convenient access to the chemistry of radical ions. Its unique ability to effect charge reversal (umpolung) makes it possible to achieve bond constructions that are otherwise very difficult to accomplish.3

The use of redox mediators to achieve a so-called “indirect electrolysis” offers many advantages compared to a direct electrolysis.1 A new class of redox mediator based on triarylimidazole framework was developed in our group and later further modified to a framework based on phenathroimidazole to achieve improved redox reversibility. These mediators undergo one electron oxidization at the anode to form a radical cation, and serve as oxidative catalysts. We also explored the potential of the mediators to serve as photocatalysts in reductive processes. Both dehalogenation of aromatics and reductive cyclization reactions have been investigated and will be discussed.

In addition, a microflow reactor designed for the cathodic coupling was studied.

Utilizing the flow reactor, the supporting electrolyte used was reduced by 450-fold, which made the process more environmentally friendly and cost efficient.

Scheme 1. Dual Catalytic Properties of Arylimidazole/Phenanthroimidazole Mediator.

References

1 a) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R. Green

Chem. 2010, 12, 2099–2119. b) Schäfer, H. J.; Harenbrock, M.; Klocke, E.; Plate, M.; Weiper-

Idelmann, A. Pure Appl. Chem. 2007, 79, 2047–2057. c) Sperry, J. B.; Wright, D. L. Chem. Soc.

Rev. 2006, 35, 605-621. d) Steckhan, E. Angew. Chem. Int. Ed. Engl. 1986, 25, 683-701. e) Utley, J.

Chem. Soc. Rev. 1997, 26, 157-167. f) Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492-

2521.

2 a) Hammerich, O., Speiser, B., Eds. Organic Electrochemistry 5th ed.; CRC Press: New York,

2015. b) Fry, A. J. Synthetic Organic Electrochemistry, Wiley: New York, 1989.

3 Little, R. D.; Moeller, K. D. Interface, 2002, 11, 36-42.

TABLE OF CONTENTS

1. Triarylimidazole, a metal free organic electrochemical mediator ...... 1

1.1. Mediated electroogranic synthesis ...... 1

1.2. Common synthetic routes to triarylamines ...... 6

1.3. Triarylimidazoles – a new class of electrooxidative mediator ...... 7

1.4. Synthesis, reversibility and redox potential range ...... 7

1.5. Cyclic voltammogram studies of triarylimidazole 3a in the

presence of p-methoxy benzyl alcohol ...... 10

1.6. Preparative scale electrolysis ...... 12

1.7. Mechanistic hypothesis ...... 15

1.8. Conclusions...... 16

Experimental ...... 20

2. Triarylimidazole Redox Catalysis:

Electrochemical Analysis and Empirical Correlations...... 48

2.1. Introduction ...... 48

2.2. Expanding the scope ...... 49

2.3. Voltammetry ...... 50

2.4. First oxidation potential ...... 51

2.5. Computational analysis and empirical relationship ...... 53

2.6. A rue of thumb ...... 56

2.7. Moving forward ...... 57

Experimenal ...... 59

3. A metal-free photoredox mediator based on

electrooxidative phenanthroimidazole mediators...... 104

3.1. Mediated electroorganic synthesis ...... 104

3.2. Triarylimidazole mediators ...... 107

3.3. Phenanthroimidazoles ...... 108

3.4. Comparing redox mediation with photoredox electron transfer

(PET) Phenanthroimidazoles ...... 110

3.5. Use of EPR to determine the lifetime of phenanthroimidazole

cation radicals. Can they serve as useful photoredox catalysts?...... 112

3.6. UV properties of phen-HHOMe ...... 113

3.7. Experimental test … useful photoredox catalyst? ...... 114

3.8. Is the chemistry generalizable? ...... 115

3.9. Cost effective? ...... 116

3.10. Qualitative rates as a function of aryl substituent ...... 117

3.11. Further mechanistic studies: isotope incorporation ...... 118

3.12. Mechanistic hypothesis...... 120

3.13. Broadening the scope...... 120

3.14. Concluding remarks...... 121

Experimenal ...... 125

4. Reductive coupling carried out in a flow microreactor...... 137

4.1. Organic electrochemistry ...... 137

4.2. Cathodic carbon-carbon coupling ...... 138

4.3. Mediated ERC and EHC reactions ...... 142

4.4. Mechanism of the ERC reaction ...... 143

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4.5. Sustainability issue ...... 145

4.6. New avenues ...... 147

4.7. Flow microreactos...... 147

4.8. Advantages of flow vs batch systesm ...... 148

4.9. Selected application of flow microreactor in electrochemistry ...... 148

4.10. Cathodic coupling in a flow reactor ...... 150

4.11. Further optimization of reaction conditions ...... 155

4.12. Scope ...... 157

4.13. Limitation of reaction scale ...... 160

4.14. Paried electrolysis without addition of proton donor or base ...... 161

4.15. Conclusion ...... 163

Experimenal ...... 169

5. On the Reactivity of N-Oxyl Radicals in the Presence of Lewis Acids:

Mild and Efficient Oxidation with TEMPO and Scandium Triflate...... 183

5.1. Introduction ...... 183

1 5.2. Oxygen and water stable Sc(OTf)3 (η --TEMPO) ...... 185

5.3. Optimization of reaction conditions ...... 186

5.4. Substituent studies ...... 187

5.5. Substrate scope ...... 190

5.6. Conclusion ...... 193

Experimenal ...... 197

6. Selective electrochemical C-O bond cleavage of -O-4 lignin model compounds

mediated by iodide ion...... 221

6.1. Introduction ...... 221

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6.2. Results and discussion ...... 224

6.3. Scope ...... 231

6.4. Conclusions...... 235

Experimenal ...... 238

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Chapter 1. Triarylimidazole, a metal free organic electrochemical mediator

Much of this chapter is reproduced with permission from Zeng, C.-C.; Zhang N.-T.;

Lam, C. M.; Little, R. D. Org. Lett. 2012, 14 (5), 1314-1317. Copyright [2012] American

Chemical Society.

1.1. Mediated electroorganic synthesis

Electroorganic synthesis has become an established, useful, and environmentally benign alternative to classic organic synthesis for the oxidation and the reduction of organic compounds.4 Electric current replaces toxic redox reagents, and the overall energy consumption is sometimes reduced.5,6 As is highlighted below, electroorganic chemistry provides convenient access to the chemistry of radical ions. Its unique ability to effect charge reversal (umpolung) makes it possible to achieve bond constructions that are otherwise very difficult to accomplish.7

The use of redox mediators to achieve a so-called “indirect electrolysis” offers many advantages compared to a direct electrolysis (vide infra).8 Indirect electrolysis represents a special case of electroorganic synthesis, where the electron transfer (ET) step is shifted from a heterogeneous process occurring at an electrode (a “direct electrolysis”), to a homogeneous process that affords a substance that serves to mediate electron transfer between it and the substrate (Scheme 1).5,9 Several examples of mediated processes follow. Those interested in more detail are referred to the recent comprehensive review by Francke and Little.5

Scheme 1. General principle of indirect electrolysis (top) and direct electrolysis

(bottom).

In many cases, a mediated electron transfer can occur against a potential gradient, meaning that compared with the direct oxidation or reduction of a substrate, less positive potentials are needed for an oxidation and less negative potentials for a reduction.

Consequently, the likelihood of undesired side-reactions is often reduced. For example, the use of para-substituted triarylamines, like tris(p-bromophenyl) amine (TBPA), and (2,2,6,6- tetramethylpiperidin-1-yl)oxyl (TEMPO) for the oxidation of benzylic alcohols to the corresponding carbonyl compounds occurred in a manner where potential differences of up to 500 mV were achievable.1,10 For inner-sphere mediators such as TEMPO and DDQ, which involve hydrogen or hydride abstraction, even larger potential differences, sometimes

>1 V, can be overcome.11 The ensuing reactions are typically more selective than those involving outer-sphere electron transfer, since the selectivity is not determined by the potential difference between mediator and substrate but by the chemical reactivity (Scheme

2).

Scheme 2. Outer and inner-sphere mechanisms for mediated electron transfer involving the conversion of substrate, SH, to S+ in the presence of base, B–.

The use of electron transfer mediators can also help to avoid electrode passivation resulting from polymer film formation on the electrode surface since direct interaction of the substrate with the electrode surface is avoided. An example depicted in Scheme 3 is the removal of a p-methoxybenzyl ether (PMB) protecting group from 4-phenyl-3-butenol by anodic oxidation (Scheme 3).12

Scheme 3. Mediated selective deprotection of PMB ethers.

Mediators come in many varieties including, for example, metal ions, organometallic complexes, halides, and polycyclic aromatics. A few are shown in Table 1.5 Enantioselective mediation and heterogeneous electrocatalysis using immobilized mediators, have also been investigated.13

Table 1. Some common organic electrochemical mediators.

Since Nelsen and co-workers first demonstrated that para-substituted triarylamines are electrochemically stable from neutral form to cation radical, these compounds have found applicability as photoconductors,14 light emitting devices,15 and in optical data storage.16 Triarylamines have also served as redox mediators for a host of interesting transformations. For example, Steckhan applied triarylamines to the deprotection of dithioacetals, the oxidation of alcohols and alkyl benzenes, and so on. 17 Fry and co-workers studied the anodic oxidation of alkenes bearing one or more strongly electron withdrawing substituents.18 The Little group has also performed the triarylamine-mediated rearrangement of housanes (Scheme 4) and have used the transformation as the key step in the total synthesis of daucene.19

Scheme 4. Electrochemical mediated rearrangement of housane leading to the bicyclo (4.3.0) framework. A similar rearrangement was used en route to daucene.16

As indicated above, both single and double mediatory systems exist. Torii et al. have been responsible for many doubly mediated transformations, including for example, asymmetric Sharpless dihydroxylation.20 Another noteworthy example of a double mediatory system consisted of a biphasic medium using an organic solvent and an aqueous electrolyte containing a halide salt (Scheme 5), wherein the active bromine species that is generated anodically reacts with the N-oxyl radical (TEMPO) to form the oxoammonium species, which in turn participates in the oxidation of an alcohol to a carbonyl. 21

Scheme 5. Double mediatory system (Br-/TEMPO) in biphasic electrolyte.

1.2. Common synthetic routes to triarylamines

Despite the great success of triarylamines as redox catalysts and in materials research, 1, 5 the synthesis of substituted frameworks can be problematic. In some instances, positional isomers are generated when substituents are appended after the triarylamine has been assembled, thereby leading to tedious chromatographic separation. Scheme 6 illustrates one such instance.22

Scheme 6. Nitration of tris(4-bromo)phenyl amine.

The triarylamine framework is frequently synthesized from aniline and aryl iodides via Ullman coupling, 23 and also by using the powerful Buchwald-Hartwig coupling chemistry.24 As illustrated in Scheme 7 and 8, these pathways nicely avoid the problems

inherent to the post-functionalization approach shown above, since the location of the substituents is pre-determined by ones choice of starting materials.

Scheme 7. Palladium catalyzed C-N bond cross coupling toward triarylamine

Scheme 8. Synthesis of triarylamines using CuI nanoparticles

1.3. Triarylimidazoles – a new class of electrooxidative mediator

We sought to develop a new class of organic redox catalysts subject to the conditions that they be:

(a) easy to synthesize,

(b) metal-free, and

1.4. Synthesis, reversibility and redox potential range

The synthetic route we chose to access the triarylimidazole framework is based on a work from Karimi-Jaberi. 25 The synthesis simply involves mixing benzils 1 and aldehydes

2 with methylamine and ammonium acetate along with a catalytic amount of sodium

dihydrogen phosphate, and heating the resulting mixture to 150 oC for 2-5 hours in a thick- walled tube under organic solvent-free conditions. The reaction proceeds smoothly to afford the desired triarylimidazoles in 85 – 92 % yield following recrystallization from acetone and water (Table 2).

Once in hand, cyclic voltammetry was performed in order to study the electrochemical behavior of the triarylimidazoles. The range of potentials accessible for five

1 structures is summarized in Table 2. The Pox values can be correlated with the electronegativity of the substituents. The more electron-donating the substituent(s), the

1 easier the substrate is to oxidize, and results in lower Pox . The five compounds 3a – 3e have

1 Pox range from 0.89 – 1.30 V, allow access to a potential range of 410 mV.

Table 2. Synthesis of triarylimidazoles 3a-3e and their oxidation potentials.

The cyclic voltammogram (CV) of triarylimidazole 3a exhibits three oxidation peaks at 1.26, 1.54, and 1.80 V vs Ag/AgCl (in 3M KCl) and one cathodic peak at 1.19V when 0.1

M LiClO4/CH3CN was used as the supporting electrolyte. The first oxidation peak and the reduction peak are quasi-reversible under the scan rate of 0.1 V/s. (Figure 1)

Figure 1. Cyclic voltammogram of 3a from 0 – 2.0 V appears on the left. The right side

illustrates the quasi-reversible character of the first oxidation peak. Ag/AgCl (3 M

KCl), Glassy carbon working electrode (ca.  = 3 mm), Pt auxiliary electrode. 1

mM concentration of 3a in 0.2 M LiClO4 in CH3CN/DCM (v:v = 4:1).

These observations indicate that the initially formed cation radical is stable on the

CV time scale (0.1 V/s). Of additional interest is the fact that following an initial decrease in current during the first three scans, the system settles down and the curve remains quasi- reversible. Even after 20 scans little change was observable; Figure 2 illustrates the CVs recorded for the first five scans. This behavior contrasts sharply with that for para- substituted triphenylamines since its aminium cation radical is known to dimerize when the para positions are not substituted, thereby leading to a nonreversible redox couple.

Figure 2. Five cyclic voltammogram scans of 3a.

It is noteworthy that the voltammogram is irreversible when the imidazole nitrogen is not alkylated (NH vs NCH3); this is reasonable since the cation radical ought to be strongly acidic and capable of protonating the starting material. Similar CV behaviors were also observed for N-methyl substituted triarylimidazoles, 3b-3e, and the results are summarized in Table 2 shown above.

1.5. Cyclic voltammogram studies of triarylimidazole 3a in the presence of p- methoxy benzyl alcohol.

Based on the reversible cyclic voltammograms, we reasoned that the triarylimidazole systems might be able to serve as redox catalysts similar to substituted triarylamines. To explore this hypothesis, the electrochemical behavior of triarylimidazole 3a in the presence of p-methoxy benzyl alcohol (4a) and an excess of 2,6-lutidine was investigated by cyclic voltammetry.

Figure 3. Cyclic voltammogran of triarylimidazole 3a in the absence and presence of p-

methoxyl benzyl alcohol (4a) and 2,6-lutidine. Ag/Ag reference electrode, glassy

carbon working electrode and platinum wire auxiliary electrode in 0.1 M LiClO4

in CH3CN. Scan rate: 0.1 V/s.

Curve a: 1 mM 3a.

Curve b: 1 mM 3a + 20 mM 4a.

Curve c: 1 mM 3a + 20 mM 4a + 50 mM 2,6-lutidine.

As shown in Figure 3, the anodic peak current for triarylimidazole 3a increases slightly when an excess of p-methoxyl benzyl alcohol 4a is present (compare curves a and b). When 2,6-lutidine is added, a catalytic current is observed, viz., the anodic peak current for 3a increases dramatically while the cathodic peak current disappears (curve c). Since the substrate (4a) and base are not oxidizable at the potentials shown in Figure 3 (the peak potential of p-methoxy benzyl alcohol and 2,6-lutidine are 1.52 and 1.89 V vs Ag/AgCl, respectively), the enhanced anodic current results from the mediator re-entering the catalytic cycle in the manner illustrated in Scheme 9. These observations provide clear evidence that the mediator serves as the hole carrier and that the neutral form is regenerated following

oxidation of the substrate. It also indicates that the added base has a large effect on the catalysis, and shifts the equilibrium to the product side. The reason for this behavior is discussed in detail later (note mechanistic Scheme 10).

Scheme 9. Catalyic cycle of electrooxidation of substrate via a mediator.

1.6. Preparative scale electrolysis

To further demonstrate the applicability of triarylimidazoles as redox catalysts, preparative scale electrolysis of a series of benzylic alcohols, 4a-4e, was performed using 10 mol % of the triarylimidazole mediator 3a and 2,6-lutidine (5 equiv.) as a base in

CH3CN/CH2Cl2 (v/v 4:1) with 0.2 M lithium perchlorate serving as the supporting electrolyte. The transformations were carried out at a controlled potential that matched that

1 of the mediator (i.e., at 1.26 V = Pox for 3a), and not that of the substrate (1.52 V vs

Ag/AgCl for 4a). The passage of charge led to the immediate appearance of a greenish color at the surface of the working electrode (Pt mesh) and its diffusion into the bulk solution. The addition of substrate led to an immediate color change from green to pink (Figure 4).

Figure 4. Photographs of preparative scale electrolysis of a mixture of 3a (0.1 mmol) and

2,6-lutidine (5 mmol). Before (left) and after (right) an addition of substrate 4a (1

mmol).

The electrolysis proceeded smoothly, converting 4a to p-methoxybenzaldehyde (5a) in a 65% isolated yield (Table 2, entry 1). To confirm that the outcome was due to electron transfer between the mediator and substrate, a control experiment was performed using identical conditions but in the absence of the mediator. No reaction took place.

Table 3. Oxidation potential of substrates and yield of oxidation product using 3a as the

electrochemical mediator.

In order to explore the generality and scope of the reaction, other benzylic alcohols were investigated. Under the same conditions, m-methoxybenzyl alcohol, 4b, delivered m- methoxybenzaldehyde (5b) in a 60 % yield (entry 2). This example constituted a meaningful challenge for the mediator in that the oxidation potential for the substrate 4b (1.68 V vs

Ag/AgCl) is ca. 420 mV more positive than that of the mediator, 3a (1.26 V). The chemistry

also proved applicable to secondary alcohols. Compound 4c, for example, was oxidized to the corresponding ketone (5c) in a good yield (entry 3). Alkylbenzenes can also be indirectly oxidized; for example, p-methoxybenzaldehyde was generated from 1-methoxy-4- methylbenzene, 4d, under the same reaction conditions albeit in diminished yield (entry 4).

It is worth noting that, for an efficient electron transfer to occur, the difference between the oxidation potential of the mediator and substrate should not be “too large”. 7a

When it is, no observable reaction takes place.14f, 26 This proved to be the case with 4e. Here, the 490 mV difference between the potentials of the mediator 3a and substrate 4e proved to be an unsurmountable thermodynamic impasse (entry 5).

Based upon the results described thus far and the seminal works of Steckhan and co- workers, 14 the products arise from the oxidative activation of benzylic C-H bonds (note

Scheme 10). This hypothesis suggests that the indirect oxidation of unsymmetrically substituted ethers, wherein one of the groups is an electron-rich benzyl unit, ought to lead to an oxocarbenium which can then undergo nucleophilic addition.

To explore this hypothesis, p-methoxybenzyl ethers 6 were subjected to indirect oxidation in the presence of 0.1 mL of water using 10 mol% of 3a as a redox catalyst. As shown in Table 3, for all p-methoxy substituted substrates 6a-6f, differing by less than 320 mV of the oxidation potentials of 3a, moderate yields of the corresponding ester, p- methoxybenzoate (42-55%) were obtained, along with a trace amount of p- methoxybenzaldehyde; good to excellent yields were obtained based on the recovered substrates (entry 7, Table 4). The electron transfer did not occur when 6g and 6h were examined, presumably because the difference between their oxidation potential and that of

3a was too large (>500 mV).

a Isolated yield. b Yield based on the recovered starting materials.

Table 4. Oxidation potentials of benzyl ether 6 and yields of esters 7.

1.7. Mechanistic hypothesis

A mechanism that accounts for the formation of both 5 and 7 is shown in Scheme 10.

It begins with oxidation of triarylimidazole 3 at the anode. The resulting cation radical then accepts an electron from the substrate, either 4 or 6, to afford a new cation radical 8 and regenerate the mediator, 3. Subsequent deprotonation by 2,6-lutidine, B, and oxidation of the resulting benzylic radical 9 leads to 10. When X = OH, its reaction with B affords 5, while a sequence involving capture by water, loss of two protons, and oxidation leads to 5 when X =

H and benzoate 7 when X = OR’. The prominent influence of 2,6-lutidine on the voltametric behavior shown in Figure 1 presumably reflects its role in the conversion of 8 to 9. That

transformation shifts the original redox equilibrium toward 9 and facilitates catalyst turnover

(3+• to 3).

Scheme 10. Plausible mechanism for the triarylimidazole induced oxidation of 4 and 6.

1.8. Conclusions

In summary, we have uncovered a new class of organic redox catalysts based on a triarylimidazole framework. The systems are easy to synthesize and are capable of accessing a reasonable range of potentials (410 mV) simply by adjusting the substituent pattern on the aromatic rings. The mediators exhibit quasi-reversibility, and a catalytic current is observed for the oxidation of benzyl alcohol in the presence of 2,6-lutidine. The preparative scale experiments demonstrate that they can be used to catalytically mediate the oxidation of p- methoxybenzyl alcohols and benzyl ethers.

4 Yan, M.; Kawamata, Y; Baran, P. S. Chem. Rev. 2017, 117, 13230-13319.

5 a) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R.

Green Chem. 2010, 12, 2099–2119. b) Schäfer, H. J.; Harenbrock, M.; Klocke, E.; Plate, M.;

Weiper-Idelmann, A. Pure Appl. Chem. 2007, 79, 2047–2057. c) Sperry, J. B.; Wright, D. L.

Chem. Soc. Rev. 2006, 35, 605-621. d) Steckhan, E. Angew. Chem. Int. Ed. Engl. 1986, 25,

683-701. e) Utley, J. Chem. Soc. Rev. 1997, 26, 157-167. (f) Steckhan, E. Top. Curr. Chem.

1987, 142, 1-69 and references cited therein.

6 a) Hammerich, O., Speiser, B., Eds. Organic Electrochemistry 5th ed.; CRC Press: New

York, 2015. b) Fry, A. J. Synthetic Organic Electrochemistry, Wiley: New York, 1989.

7 Little, R. D.; Moeller, K. D. Interface, 2002, 11, 36-42.

8 Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492.

9 Simonet, J.; Pilard, J.-F.in Organic Electrochemistry, 4th ed; Lund, H.; Hammerich, O.,

Eds.; Marcel Dekker: New York, 2001; 1163–1225.

10 (a) Zhang, N.-T.; Zeng, C.-C.; Lam, C. M.; Gbur, R. K.; Little, R. D. J. Org. Chem.

2013, 78, 2104-2110.

11 Utley, J.; Rozenberg, G.; J. Appl. Electrochem. 2003, 33, 525-532.

12 Schmidt, W.; Steckhan, E. Angew. Chem. Int. Ed. Engl. 1978, 9, 673-674.

13 (a) Savéant, J.-M. Chem. Rev. 2008, 108, 2348–2378. (b) Savéant, J.-M. Elements of

Molecular and Biomolecular Electrochemistry, Wiley-Interscience, Hoboken, N.J, 2006. (c)

Costentin, C.; Drouet, S.; Robert, M.; Savéant, J.-M. J. Am. Chem. Soc. 2012, 134, 11235–

11242. (d) Zhang, N.-T.; Zeng, C.-C.; Lam, C. M.; Gbur, R. K.; Little, R. D. J. Org. Chem.

2013, 78, 2104–2110.

14 Stolka, M.; Yanus, J. F.; Pai, D. M. J. Phys. Chem. 1984, 88, 4707-4714.

15 Thomas, B.; David, C.; Muller, M. G.; Klaus, M.; Oskar, N. Macromol. Rapid

Commun. 2000, 21, 583-589.

16 (a) Moerner, W. E.; Silence, S. M. Chem. Rev. 1994, 94, 127-155. (b) Wu, W.; Tang,

R.; Li, Q.; Li, Z. Chem. Soc. Rev. 2015, 44, 3997-4022.

17 (a) Brinkhaus, K. G.; Steckhan, E.; Schmidt, W. Acta Chem. Scand., Ser. B, 1983, 37,

499-507. (b) Schmidt, W.; Steckhan, E. Angew. Chem. Int. Ed. Engl. 1978, 17, 673-674. (c)

Schmidt, W.; Steckhan, E. Angew. Chem. Int. Ed. 1979, 18, 801-802. (d) Dapperheld, S.;

Steckhan, E. Angew. Chem. Int. Ed. Engl. 1982, 21, 780-781. (e) Platen, M.; Steckhan, E.

Chem. Ber. 1984, 117, 1679-1694. (f) Haberl, U.; Steckhan, E.; Blechert, S.; Wiest, O.

Chem. -Eur. J. 1999, 5, 2859-2865.

18 (a) Wu, X.; Davis, A. P.; Lambert, P. C.; Steffen, L. K.; Toy, O.; Fry, A. J.

Tetrahedron, 2009, 65, 2408-2414. (b) Wu, X.; Davis, A. P.; Fry, A. J. Org. Lett. 2007, 9,

5633-5636.

19 Park, Y. S.; Wang, S. C.; Tantillo, D. J.; Little, R. D. J. Org. Chem. 2007, 72, 4351-

4357.

20 a) Torri, S.; Liu, P.; Bhuvaneswari, N.; Amatore, C.; Jutand, A. J. Org. Chem. 1996,

61, 3055-3060. b) Jutand, A. Chem. Rev. 2008, 108, 2300-2347.

21 Inokuchi, T.; Matsumoto, S.; Torii, S. J. Org. Chem. 1991, 56, 2416–2421.

22 (a) Wu, X.; Dube, M. A.; Fry, A. J. Tetrahedron Lett, 2006, 47, 7667-7669. (b) Lartia,

R; Allain, C.; Bordeau, G.; Schmidt, F.; Fiorini-Debuisschert, C. Charra, F; Teulade-Fichou,

M.-P. J. Org. Chem. 2008, 73, 1732-1744.

23 (a) Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64, 670-674. (b) Hassan, J.;

Sevignon, M.; Gozzi, C.; Schulz, E.; Lemair, M. Chem. Rev. 2002, 102, 1359-1470. (c)

Safaei-Ghomi, J.; Akbarzadeh, Z.; Ziarati, A. RSC Adv. 2014, 4, 16385-16390.

24 (a) Kataoka, N.; Shelby, Q. Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67,

5553-5566. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin J. J.; Buchwald, S. L. J. Org.

Chem. 2000, 65, 1158-1174. (c) Hartwig, J. F., Angew. Chem. Int. Ed. Engl. 1998, 37, 2046-

2067. (d) Louie, J; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 11695 – 11696. (e) Hartwig,

J. F. Synlett, 1997, 4, 329-340.

25 Karimi-Jaberi, Z.; Barekat, M. Chin. Chem. Lett. 2010, 21, 1183-1186.

26 Miranda, J. A.; Wade, C. J.; Little, R. D. J. Org. Chem. 2005, 70, 8017-8026.

Triarylimidazole, a metal free organic electrochemical mediator Experimental

Much of this chapter is reproduced with permission from Zeng, C.-C.; Zhang N.-T.;

Lam, C. M.; Little, R. D. Org. Lett. 2012, 14 (5), 1314-1317. Copyright [2012] American

Chemical Society.

Experimental Section

General information

All solvents were of commercial quality and were dried and purified by conventional methods. Melting points (mp) were determined on XT4A Electrothermal apparatus quipped with a microscope and were uncorrected. Infrared spectra (IR) were recorded as thin films on

KBr plates with a Bruker IR spectrophotometer and are expressed in v (cm-1). The 1H NMR and 13C NMR spectra were obtained using an AV 400 M Bruker spectrometer in solvent

(CDCl3 or DMSO-d6) with TMS as internal reference. Anisyl acetate was synthesized as previously described and all spectroscopic data were consistent with those reported for this compound.27

General procedure for the synthesis of triarylimidazoles.

A mixture of the benzil of choice (5 mmol), methylamine (5 mmol), aldehyde (5 mmol), ammonium acetate (5 mmol) and NaH2PO4 (1.5 mmol) was added to a thick-walled test-tube with a screw-on Teflon top. The reaction mixture was heated to 150 oC and maintained at the temperature for 2-5 hours; the reaction mixture was stirred throughout.

Then the reaction mixture was cooled to room temperature. Acetone was added to dissolve

the mixture and the undissolved residue was removed by filtration. After evaporation of the solvent under reduced pressure, the resulting solid residue was recrystallized from acetone– water to obtain pure products 3.

2-(4-Bromophenyl)-1-methyl-4,5-diphenyl-1H-imidazole (3a).28 Yield: 92%; Yellow

o 1 needles, m.p.: 201-202 C; H NMR (400 MHz, CDCl3): 3.50 (s, 3H, CH3), 7.16 (t,

1H, J = 7.2 Hz, Ar-H), 7.22 (t, 2H, J = 7.2 Hz, Ar-H), 7.39-7.41 (m, 2H, Ar-H), 7.45-7.48

(m, 3H, Ar-H), 7.52-7.54 (m, 2H, Ar-H), 7.63 (d, 2H, J = 8.8 Hz, Ar-H), 7.65 (d, 2H, J =

8.8 Hz, Ar-H).

2-(4-Bromophenyl)-4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole (3b). Yield:

87%; Yellow needles, m.p.: 169-171 oC; IR: 3430, 2949, 2831, 1614, 1464, 1105, 1010,

1 834; H NMR (400 MHz, CDCl3): 3.49 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 3.88 (s, 3H,

OCH3), 6.78 (d, 2H, J = 8.8 Hz, Ar-H), 7.00 (d, 2H, J = 8.8 Hz, Ar-H), 7.30 (d, 2H, J = 8.8

Hz, Ar-H), 7. (d, 2H, J = 8.8 Hz, Ar-H), 7.62 (d, 2H, J = 8.8 Hz, Ar-H), 7.65 (d, 2H, J =

13 8.8 Hz, Ar-H); C NMR (100 MHz, CDCl3): 33.1, 55.1, 55.3, 113.5, 114.5, 122.9, 123.1,

127.3, 128.0, 129.8, 130.0, 130.4, 131.8, 132.1, 137.6, 146.3, 158.2, 159.8. HRMS

(+ESI/TOF) m/z calculated for C24H22N2O2Br [M+H]+ 449.0865; found 449.0850.

2,4,5-Tris(4-bromophenyl)-1-methyl-1H-imidazole (3c). Yield: 86%; Yellow needles,

o 1 m.p.: 229-231 C; IR: 3432, 2918, 1475, 1009, 834; H NMR (400 MHz, DMSO-d6):

3.49 (s, 3H, CH3), 7.36 (d, 2H, J = 8.4 Hz, Ar-H), 7.42 (d, 2H, J = 8.4 Hz, Ar-H), 7.47

13 (d, 2H, J = 8.4 Hz, Ar-H), 7.75-7.76 (m, 6H, Ar-H); C NMR (100 MHz, CDCl3): 33.3,

120.6, 123.3, 123.4, 128.5, 129.4, 129.5, 129.8, 130.5, 131.4, 131.9, 132.3, 132.6, 133.1,

137.3, 147.3. HRMS (+ESI/TOF) m/z calculated for C22H16N2Br3 [M+H]+ 544.8864; found

544.8845.

2-(4-Methoxyphenyl)-1-methyl-4,5-diphenyl-1H-imidazole (3d).29 Yield:88%; White

o 1 needles, m.p.: 166-167 C; H NMR (400 MHz, CDCl3): 3.48 (s, 3H), 3.87 (s, 3H), 7.02

(d, J = 8.8 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 2H), 7.40-7.42 (m, 2H),

7.44-7.48 (m, 3H), 7.54-7.56 (m, 2H), 7.68 (d, J = 8.8 Hz, 2H).

2,4,5-Tris(4-methoxyphenyl)-1-methyl-1H-imidazole (3e).30 Yield: 85%; White

o needles, m.p.: 116-118 C; 1H NMR (400 MHz, CDCl3): 3.45 (s, 3H), 3.77 (s, 3H), 3.87

(s, 3H), 3.88 (s, 3H), 6.77 (d, J = 8.8 Hz, 2H), 6.99-7.02 (m, 4H), 7.31 (d, J = 8.8 Hz, 2H),

7.49 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H).

Cyclic voltammetry measurement of redox catalyst 3a and substrates 4 and 6.

Cyclic voltammograms were measured using a 273A Potentiostat/Galvanostat

(Princeton Applied Research) equipped with an electrochemical analysis software, using a conventional three-electrode cell. The working electrode was a glassy carbon disk electrode

(ca. = 3 mm). The auxiliary and reference electrodes in these studies were Pt wire and

-1 Ag/AgCl (in 3 M KCl), respectively. LiClO4 (0.2 mol L ) in mixed solution of acetonitrile and dichloromethane (V:V = 4:1) was used as supporting electrolyte system. The concentration of each triarylimidazole was 1 mM.

Synthesis of benzyl ether substrates

The synthesis of each benzyl ether follows a known procedure.31

1-Bromo-4-((4-methoxybenzyloxy)methyl)benzene (5a). 32 White solid, m.p.: 32-33

o 1 C; H NMR (400 MHz, CDCl3): 3.81 (s, 3H, OCH3), 4.47 (s, 2H, OCH2), 4.48 (s, 2H,

OCH2), 6.89 (d, 2H, J = 8.8 Hz, Ar-H), 7.23 (d, 2H, J = 8.0 Hz, Ar-H), 7.28 (d, 2H, J = 8.8

Hz, Ar-H), 7.70 (d, 2H, J = 8.0 Hz, Ar-H).

1-Chloro-4-((4-methoxybenzyloxy)methyl)benzene (5b).33 Yellow oil, 1H NMR (400

MHz, CDCl3): 3.79 (s, 3H, OCH3), 4.47 (s, 2H, OCH2), 4.48 (s, 2H, OCH2), 6.88 (d,

2H, J = 8.8 Hz, Ar-H), 7.13-7.32 (m, 6H, Ar-H).

1-(Benzyloxymethyl)-4-methoxybenzene (5c).34 Yellow oil, 1H NMR (400 MHz,

CDCl3): 3.81 (s, 3H, OCH3), 4.49 (s, 2H, OCH2), 4.53 (s, 2H, OCH2), 6.89 (d, 2H, J = 8.4

Hz, Ar-H), 7.28-7.30 (m, 3H, Ar-H) 7.35-7.36 (m, 4H, Ar-H).

1-Bromo-3-((4-methoxybenzyloxy)methyl)benzene (5d). (CAS No.: 1274038-52-6)

1 Yellow oil, H NMR (400 MHz, CDCl3): 3.82 (s, 3H, OCH3), 4.49 (s, 2H, OCH2), 4.50

(s, 2H, OCH2), 6.90 (d, 2H, J = 8.4 Hz, Ar-H), 7.21 (t, 1H, J = 7.6 Hz, Ar-H), 7.29 (d, 2H, J

= 8.4 Hz, Ar-H) 7.41 (d, 1H, J = 8.0 Hz, Ar-H), 7.52 (s, 1H, Ar-H.).

1-Methoxy-4-((4-methylbenzyloxy)methyl)benzene (5e).7 (CAS No.: 7500-74-5)

1 Yellow oil, H NMR (400 MHz, CDCl3): 2.38 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.50 (s,

2H, OCH2), 4.52 (s, 2H, OCH2), 6.92 (d, 2H, J = 8.8 Hz, Ar-H), 7.19 (d, 2H, J = 7.6 Hz, Ar-

H), 7.27-7.33 (m, 4H, Ar-H).

4,4'-Oxybis(methylene)bis(methoxybenzene) (5f).8 White solid, m.p.: 37-38 oC; 1H

NMR (400 MHz, CDCl3): 3.81 (s, 6H, OCH3), 4.46 (s, 4H, OCH2), 6.89 (d, 4H, J = 8.4

Hz, Ar-H), 7.29 (d, 4H, J = 8.0 Hz, Ar-H)

1-((4-Bromobenzyloxy)methyl)-3-methoxybenzene (5g). (CAS No.: 1275106-87-0)

Yellow oil, 1H NMR (400 MHz, CDCl3): 3.81 (s, 3H, OCH3), 4.50 (s, 2H, OCH2),

4.53 (s, 2H, OCH2), 6.83-6.94 (m, 3H, Ar-H), 7.23-7.29 (m, 3H, Ar-H), 7.47-7.49 (m,

2H, Ar-H).

1-Bromo-3-((3-methoxybenzyloxy)methyl)benzene (5h). (CAS No.: 1274037-93-2)

Yellow oil, 1H NMR (400 MHz, CDCl3): 3.81 (s, 3H, OCH3), 4.51 (s, 2H, OCH2),

4.54 (s, 2H, OCH2), 6.84-7.53 (m, 8H, Ar-H).

General procedure for the preparative scale electrolysis of 4.

The preparative scale electrolytic setup consists of a 100 mL H-type cell equipped with a medium glass frit as a membrane. The anode compartment is fitted with a platinum mesh (2 × 3 cm) as the anode and a polished silver wire as the quasi-reference electrode, immersed in electrolyte solution in a glass cylinder with a fine glass frit at its end. A platinum plate (1×2 cm) served as the counter electrode and resides in the cathode compartment.

To the anode and cathode compartments of the H-type cell was added, respectively30 mL and 10 mL of 0.2 M LiClO4 supporting electrolyte in CH3CN/CH2Cl2 (V:V = 4:1) mixed solution. Then redox catalyst 3a (0.1 mmol), substrate 4 (1 mmol) and 2,6-lutidine (5 mmol) were added to the anode compartment and electrolysis was performed at potential 1.26 V

(vs. Ag/AgCl, 1.06 V vs Ag wire) controlled by the 273A Potentiostat/Galvanostat. During electrolysis, the mixture was stirred using a magnetic stirrer. The electrolysis was terminated when the current decreased to less than 1 mA. After electrolysis, the anolyte solution was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with water (2 × 20 mL). The organic layer was dried over MgSO4. Pure product was isolated by flash chromatography, eluting with a mixture of ethyl acetate and petroleum ether.

Photographs of preparative scale electrolysis

Electrolysis of a mixture of mediator 3a (0.1 mmol) and lutidine (5 mmol) before (left photo) and after (right photo) an addition of substrate 4a (1 mmol)

35 1 4-Methoxybenzaldehyde. Clear oil, H NMR (400 MHz, CDCl3): δ 3.89 (s, 3H,

OCH3), 7.01 (d, 2H, J = 8.8 Hz, Ar-H), 7.85 (d, 2H, J = 8.8 Hz, Ar-H), 9.89 (s, 1H,

CHO).

9 1 3-Methoxybenzaldehyde. Clear oil, H NMR (400 MHz, CDCl3): δ 3.88 (s, 3H,

OCH3), 7.18-7.56 (m, 4H), 10.00 (s, 1H, CHO).

36 1 1-(4-Methoxyphenyl)ethanone. Clear oil, H NMR (400 MHz, CDCl3): δ 2.56 (s,

3H, CH3), 3.87 (s, 3H, OCH3), 6.93 (d, 2H, J = 8.8 Hz, Ar-H), 7.94 (d, 2H, J = 8.8 Hz,

Ar-H).

General procedure for the preparative scale of electrolysis of benzyl

Ethers.

To the anode and cathode compartments of the H-type cell was added, respectively,

30 mL and 10 mL of 0.2 M LiClO4 supporting electrolyte in moist (0.1 mL of water was added to the anode compartment) CH3CN/CH2Cl2 (V:V = 4:1) mixed solution. Then redox catalyst 3a (0.1 mmol), benzyl ether 6 (1 mmol) and 2,6-lutidine (5 mmol) were added to the anode compartment and electrolysis was performed at potential 1.26 V (vs. Ag/AgCl, 1.06 V vs Ag wire) controlled by the 273A Potentiostat/Galvanostat. During the electrolysis, a magnetic stirrer was used. The electrolysis was terminated when the current decreased to less than 1 mA. After electrolysis, the anolyte solution was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with water (2 × 20 mL). The organic layer was dried over MgSO4. Pure product was isolated by flash chromatography eluted with a mixture of ethyl acetate and petroleum ether.

4-Bromobenzyl 4-methoxybenzoate (6a).37 (CAS No.: 108939-27-1) White crystal,

o 1 m.p.: 88-89 C; H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H, OCH3), 5.28 (s, 2H,

OCH2), 6.92 (d, 2H, J = 8.8 Hz, Ar-H), 7.31 (d, 2H, J = 8.0 Hz, Ar-H), 7.51 (d, 2H, J

13 = 8.0 Hz, Ar-H), 8.01 (d, 2H, J = 8.8 Hz, Ar-H); C NMR (100 MHz, CDCl3): δ 55.5,

65.6, 113.7, 122.3, 128.9, 129.8, 130.9, 131.7, 135.3, 163.6, 166.1.

4-Chlorobenzyl 4-methoxybenzoate (6b).38 White crystal, m.p.: 78-79 oC; 1H NMR

(400 MHz, CDCl3): δ 3.86 (s, 3H, OCH3), 5.29 (s, 2H, OCH2), 6.92 (d, 2H, J = 8.8 Hz,

Ar-H), 7.34-7.39 (m, 4H, Ar-H), 8.02 (d, 2H, J = 8.8 Hz, Ar-H); 13C NMR (100 MHz,

CDCl3): δ 55.5, 65.6, 113.6, 122.3, 128.7, 129.4, 131.7, 134.0, 134.8, 163.5, 166.0.

12 Benzyl 4-methoxybenzoate (6c). Clear oil, 1H NMR (400 MHz, CDCl3): δ 3.86 (s,

3H, OCH3), 5.34 (s, 2H, OCH2), 6.91 (d, 2H, J = 8.8 Hz, Ar-H), 7.34-7.45 (m, 5H,

Ar-H), 8.04 (d, 2H, J = 8.8 Hz, Ar-H).

3-Bromobenzyl 4-methoxybenzoate (6d). (CAS No.: 671803-63-7) Clear oil, 1H

NMR (400 MHz, CDCl3): δ 3.87 (s, 3H, OCH3), 5.30 (s, 2H, OCH2), 6.94 (d, 2H, J =

8.8 Hz, Ar-H), 7.24-7.71 (m, 4H, Ar-H), 8.04 (d, 2H, J = 8.8 Hz, Ar-H); 13C NMR (100

MHz, CDCl3): δ 55.5, 65.6, 113.7, 122.2, 122.6, 126.6, 130.2, 131.0, 131.2, 131.8, 138.6,

163.6, 166.0.

39 4-Methylbenzyl 4-methoxybenzoate (6e). Clear oil, 1H NMR (400 MHz, CDCl3): δ

2.35 (s 3H, CH3), 3.85 (s, 3H, OCH3), 5.29 (s, 2H, OCH2), 6.90 (d, 2H, J = 8.8 Hz,

Ar-H), 7.19 (d, 2H, J = 8.0 Hz, Ar-H), 7.34 (d, 2H, J = 8.0 Hz, Ar-H), 8.02 (d, 2H, J =

8.8 Hz, Ar-H).

12 4-Methoxybenzyl 4-methoxybenzoate (6f). Clear oil, 1H NMR (400 MHz, CDCl3):

δ 3.82 (s 3H, OCH3), 3.85 (s, 3H, OCH3), 5.27 (s, 2H, OCH2), 6.88-6.92 (m, 4H,

Ar-H), 7.38 (d, 2H, J = 8.4 Hz, Ar-H), 8.01 (d, 2H, J = 8.8 Hz, Ar-H).

Spectral data – redox catalyst 3b and 3c.

1H NMR spectrum of redox catalyst 3b (peak at ~2.1 is acetone; it was used in recrystallization). HRMS (+ESI/TOF) m/z calculated for C24H22N2O2Br [M+H]+ 449.0865; found 449.0850.

13C NMR spectrum of redox catalyst 3b

IR spectrum of redox catalyst 3b

1H NMR spectrum of redox catalyst 3c (peak at ~2.1 is acetone, ~ 2.5 corresponds to

6 incompletely deuterated DMSO-d , ~3.3 to water in the DMSO-d6). HRMS (+ESI/TOF) m/z calculated for C22H16N2Br3 [M+H]+ 544.8864; found 544.8845.

13C NMR spectrum of redox catalyst 3c

IR spectrum of redox catalyst 3c

30 mL and 10 mL of 0.2 M LiClO4 supporting electrolyte in CH3CN/CH2Cl2 (V:V = 4:1) mixed solution. Then redox catalyst 3a (0.1 mmol), substrate 4 (1 mmol) and 2,6-lutidine (5 mmol) were added to the anode compartment and electrolysis was performed at potential

1.26 V (vs. Ag/AgCl, 1.06 V vs Ag wire) controlled by the 273A Potentiostat/Galvanostat.

During electrolysis, the mixture was stirred using a magnetic stirrer. The electrolysis was terminated when the current decreased to less than 1 mA. After electrolysis, the anolyte solution was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with water (2 × 20 mL). The organic layer was dried over MgSO4. Pure product was isolated by flash chromatography, eluting with a mixture of ethyl acetate and petroleum ether.

Photographs of preparative scale electrolysis

Electrolysis of a mixture of mediator 3a (0.1 mmol) and lutidine (5 mmol) before (left photo) and after (right photo) an addition of substrate 4a (1 mmol)

40 1 4-Methoxybenzaldehyde. Clear oil, H NMR (400 MHz, CDCl3): δ 3.89 (s, 3H,

OCH3), 7.01 (d, 2H, J = 8.8 Hz, Ar-H), 7.85 (d, 2H, J = 8.8 Hz, Ar-H), 9.89 (s, 1H,

CHO).

9 1 3-Methoxybenzaldehyde. Clear oil, H NMR (400 MHz, CDCl3): δ 3.88 (s, 3H,

OCH3), 7.18-7.56 (m, 4H), 10.00 (s, 1H, CHO).

41 1 1-(4-Methoxyphenyl)ethanone. Clear oil, H NMR (400 MHz, CDCl3): δ 2.56 (s,

3H, CH3), 3.87 (s, 3H, OCH3), 6.93 (d, 2H, J = 8.8 Hz, Ar-H), 7.94 (d, 2H, J = 8.8 Hz,

Ar-H).

General procedure for the preparative scale of electrolysis of benzyl

Ethers.

To the anode and cathode compartments of the H-type cell was added, respectively,

4-Bromobenzyl 4-methoxybenzoate (6a).42 (CAS No.: 108939-27-1) White crystal,

o 1 m.p.: 88-89 C; H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H, OCH3), 5.28 (s, 2H,

OCH2), 6.92 (d, 2H, J = 8.8 Hz, Ar-H), 7.31 (d, 2H, J = 8.0 Hz, Ar-H), 7.51 (d, 2H, J

13 = 8.0 Hz, Ar-H), 8.01 (d, 2H, J = 8.8 Hz, Ar-H); C NMR (100 MHz, CDCl3): δ 55.5,

65.6, 113.7, 122.3, 128.9, 129.8, 130.9, 131.7, 135.3, 163.6, 166.1.

4-Chlorobenzyl 4-methoxybenzoate (6b).43 White crystal, m.p.: 78-79 oC; 1H NMR

(400 MHz, CDCl3): δ 3.86 (s, 3H, OCH3), 5.29 (s, 2H, OCH2), 6.92 (d, 2H, J = 8.8 Hz,

Ar-H), 7.34-7.39 (m, 4H, Ar-H), 8.02 (d, 2H, J = 8.8 Hz, Ar-H); 13C NMR (100 MHz,

CDCl3): δ 55.5, 65.6, 113.6, 122.3, 128.7, 129.4, 131.7, 134.0, 134.8, 163.5, 166.0.

12 Benzyl 4-methoxybenzoate (6c). Clear oil, 1H NMR (400 MHz, CDCl3): δ 3.86 (s,

3H, OCH3), 5.34 (s, 2H, OCH2), 6.91 (d, 2H, J = 8.8 Hz, Ar-H), 7.34-7.45 (m, 5H,

Ar-H), 8.04 (d, 2H, J = 8.8 Hz, Ar-H).

3-Bromobenzyl 4-methoxybenzoate (6d). (CAS No.: 671803-63-7) Clear oil, 1H

NMR (400 MHz, CDCl3): δ 3.87 (s, 3H, OCH3), 5.30 (s, 2H, OCH2), 6.94 (d, 2H, J =

8.8 Hz, Ar-H), 7.24-7.71 (m, 4H, Ar-H), 8.04 (d, 2H, J = 8.8 Hz, Ar-H); 13C NMR (100

MHz, CDCl3): δ 55.5, 65.6, 113.7, 122.2, 122.6, 126.6, 130.2, 131.0, 131.2, 131.8, 138.6,

163.6, 166.0.

44 4-Methylbenzyl 4-methoxybenzoate (6e). Clear oil, 1H NMR (400 MHz, CDCl3): δ

2.35 (s 3H, CH3), 3.85 (s, 3H, OCH3), 5.29 (s, 2H, OCH2), 6.90 (d, 2H, J = 8.8 Hz,

Ar-H), 7.19 (d, 2H, J = 8.0 Hz, Ar-H), 7.34 (d, 2H, J = 8.0 Hz, Ar-H), 8.02 (d, 2H, J =

8.8 Hz, Ar-H).

12 4-Methoxybenzyl 4-methoxybenzoate (6f). Clear oil, 1H NMR (400 MHz, CDCl3):

δ 3.82 (s 3H, OCH3), 3.85 (s, 3H, OCH3), 5.27 (s, 2H, OCH2), 6.88-6.92 (m, 4H,

Ar-H), 7.38 (d, 2H, J = 8.4 Hz, Ar-H), 8.01 (d, 2H, J = 8.8 Hz, Ar-H).

Spectral data – redox catalyst 3b and 3c.

1H NMR spectrum of redox catalyst 3b (peak at ~2.1 is acetone; it was used in recrystallization). HRMS (+ESI/TOF) m/z calculated for C24H22N2O2Br [M+H]+ 449.0865; found 449.0850.

13C NMR spectrum of redox catalyst 3b

IR spectrum of redox catalyst 3b

1H NMR spectrum of redox catalyst 3c (peak at ~2.1 is acetone, ~ 2.5 corresponds to

6 incompletely deuterated DMSO-d , ~3.3 to water in the DMSO-d6). HRMS (+ESI/TOF) m/z calculated for C22H16N2Br3 [M+H]+ 544.8864; found 544.8845.

13C NMR spectrum of redox catalyst 3c

IR spectrum of redox catalyst 3c

References

27 (a) Ardeshir, K.; Amin, R.; Fatemeh, M. Chin. Chem. Lett. 2010, 21, 1430-1434. (b)

Hilborn, J. W.; MacKnight, E.; Pincock, J. A.; Wedge, P. J. J. Am. Chem. Soc. 1994, 116,

3337-3346.

28 Alireza, E.; Abdolkarim, Z.; Mohsen, S.; Javad, A.R. J. Comb. Chem. 2010, 12, 844-

849.

29 Zoltan, M.; Csaba, H.; Jozsef, N.; Jeno, F.; Maria, K. P.; Jozsef, N. ACH - Models

Chem. 1999, 136, 393-405.

30 Fumitoshi, S.; Eiji, Y.; Toshiaki, M. J. Org. Chem. 2011, 76, 2680-2693.

31 Chakraborti, A. K.; Chankeshwara, S. V. J. Org. Chem. 2009, 74, 1367-1370.

32 Donde, Y,; Nguyen, J. H. PCT Int. Appl., 2006063179, 15 Jun 2006.

33 Pratt, E. F.; Erickson, P. W. J. Am. Chem. Soc. 1956, 78, 76-78.

34 Molander, G. A.; Canturk, B. Org. Lett. 2008, 10, 2135-2138.

35 Miao, C. X.; He, L. N.; Wang, J. L.; Wu, F. J. Org. Chem. 2010, 75, 257-260.

36 Liu, Y.; Yao, B.; Deng, C. L.; Tang, R. Y.; Zhang, X. G. ; Li, J. H. Org. Lett. 2011, 13,

2184-2187.

37 Fiekers, B. A.; Di Geronimo, E. M. J. Am. Chem. Soc. 1948, 70, 1654-1654.

38 Yamashita, M.; Ohishi, T. Appl. Organomet. Chem. 1993, 7, 357-361.

39 Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777-12782.

40 Miao, C. X.; He, L. N.; Wang, J. L.; Wu, F. J. Org. Chem. 2010, 75, 257-260.

41 Liu, Y.; Yao, B.; Deng, C. L.; Tang, R. Y.; Zhang, X. G. ; Li, J. H. Org. Lett. 2011, 13,

2184-2187.

42 Fiekers, B. A.; Di Geronimo, E. M. J. Am. Chem. Soc. 1948, 70, 1654-1654.

43 Yamashita, M.; Ohishi, T. Appl. Organomet. Chem. 1993, 7, 357-361.

44 Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777-12782.

Chapter 2. Triarylimidazole Redox Catalysis: Electrochemical

Analysis and Empirical Correlations.

Much of this chapter is reproduced with permission from Zhang, N.-T.; Zeng, C.-C.;

Lam, C. M.; Gbur, R. K.; Little, R. D. J. Org. Chem. 2013, 78, 2104-2110. Copyright [2013]

American Chemical Society.

2.1. Introduction

The synthesis and characterization of a new class of metal-free organic redox mediators based on the triarylimidazole scaffold was first reported by Zeng and Little in

2012.1 The synthetic route used to access them is shown in Scheme 1. It follows a known procedure wherein an aqueous solution consisting of a mixture of a benzil (1), an aldehyde

(2), methylamine and ammonium acetate in the presence of a catalytic amount of sodium dihydrogen phosphate, are heated to 150 °C in a thick-walled tube fitted with a screw-on

Teflon top.2 The reaction proceeds smoothly to afford the desired triarylimidazoles in excellent yields (generally >85%).

Scheme 1. Synthesis of triarylimidazoles.

The mediators are electrochemically stable and served as effective mediators for the oxidation of electron-rich benzylic alcohols and ethers, converting each to the corresponding carbonyl compounds (Scheme 2). Given these promising results, coupled with the prospect that like the widely used triarylamines,3 the triarylimidazoles might find applicability as light emitting devices and/or in lithium ion battery research,4 we elected to expand the scope of the investigations.

Scheme 2. Indirect anodic oxidation mediated by 3af.

2.2. Expanding the scope

Herein we (1) describe the synthesis and electrochemical characterization of a series of 30 triarylimidazoles (Table 1), (2) demonstrate the generality of the synthetic route, (3) address how the nature of substituents influence the oxidation potential of the mediator, and

(4) correlate redox properties with molecular structure. The existence of a linear correlation between the first oxidation potential of the redox catalysts and both Hammett σ+ substituent constants (Σσ+) as well as the calculated ionization potentials is also demonstrated.5 These correlations allow one to predict the potential for systems yet to be synthesized and will assist in determining which catalyst may be best suited to a particular need.

2.3. Voltammetry

The electrochemical properties of the triarylimidazoles were studied using cyclic voltammetry and the results are summarized in Table 1. Samples were dissolved in a solution of acetonitrile and dichloromethane (4:1 V:V) containing 0.2 M LiClO4 as the supporting electrolyte. A glassy carbon disk served as the working electrode and a Pt wire

1 the counter electrode. The oxidation potentials, measured at the peak are designated as Eox , and are reported relative to 0.1 M Ag/AgCl. With one exception (structure 3ai), all 30 imidazoles exhibit three oxidation peaks and one cathodic peak, the latter being associated with the first of the three peaks. The first redox couple is quasi-reversible with the current being slightly smaller during the reduction scan. Thus, the initially formed cation radicals display good stability on the time scale of the CV measurement.

Figure 1. The quasi-reversible character of triarylimidazole mediator 3af.

2.4. First oxidation potential

a The value in parentheses corresponds to oxidation potential of the correspondingly substituted triarylamine (data from Fry et al.)6.

1 Table 1. Peak potential, Eox , of the first oxidation peak for three series of triarylimidazoles

The data in Table 1 is organized into three columns and ten rows. In each column, R2 is held constant, namely, H for 3aa−3aj, OMe for 3ba−3bj, and Br for 3ca−3cj, while R1 varies, becoming progressively more electron withdrawing as one reads down a column. For

1 1 1 the family 3aa−3aj, Eox spans from 0.77 for 3aa (R = 4-N(CH3)2) to 1.37 V for 3aj (R =

4-NO2), a range of 600 mV.

In the case of redox catalyst 3ae where R1 is H, its oxidation potential is 1.23 V.

1 When R is -N(Me)2, OMe or Me, the potentials shift in accord with the electron donating

character of the substituent, from 0.77 V (3aa), to 1.14 V (3ab), to 1.22 V (3ad), respectively. In contrast, the oxidation occurs at more positive potentials when R1 is electron withdrawing. For example, the oxidation potentials of 3ag and 3ai increase to 1.29 and 1.38

1 V when R is either F or CF3, respectively.

Similar trends are observed for the family of redox catalysts 3ba−3bj (R2 = OMe) and 3ca−3cj (R2 = Br). For the former, the oxidation potentials span 400 mV, changing from

0.71 to 1.11 V, while for 3ca−3cj the range is 620 mV, spanning from 0.82 to 1.44 V. Once

1 1 again, we see that the Eox values are affected qualitatively by the electronic character of R , namely, the more electron donating the substituent(s), the easier the substrate is to oxidize.

1 The Eox values of the redox catalysts are also dependent upon the electronic character of R2 when values are compared for the same R1 groups. For example, the

1 oxidation potential of 3aa (R = N(CH3)2) is 0.77 V, and rises to 0.82 V when an inductively withdrawing Br is introduced, and decreases to 0.71 when OMe is present. Similarly, when

R1 = H, the oxidation potentials changes from 1.23 for 3ae (R2 = H), to 1.02 V (3be; R2 =

OMe) to 1.30 V (3ce, R2 = Br).

The inductively withdrawing character of Br is clearly evident when one compares the data for the series of redox catalysts 3ae-3af-3ce-3cf. Each member of the series has one more p-Br group than the one following it in the list, and the potentials increase steadily

(1.23, 1.28, 1.30 and 1.37 V). It is worth noting that structure 3cf is the triarylimidazole analog of tris(4-bromophenyl)amine, probably the most frequently used of the triarylamine redox mediators and in this regard, it is of interest to compare their oxidation potentials: for

3cf the value is 1.37 while for tris(4-bromophenyl)amine, it is 0.78.6

Finally, we observe that the potentials for the triarylimidazoles are uniformly larger than those observed for the corresponding triarylamine when the substituents are the same.

Compare, for example, the values listed in parentheses in Table 1 for the triphenylimidazole

1 1 3ae (Eox = 1.23) with triphenylamine (0.54), trimethoxyimidazole 3bc (Eox = 0.96) with its

1 amine counterpart (0.25), and tribromoimidazole 3cf (Eox = 1.37) with the tribromoamine

(0.78).

a Oxidation potential in volts versus Ag/0.1 M AgNO3 in CH3CN/0.1 M LiClO4. b Ionization potential in eV computed at the density functional B3LYP/6-31G(d) level. c Sum of Hammett σ+ constants of ring substituents.

Table 2. Fry’s calculated IP values and oxidation measured potentials of triarylamines.

2.5. Computational analysis and empirical relationships.

Five of the imidazoles, 3bc, 3bf, 3ac, 3af, and 3cf, were examined to determine

1 whether there was an empirical relationship between the first oxidation potential, Eox , and

(a) the sum of Hammett σ+ values, Σσ+,7 for the substituents appended to the three aromatic rings, and (b) the calculated ionization potentials (IP). Should they exist, the correlations would provide a convenient means by which to predict the potential for systems yet to be synthesized and also to assess how effectively these systems respond to changes in their electronic character.5,8,9

Table 3. Summary of data used to correlate potential with calculated IP and Σσ+.

IPs were calculated using the B3LYP hybrid functional and a 6-31+G(d) basis set, with acetonitrile as the solvent for both the neutral and cation forms.10 The cation radical energies correspond to the geometry-optimized structures. This accords with the philosophy that in contrast with an electronic excitation, the time scale of a voltammetric experiment is

significantly longer, thereby giving the ion radical time to relax its geometry to that of an energy minimum. This approach is similar to that previously adopted by Fry and co-workers when they developed empirical relationships for triarylamines. The calculated IP was then assumed to be the difference in energy between that of the neutral and ion radical forms, each in acetonitrile. Table 3 summarizes the data, and Figure 2 illustrates the excellent correlations for Σσ+ (R2 = 0.976) and for IP (R2 = 0.998) as well as the resulting empirical relationships.

+ 1 Figure 2. (a) Graph of observed potential vs Σσ for systems 3bc, 3bf, 3ac, 3af, and 3cf. Eox = 0.144(Σσ+) + 1.273 (R2 = 0.976). (b) Graph of observed potential vs calculated IP 1 2 for systems 3bc, 3bf, 3ac, 3af, and 3cf. Eox = 0.770 (IP) − 2.614 (R = 0.998).

Interestingly, the slope associated with each correlation is small, namely, 0.144 for

Σσ+ and 0.770 for IP (Figure 2). We were surprised to discover that the slopes are also small for the triarylamines and also to note the very similar relationships between the observed potential and calculated IP, it being −3.190 + 0.789(IP) for the triarylamines, and −2.614 +

0.770(IP) for the imidazoles. Thus, neither framework responds dramatically to substituent effects, though each responds in the anticipated manner with the more electron rich systems being easiest to oxidize. Undoubtedly the small slopes are due, at least in part, to the fact that both frameworks must distort to avoid steric interactions, thereby reducing conjugation and therefore, the ability of the substituent to express its character (Figure 3).

The aryl units at C-2 and C-5, positioned closest to the N-methyl group of the imidazole, twist most severely. The torsion angle between the imidazole core and the Ph unit at C-5, for example, is 120°. In addition, interaction between the vicinal aryl groups located at C-4 and

C-5 also leads to deviation from planarity. Both distortions are shown clearly in the space- filling rendition of the X-ray structure for 3ac (R1 = OMe, R2 = H), portrayed below.

Figure 3. X-ray structure for 3ac. Twisting of the aryl groups out of planarity reduces interaction with substituents.

In summary, we have discovered that the triarylimidazoles are particularly easy to synthesize, leading to a broad spectrum of structures and access to a range of potentials, from 0.71 to 1.44 V, a difference of 730 mV. This difference is nearly double the range that was exhibited by triarylimidazoles prior to this investigation, and therefore marks a significant advance in terms of the types of oxidation reactions that can be mediated Scheme

3).

2.6. A rule of thumb

The range is wide enough to allow one to oxidize a host of common functional

11 groups including, for example the oxidation of benzylic alcohols and xylenes (Eox ~1.6 V).

We suggest that the operational range is even larger based upon the following “rule of thumb”, a rule that is intended to serve as a useful guideline.12,13 The rule states that for a mediated electron transfer, the upper limit of accessible potentials can be extended by at least 500 mV, a value that is founded in our work (vide infra) and that of others, most notably the late Eberhard Steckhan.11 The implication is that one can use the mediator to oxidize (reduce) a substrate whose oxidation (reduction) potential exceeds that of the

mediator by 500 mV, perhaps more, depending upon the equilibrium constant for the electron transfer and the rate of the follow up reaction that drains the unfavorable equilibrium.11

The examples shown in Scheme 3 illustrate the rule of thumb in action. In the first instance, the mediated oxidation of p-methoxybenzyl alcohol was carried out at the potential of the mediator. Nevertheless, it occurs smoothly despite the fact that the triarylimidazole

3af is 260 mV easier to oxidize than the substrate. The second example, stemming from our previous exploration of the use of triarylamine mediators in synthesis,14 exemplifies the rearrangement of the strained hydrocarbon, housane, 5 using tris(4-bromophenyl)amine as the mediator, a substance that is ∼520 mV easier to oxidize than the substrate. Yet, when the operating potential is set at that of the mediator, the rearrangement occurs smoothly to deliver 5 in a 66% isolated yield.

Scheme 3. Examples of the “Rule of Thumb”.

2.7. Moving forward

While the range of accessible potentials is good, the significant distortion from planarity presents a problem, one that limits the effectiveness of substituents to influence potential. One way to obviate this problem would be to link the ortho carbons of the

aromatics positioned at C-4 and C-5 to generate the fused framework 6. Does the anticipated improvement in behavior occur? The response to this query is found in the next chapter.

Triarylimidazole Redox Catalysis: Electrochemical Analysis and Empirical

Correlations.

Much of this chapter is reproduced with permission from Zhang, N. -T.; Zeng, C.-C.;

Lam, C. M.; Gbur, R. K.; Little, R. D. J. Org. Chem. 2013, 78, 2104-2110. Copyright [2013]

American Chemical Society.

Experimental Section

General Information. All solvents were of commercial quality and were dried and purified by conventional methods. The 1H NMR and 13C NMR spectra were obtained using either a 300 or 400 MHz spectrometer in solvent (CDCl3) with TMS as internal reference.

Data for structures 3ac, 3af, 3bc, 3bf, 3cf have been reported previously.1 High resolution mass spectra were obtained using a time-of-Flight (TOF) mass spectrometer fitted with an electron ionization (EI) source.

General Procedure for the Synthesis of Triarylimidazoles.

A mixture of the benzil of choice (5 mmol), methylamine (5 mmol; or another amine of interest), aldehyde (5 mmol), ammonium acetate (5 mmol) and NaH2PO4 (1.5 mmol) was added to a thick-walled test tube with a screw-on Teflon top. The reaction mixture was heated to 150 °C and maintained at the temperature for 2−5 h; the reaction mixture was stirred throughout. Then the reaction mixture was cooled to room temperature. Acetone was added to dissolve the mixture and the undissolved residue was removed by filtration. After evaporation of the solvent under reduced pressure, the resulting solid residue was recrystallized from acetone−water to obtain pure products 3.

N,N-Dimethyl-4-(1-methyl-4,5-diphenyl-1H-imidazol-2-yl)-aniline (3aa).2 325.2 mg

1 (0.92 mmol), 92%; brown powder, mp: 227−229 °C; H NMR (400 MHz, CDCl3): δ 3.02 (s,

6H), 3.49 (s, 3H), 6.80 (d, J = 8.8 Hz, 2H), 7.11−7.15 (m, 1H), 7.19−7.22 (m, 2H),

7.40−7.48 (m, 5H), 7.56 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H).

2-(3,4-Dimethoxyphenyl)-1-methyl-4,5-diphenyl-1H-imidazole (3ab). 314.9 mg (0.85 mmol), 85%; white needles, mp: 197−198 °C; IR (KBr): ν 3436, 2955, 1602, 1586,

1528,1322 cm−1; 1H NMR (400 MHz, CDCl3): δ 3.52 (s, 3H), 3.96 (s, 3H), 4.00 (s, 3H),

6.98 (d, J =8.4 Hz, 1H), 7.16 (t, J = 6.8 Hz,, 1H), 7.21−7.7.25 (m, 3H), 7.37 (s, 1H),

7.42−7.58 (m, 7H); 13C NMR (100 MHz, CDCl3): δ 33.2, 55.9, 56.0, 110.8, 112.5, 121.5,

123.7, 126.3, 127.0, 128.1, 128.5, 129.0, 130.3, 130.9, 131.3, 134.6, 137.4, 147.9, 149.0,

149.6. HRESI-MS (m/z) calcd. for C24H23N2O2 (M + H) 371.1760, found 371.1749.

1-Methyl-4,5-diphenyl-2-(p-tolyl)-1H-imidazole (3ad).3 292.0 mg (0.9 mmol), 90%; white needles, mp: 211−212 °C; 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 3.50 (s, 3H),

7.12−7.16 (m, 1H), 7.19−7.23 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.40−7.48 (m, 5H),

7.54−7.56 (m, 2H), 7.64 (d, J = 8.0 Hz, 2H).

1-Methyl-2,4,5-triphenyl-1H-imidazole (3ae). 276.2 mg (0.89 mmol), 89%; white

1 needles, mp: 143−145 °C; H NMR (400 MHz, CDCl3): δ 3.51 (s, 3H), 7.15−7.17 (m, 1H),

7.20−7.24 (m, 2H), 7.40−7.52 (m, 8H), 7.54−7.57 (m, 2H), 7.75−7.77 (m, 2H).

2-(4-Fluorophenyl)-1-methyl-4,5-diphenyl-1H-imidazole (3ag). 279.1 mg (0.85 mmol), 85%; yellow powder, mp: 158−160 °C; IR (KBr): ν 3440, 2919, 2850, 1603, 1528,

1467, 1225 cm−1; 1H NMR (400 MHz, CDCl3): δ 3.49 (s, 3H), 7.13−7.23 (m, 5H), 7.41 (d,

J = 7.6 Hz, 2H), 7.45−7.54 (m, 5H), 7.71−7.75 (m, 2H); 13C NMR (100 MHz, CDCl3): δ

33.1, 115.6 (d, JC−F = 22.0 Hz), 126.4, 126.9, 127.1 (d, JC−F = 3.0 Hz), 128.1, 128.7, 129.1,

130.5, 130.8, 130.9 (d, JC−F = 9.0 Hz), 131.1, 134.5, 137.7, 146.9, 163.0 (d, JC−F = 247.0

Hz). HREIMS (m/z) calcd. for C22H17N2F (M) 328.1376, found 328.1359, calcd. for

C22H16N2F (M − H) 327.1298, found 327.1302.

2-(3,4-Difluorophenyl)-1-methyl-4,5-diphenyl-1H-imidazole (3ah). 287.5 mg (0.83 mmol), 83%; white powder, mp: 130−131 °C; IR (KBr): ν 3434, 2918, 2850, 1603, 1535,

1501, 1484, 1225 cm−1; 1H NMR (400 MHz, CDCl3): δ 3.51 (s, 3H), 7.15−7.24 (m, 3H),

7.28−7.33 (m, 1H), 7.39−7.41 (m, 2H), 7.48−7.53 (m, 6H), 7.60−7.64 (m, 1H); 13C NMR

(100 MHz, CDCl3): δ 33.1, 117.6 (d, JC−F = 17.0 Hz), 118.3 (d, JC−F = 18.0 Hz), 125.1, 125.2

(dd, JC−F = 6.0, 4.0 Hz), 126.5, 126.9, 127.9−128.0 (m), 128.2, 128.8, 129.1, 130.8, 130.9,

134.3, 138.0, 145.7, 150.3 (dd, JC−F = 250.0, 15.0 Hz), 150.7 (dd, JC−F = 252.0, 16.0 Hz).

HREI-MS (m/z) calcd. for C22H16N2F2 (M) 346.1282, found 346.1273, calcd. For

C22H15N2F2 (M − H) 345.1203, found 345.1213.

1-Methyl-4,5-diphenyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole (3ai). 321.6 mg

(0.85 mmol), 85%; white powder, mp: 147−148 °C; IR (KBr): ν 3432, 2923, 1616, 1324,

1160 cm−1; 1H NMR (400 MHz, CDCl3): δ 3.55 (s, 3H), 7.15−7.25 (m, 3H), 7.41−7.43 (m,

2H), 7.46−7.55 (m, 5H), 7.76 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H); 13C NMR (100

MHz, CDCl3): δ 33.3, 125.6 (q, JC−F = 4.0 Hz), 126.6, 126.9, 128.2, 128.8, 129.1, 129.2,

130.7, 130.8, 130.9, 131.2, 134.3, 134.4, 138.3, 146.3; HREI-MS (m/z) calcd. for

C23H17N2F3 (M) 378.1344, found 378.1330, calcd. for C23H16N2F3 (M − H) 377.1266, found

377.1274.

1-Methyl-2-(4-nitrophenyl)-4,5-diphenyl-1H-imidazole (3aj).4 316.3 mg (0.89 mmol),

89%; golden-colored powder, mp: 199−200 °C; 1H NMR (400 MHz, CDCl3): δ 3.59 (s,

3H), 7.18−7.24 (m, 3H), 7.40−7.43 (m, 2H), 7.49−7.54 (m, 5H), 7.99 (d, J = 8.8 Hz, 2H),

8.37 (d, J = 8.8 Hz, 2H).

4-(4,5-Bis(4-methoxyphenyl)-1-methyl-1H-imidazol-2-yl)-N,N-dimethylaniline

(3ba). 372.2 mg (0.90 mmol), 90%; yellow powder, mp: 153−154 °C; IR (KBr): ν 3436,

−1 2920, 1612, 1563, 1518, 1247 cm ; 1H NMR (400 MHz, CDCl3): δ 3.02 (s, 6H), 3.46 (s,

3H), 3.76 (s, 3H), 3.87 (s, 3H), 6.76 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.99 (d, J

= 8.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H);

13 C NMR (100 MHz, CDCl3): δ33.0, 40.4, 55.1, 55.3, 112.0, 113.4, 114.4, 118.9, 123.8,

127.9, 128.0, 128.7, 129.9, 132.2, 136.9, 148.2, 150.5, 158.0, 159.5. HRESI-MS (m/z) calcd. for C26H28N3O2 (M + H) 414.2182, found 414.2177.

2-(3,4-Dimethoxyphenyl)-4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole (3bb).

347.0 mg (0.86 mmol), 86%; yellow powder, mp: 125−126 °C; IR (KBr): ν 3436, 2932,

−1 1611, 1519, 1494 cm ; 1H NMR (400 MHz, CDCl3): δ 3.47 (s, 3H), 3.77 (s, 3H), 3.88 (s,

3H), 3.94 (s, 3H), 3.98 (s, 3H), 6.77 (d, J = 8.8 Hz, 2H), 6.95−6.97 (m, 1H), 7.00 (d, J = 8.8

Hz, 2H), 7.19−7.21 (m, 1H), 7.31−7.33 (m, 3H), 7.49 (d, J = 8.8 Hz, 2H); 13C NMR (100

MHz, CDCl3): δ 33.0, 55.1, 55.3, 56.0, 56.1, 110.9, 112.6, 113.5, 114.5, 121.4, 123.5,

123.9, 127.6, 128.0, 129.1, 132.2, 137.1, 147.4, 149.1, 149.5, 158.2, 159.7. HREI-MS (m/z) calcd. for C26H27N2O4 (M + H) 431.1971, found 431.1962.

4,5-Bis(4-methoxyphenyl)-1-methyl-2-(p-tolyl)-1H-imidazole (3bd). 342.2 mg (0.89 mmol), 89%; yellow needles, mp: 129−131 °C; IR (KBr): ν 3435, 2919, 1614, 1517, 1495,

−1 1 1247 cm ; H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 3.46 (s, 3H), 3.76 (s, 3H), 3.88 (s,

3H), 6.77 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.32 (d, J =

8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,

CDCl3): δ 21.4, 33.0, 55.2, 55.3, 113.5, 114.5, 123.5, 127.6, 128.0, 128.2, 128.9, 129.1,

129.2, 132.2, 137.2, 138.5, 147.5, 158.1, 159.7. HREI-MS (m/z) calcd. for C25H24N2O2 (M)

384.1838, found 384.1850.

4,5-Bis(4-methoxyphenyl)-1-methyl-2-phenyl-1H-imidazole (3be). 326.0 mg (0.88

1 mmol), 88%; white needles, mp: 158−161 °C; H NMR (300 MHz, CDCl3): δ 3.48 (s, 3H),

3.76 (s, 3H), 3.87 (s, 3H), 6.77 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7

Hz, 2H), 7.40−7.51 (m, 5H), 7.73−7.75 (m, 2H).

2-(4-Fluorophenyl)-4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole (3bg). 314.6 mg (0.81 mmol), 81%; yellow powder, mp: 148−150 °C; IR (KBr): ν 3435, 2938, 2837,

−1 1 1612, 1519, 1495, 1248 cm ; H NMR (400 MHz, CDCl3): δ 3.46 (s, 3H), 3.77 (s, 3H),

3.88 (s, 3H), 6.77 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.18 (t, J = 8.8 Hz, 2H), 7.31

(d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.72 (dd, J = 8.4, 5.2 Hz, 2H); 13C NMR (100

MHz, CDCl3): δ 3.0, 55.2, 55.3, 113.6, 114.5, 115.6 (d, JC−F = 22.0 Hz), 123.3, 127.2,

127.4, 128.0, 129.3, 130.9 (d, JC−F = 8.0 Hz), 132.2, 137.3, 146.4, 158.2, 159.8, 163.0 (d,

JC−F = 248.0 Hz). HREI-MS (m/z) calcd. for C24H21N2O2F (M) 388.1587, found 388.1585.

2-(3,4-Difluorophenyl)-4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole (3bh).

357.6 mg (0.88 mmol), 88%; yellow powder, mp: 135−137 °C; IR (KBr): ν 3436, 2928,

−1 1 2838, 1609, 1519, 1495, 1247 cm ; H NMR (400 MHz, CDCl3): δ 3.48 (s, 3H), 3.77 (s,

3H), 3.88 (s, 3H), 6.77 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.24−7.32 (m, 3H),

13 7.45−7.46 (m, 3H), 7.57−7.62 (m, 1H); C NMR (100 MHz, CDCl3): δ 33.0, 55.2, 55.3,

113.6, 114.6, 117.5 (d, JC−F = 18.0 Hz), 118.1 (d, JC−F = 19.0 Hz), 123.0, 125.1 (dd, JC−F =

3.0, 3.0 Hz), 127.2, 128.0, 128.0−128.2 (m), 129.8, 132.1, 137.7, 145.2, 150.3 (d, JC−F =

234.0 Hz), 150.6 (dd, JC−F = 234.0, 10.0 Hz), 158.3, 159.9; HRESI-MS (m/z) calcd. for

C24H21N2O2F2 (M + H) 407.1571, found 407.1563.

4,5-Bis(4-methoxyphenyl)-1-methyl-2-(4-(trifluoromethyl)-phenyl)-1H-imidazole

(3bi). 368.3 mg (0.84 mmol), 84%; yellow powder, mp: 141−144 °C; IR (KBr): ν 3436,

−1 1 2949, 2837, 1616, 1517, 1328 cm ; H NMR (400 MHz, CDCl3): δ 3.52 (s, 3H), 3.77 (s,

3H), 3.88 (s, 3H), 6.78 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz,

2H), 7.48 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H); 13C NMR

(100 MHz, CDCl3): δ 33.2, 55.2, 55.3, 113.6, 114.3, 114.6, 122.8, 125.5 (q, JC−F = 4.0 Hz),

127.0, 128.1, 129.2, 130.2, 132.1, 132.4, 134.3, 137.9, 145.8, 158.4, 159.9; HRESIMS (m/z) calcd. for C25H22N2O2F3 (M + H) 439.1633, found 439.1621.

4,5-Bis(4-methoxyphenyl)-1-methyl-2-(4-nitrophenyl)-1H-imidazole (3bj).5 361.4

1 mg (0.87 mmol), 87%; orange powder, mp: 123−125 °C; H NMR (400 MHz, CDCl3): δ

3.57 (s, 3H), 3.78 (s, 3H), 3.89 (s, 3H), 6.79 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H),

7.32 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 8.35 (d, J = 8.8

Hz, 2H).

4-(4,5-Bis(4-bromophenyl)-1-methyl-1H-imidazol-2-yl)-N,N-dimethylaniline (3ca).

460.1 mg (0.90 mmol), 90%; yellow powder, mp: 212−214 °C; IR (KBr): ν 3434, 2920,

−1 1 2838, 1612, 1543, 1487, 1443cm ; H NMR (400 MHz, CDCl3): δ 3.03 (s, 6H), 3.48 (s,

3H), 6.80 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.40 (d, J =

8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,

CDCl3): δ 33.3, 40.3, 112.0, 118.0, 120.2, 122.9, 128.6, 128.8, 129.9, 130.2, 131.2, 132.3,

132.4, 133.7, 149.3, 150.7; HREI-MS (m/z) calcd. for C24H21N3Br2 (M) 509.0102, found

509.0089, calcd. For C24H20N3Br2 (M − H) 508.0024, found 508.0006.

4,5-Bis(4-bromophenyl)-2-(3,4-dimethoxyphenyl)-1-methyl-1H-imidazole (3cb).

449.0 mg (0.85 mmol), 85%; white powder, mp: 176−178 °C; IR (KBr): ν 3466, 2921, 1631,

−1 1 1531, 1488, 1224 cm ; H NMR (400 MHz, CDCl3): δ 3.50 (s, 3H), 3.95 (s, 3H), 3.98 (s,

3H), 6.97 (d, J = 8.4 Hz, 1H), 7.19−7.21 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.35

(d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,

CDCl3): δ 33.3, 56.0, 56.1, 110.9, 112.5, 120.4, 121.5, 123.1, 128.6, 129.2, 129.8, 131.3,

132.3, 132.5, 133.3, 136.8, 148.4, 149.1, 149.8. HRESI-MS (m/z) calcd. For C24H21N2O2Br2

(M + H) 526.9970, found 526.9954.

4,5-Bis(4-bromophenyl)-2-(4-methoxyphenyl)-1-methyl-1H-imidazole (3cc). 413.5 mg (0.83 mmol), 83%; white powder, mp: 145−147 °C; IR (KBr): ν 3434, 2953, 2924, 1612,

−1 1 1577, 1531, 1479, 1402, 838 cm ; H NMR (400 MHz, CDCl3): δ 3.47 (s, 3H), 3.87 (s,

3H), 7.02 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.39 (d, J =

8.8 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,

CDCl3): δ 33.2, 55.4, 114.1, 120.4, 123.0, 123.1, 128.5, 129.1, 129.9, 130.4, 131.3, 132.3,

132.5, 133.4, 136.8, 148.4, 160.2. HREI-MS (m/z) calcd. for C23H18N2OBr2 (M) 495.9786, found 495.9786.

4,5-Bis(4-bromophenyl)-1-methyl-2-(p-tolyl)-1H-imidazole (3cd). 400.2 mg (0.83 mmol), 83%; white powder, mp: 189−190 °C; IR (KBr): ν 3433, 2919, 1638, 1478, 1391,

−1 1 833 cm ; H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H), 3.49 (s, 3H), 7.27 (d, J = 8.4 Hz,

2H), 7.30 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.59−7.63

13 (m, 4H); C NMR (100 MHz, CDCl3): δ 21.4, 33.2, 120.4, 123.1, 127.6, 128.6, 128.9,

129.2, 129.4, 129.9, 131.3, 132.3, 132.5, 133.4, 137.0, 139.0, 148.6. HREI-MS (m/z) calcd.

For C23H18N2Br2 (M) 479.9837, found 479.9831.

4,5-Bis(4-bromophenyl)-1-methyl-2-phenyl-1H-imidazole (3ce). 412.0 mg (0.88 mmol), 88%; white powder, mp: 201−203 °C; IR (KBr): ν 3435, 3061, 2920, 1494, 1474,

−1 1 837 cm ; H NMR (300 MHz, CDCl3): δ 3.50 (s, 3H), 7.27 (d, J = 8.4 Hz, 2H), 7.35 (d, J =

8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.45−7.53 (m, 3H), 7.63 (d, J = 8.4 Hz, 2H),

13 7.70−7.73 (m, 2H); C NMR (100 MHz, CDCl3): δ 33.2, 120.5, 123.2, 128.6, 128.7, 129.0,

129.4, 129.8, 130.5, 131.3, 132.3, 132.5, 133.3, 137.1, 148.5. HRESI-MS (m/z) calcd. for

C22H16N2Br2 (M) 465.9680, found 465.9689.

4,5-Bis(4-bromophenyl)-2-(4-fluorophenyl)-1-methyl-1H-imidazole (3cg). 393.8 mg

(0.81 mmol), 81%; white powder, mp: 172−174 °C; IR (KBr): ν 3450, 2919, 1639, 1479,

−1 1 1447, 833 cm ; H NMR (400 MHz, CDCl3): δ 3.48 (s, 3H), 7.20 (d, J = 8.4 Hz, 1H), 7.22

(d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz,

2H), 7.63 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H); 13C NMR

(100 MHz, CDCl3): δ 33.2, 115.8 (d, JC−F = 21.0 Hz), 120.5, 123.3, 126.8, 128.5, 129.4,

129.7, 130.9 (d, JC−F = 4.0 Hz), 131.3, 132.3, 132.5, 133.2, 137.1, 147.5, 163.2 (d, JC−F =

248.0 Hz). HREI-MS (m/z) calcd. for C22H15N2Br2F (M) 483.9586, found 483.9580, calcd. for C22H14N2Br2F (M − H) 482.9508, found 482.9509.

4,5-Bis(4-bromophenyl)-2-(3,4-difluorophenyl)-1-methyl-1H-imidazole (3ch). 438.6 mg (0.97 mmol), 87%; white powder, mp: 144−146 °C; IR (KBr): ν 3449, 1604, 1568, 1533,

−1 1 1484, 1321, 835 cm ; H NMR (400 MHz, CDCl3): δ 3.50 (s, 3H), 7.24−7.33 (m, 3H),

7.34−7.39 (m, 4H), 7.45−7.47 (m, 1H), 7.56−7.60 (m, 1H), 7.62−7.64 (m, 2H); 13C NMR

(100 MHz, CDCl3): δ 33.2, 117.7 (dd, JC−F = 14.0, 5.0 Hz), 118.3 (d, JC−F = 18 Hz, 2.0 Hz),

120.7, 123.4, 125.2 (t, JC−F = 5.0 Hz), 127.0−127.6 (m), 128.5, 129.4, 129.8, 131.4, 132.3,

132.6, 133.0, 137.3, 146.3, 150.3 (dd, JC−F = 250.0 Hz, 15.0 Hz), 150.9(dd, JC−F = 251.0 Hz,

14.0 Hz). HRESI-MS (m/z) calcd. For C22H14N2Br2F2 (M) 501.9492, found 501.9485.

4,5-Bis(4-bromophenyl)-1-methyl-2-[4-(trifluoromethyl)-phenyl]-1H-imidazole

(3ci). 450.4 mg (0.84 mmol), 84%; white powder, mp: 154−156 °C; IR (KBr): ν 3450, 2924,

1 1619, 1496, 1327, 1167, 1134, 1073, 832 cm−1; H NMR (400 MHz, CDCl3): δ 3.54 (s,

3H), 7.27 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.64 (d, J =

8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,

CDCl3): δ 33.4, 120.8, 122.6, 123.5, 125.3, 125.6 (q, JC−F = 3.0 Hz), 128.5, 129.2, 130.1,

130.7, 131.1, 131.4, 132.3, 132.6, 132.8, 137.5, 146.8; HREI-MS (m/z) calcd. For

C23H15N2Br2F3 (M) 533.9554, found 533.9541, calcd. For C23H14N2Br2F3 (M − H)

532.9476, found 532.9478.

4,5-Bis(4-bromophenyl)-1-methyl-2-(4-nitrophenyl)-1H-imidazole (3cj). 456.7 mg

(0.89 mmol), 89%; yellow powder, mp: 131−133 °C; IR (KBr): ν 3433, 2920, 1637, 1522,

−1 1 1344 cm ; H NMR (400 MHz, CDCl3): δ 3.59 (s, 3H), 7.27 (d, J = 8.0 Hz, 2H), 7.38 (s,

4H), 7.66 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 8.36 (d, J = 8.4 Hz, 2H); 13C NMR

(100 MHz, CDCl3): δ 33.6, 121.0, 123.7, 124.0, 128.5, 129.0, 129.4, 131.0, 131.5, 132.2,

132.7, 132.8, 136.6, 138.2, 146.0, 147.7. HREI-MS (m/z) calcd. For C22H15N3O2Br2 (M)

510.9531, found 510.9534.

Cyclic Voltammetry Measurements.

Cyclic voltammograms were measured using a 273A Potentiostat/Galvanostat (Princeton

Applied Research) equipped with electrochemical analysis software, using a conventional three-electrode cell. The working electrode was a glassy carbon disk electrode (ca. ϕ = 3 mm). The auxiliary and reference electrodes for these studies corresponded to a Pt wire and

Ag/AgCl (in 3 M KCl), respectively; LiClO4 (0.2 M) in a solution of acetonitrile and dichloromethane (4:1 by volume) was used as the supporting electrolyte system. The concentration of each triarylimidazole was 1 mM.

Calculations.

Calculations were performed using the Spartan ’08 software package.6 As indicated in the text, the quantities used to calculate IP values refer to energy minimized structures for both the neutral and cation radical forms, in acetonitrile as the solvent. The B3LYP hybrid functional was used along with the 6-31+G(d) basis set.

Table of redox data for 30 imidazole mediators

1 2 3 1 Compound Eox Eox Eox Ered 3aa 0.774 1.050 1.500 0.684 3ab 1.144 1.360 1.688 1.030 3ac 1.142 1.372 1.684 1.054 3ad 1.216 1.498 1.762 1.138 3ae 1.228 1.480 1.740 1.144 3af 1.276 1.550 1.818 1.216 3ag 1.290 1.604 1.860 1.186 3ah 1.304 1.648 1.860 1.238 3ai 1.376 1.740 —— 1.270 3aj 1.372 1.678 1.880 1.290 3ba 0.712 0.882 1.434 0.638 3bb 0.966 1.236 1.480 0.886 3bc 0.958 1.254 1.478 0.890 3bd 1.014 1.326 1.544 0.936 3be 1.024 1.298 1.508 0.936 3bf 1.054 1.348 1.548 0.988 3bg 1.076 1.372 1.608 0.966 3bh 1.072 1.364 1.576 0.990 3bi 1.098 1.388 1.580 1.016 3bj 1.114 1.380 1.576 1.048 3ca 0.824 1.112 1.536 0.716 3cb 1.164 1.418 1.638 1.096 3cc 1.210 1.410 1.708 1.136 3cd 1.282 1.524 1.802 1.206 3ce 1.302 1.528 1.786 1.226 3cf 1.372 1.632 1.916 1.260 3cg 1.406 1.678 1.910 1.196 3ch 1.370 1.644 1.872 1.290 3ci 1.398 1.710 1.896 1.310 3cj 1.444 1.694 1.928 1.360 The data listed in the table are the raw data from cyclic voltammogram software output.

Typical CV data for redox catalysts 3ag, 3bc and 3ch and their quasi-reversible first oxidation peak

Fig. 1. CV of 3ag

Fig. 2. CV of 3ag (first oxidation peak)

Fig. 3. CV of 3bc 75

Fig. 4. CV of 3bc (first oxidation peak)

Fig. 5. CV of 3ch 76

Fig. 6. CV of 3ch (first oxidation peak)

Spectra (1H and 13C NMR) for imidazole redox catalysts

Fig. 7. 1H NMR spectrum of 3aa

Fig. 8. 1H NMR spectrum of 3ab

Fig. 9. 13C NMR spectrum of 3ab 79

Fig. 10. 1H NMR spectrum of 3ad

Fig. 11. 1H NMR spectrum of 3ae 80

Fig. 12. 1H NMR spectrum of 3ag

Fig. 13. 13C NMR spectrum of 3ag 81

Fig. 14. 1H NMR spectrum of 3ah

Fig. 15. 13C NMR spectrum of 3ah 82

Fig. 16. 1H NMR spectrum of 3ai

Fig. 17. 13C NMR spectrum of 3ai 83

Fig. 18. 1H NMR spectrum of 3aj

Fig. 19. 1H NMR spectrum of 3ba 84

Fig. 20. 13C NMR spectrum of 3ba

Fig. 21. 1H NMR spectrum of 3bb 85

Fig. 22. 13C NMR spectrum of 3bb

Fig. 23. 1H NMR spectrum of 3bd 86

Fig. 24. 13C NMR spectrum of 3bd

Fig. 25. 1H NMR spectrum of 3be 87

Fig. 26. 1H NMR spectrum of 3bg

Fig. 27. 13C NMR spectrum of 3bg 88

Fig. 28. 1H NMR spectrum of 3bh

Fig. 29. 13C NMR spectrum of 3bh 89

Fig. 30. 1H NMR spectrum of 3bi

Fig. 31. 13C NMR spectrum of 3bi 90

Fig. 32. 1H NMR spectrum of 3bj

Fig. 33. 1H NMR spectrum of 3ca 91

Fig. 34. 13C NMR spectrum of 3ca

Fig. 35. 1H NMR spectrum of 3cb 92

Fig. 36. 13C NMR spectrum of 3cb

Fig. 37. 1H NMR spectrum of 3cc 93

Fig. 38. 13C NMR spectrum of 3cc

Fig. 39. 1H NMR spectrum of 3cd 94

Fig. 40. 13C NMR spectrum of 3cd

Fig. 41. 1H NMR spectrum of 3ce 95

Fig. 42. 13C NMR spectrum of 3ce

Fig. 43. 1H NMR spectrum of 3cg 96

Fig. 44. 13C NMR spectrum of 3cg

Fig. 45. 1H NMR spectrum of 3aa 97

Fig. 46. 13C NMR spectrum of 3ch

Fig. 47. 1H NMR spectrum of 3ci 98

Fig. 48. 13C NMR spectrum of 3ci

Fig. 49. 1H NMR spectrum of 3cj 99

Fig. 50. 13C NMR spectrum of 3cj

Fig. 51. Thermal ellipsoid plot for the crystal structure of 3ac 100

1 Zeng, C.-C.; Zhang, N.-T.; Lam, C. M.; Little, R. D. Org. Lett. 2012, 14, 1314-1317.

2 Karimi-Jaberi, Z.; Barekat, M. Chin. Chem. Lett. 2010, 21, 1183-1185.

3 (a) Steckhan, E. Angew. Chem., Int. Ed. 1986, 25, 683−701. (b) Shirota, Y.; Kageyama,

H. Chem. Rev. 2007, 107, 953−1010. (c) Gretton, M. J.; Kamino, B. A.; Brook, M. A.;

Bender, T. P. Macromolecules 2012, 45, 723−728.

4 (a) Thomas, B.; David, C.; Muller, M. G.; Klaus, M.; Oskar, N. Macromol. Rapid

Commun. 2000, 21, 583−589. (b) Moerner, W. E.; Scott, M. S. Chem. Rev. 1994, 94,

127−155.

5 For a tabulation of σ+ values, see: Gordon, A. J.; Ford, R. A. The Chemist’s

Companion; Wiley: New York, 1972; 145-153.

6 Wu, X.; Davis, A. P.; Lambert, P. C.; Steffen, L. K.; Toy, O.; Fry, A. J. Tetrahedron

2009, 65, 2408-2414.

7 van Bekkum, H.; Verkade, P. E.; Wepster, B. M. Recl. Trav. Chim. Pays-Bas 1959, 78,

815-850.

8 Zuman, P. Substituent Effects in Organic Polarography; Plenum Press: New York,

1967.

9 Davis, A. P.; Fry, A. J. J. Phys. Chem. A 2010, 114, 12299-12304.

10 Shao, Y.; Molnar, L. F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.; Brown, S. T.; Gilbert,

A. T. B.; Slipchenko, L. V.; Levchenko, S. V.; O’Neill, D. P.; DiStasio, R. A., Jr.; Lochan,

R. C.; Wang, T.; Beran, G. J. O.; Besley, N. A.; Herbert, J. M.; Lin, C. Y.; Van Voorhis, T.;

Chien, S. H.; Sodt, A.; Steele, R. P.; Rassolov, V. A.; Maslen, P. E.; Korambath, P. P.;

Adamson, R. D.; Austin, B.; Baker, J.; Byrd, E. F. C.; Dachsel, H.; Doerksen, R. J.; Dreuw,

A.; Dunietz, B. D.; Dutoi, A. D.; Furlani, T. R.; Gwaltney, S. R.; Heyden, A.; Hirata, S.;

101

Hsu, C.-P.; Kedziora, G.; Khalliulin, R. Z.; Klunzinger, P.; Lee, A. M.; Lee, M. S.; Liang,

W. Z.; Lotan, I.; Nair, N.; Peters, B.; Proynov, E. I.; Pieniazek, P. A.; Rhee, Y. M.; Ritchie,

J.; Rosta, E.; Sherrill, C. D.; Simmonett, A. C.; Subotnik, J. E.; Woodcock, H. L., III; Zhang,

W.; Bell, A. T.; Chakraborty, A. K.; Chipman, D. M.; Keil, F. J.; Warshel, A.; Hehre, W. J.;

Schaefer, H. F.; Kong, J.; Krylov, A. I.; Gill, P. M. W.; Head-Gordon, M. Phys. Chem.

Chem. Phys. 2006, 8, 3172−3191.

11 Weinberg, N. L.; Weinberg, H. R. Chem. Rev. 1968, 4, 449-523.

12 Steckhan, E. Angew. Chem., Int. Ed. 1986, 25, 683−70.

13 Topics in Current Chemistry,Electrochemistry I; Steckhan, E., Ed.; Springer: Berlin,

1987; Vol. 142.

14 Park, Y. S.; Little, R. D. J. Org. Chem. 2008, 73, 6807-6815.

1 Zeng, C.-C.; Zhang, N.-T.; Lam, C. M.; Little, R. D. Org. Lett. 2012, 14, 1314−1317.

2 Sanaeva, E. P.; Tanaseichuk, B. S. Deposited Doc. 1981, SPSTL 426 Khp-D81.

3 Alireza, E.; Abdolkarim, Z.; Mohsen, S.; Javad, A. R. J. Comb.Chem. 2010, 12,

844−849.

4 Srinivas, K.; Srinivas, U.; Bhanuprakash, K.; Harakishore, K.; Murthy, U. S. N.; Rao,

V. J. Eur. J. Med. Chem. 2006, 41, 1240−1246.

5 Santos, J.; Mintz, E. A.; Zehnder, O.; Bosshard, C.; Bu, X. R.;Gunter, P. Tetrahedron

Lett. 2001, 42, 805−808.

6 Shao, Y.; Molnar, L. F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.; Brown, S. T.; Gilbert,

A. T. B.; Slipchenko, L. V.; Levchenko, S. V.; O’Neill, D. P.; DiStasio, R. A., Jr.; Lochan,

R. C.; Wang, T.; Beran, G. J. O.; Besley, N. A.; Herbert, J. M.; Lin, C. Y.; Van Voorhis, T.;

Chien, S. H.; Sodt, A.; Steele, R. P.; Rassolov, V. A.; Maslen, P. E.; Korambath, P. P.;

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Adamson, R. D.; Austin, B.; Baker, J.; Byrd, E. F. C.; Dachsel, H.; Doerksen, R. J.; Dreuw,

A.; Dunietz, B. D.; Dutoi, A. D.; Furlani, T. R.; Gwaltney, S. R.; Heyden, A.; Hirata, S.;

Hsu, C.-P.; Kedziora, G.; Khalliulin, R. Z.; Klunzinger, P.; Lee, A. M.; Lee, M. S.; Liang,

W. Z.; Lotan, I.; Nair, N.; Peters, B.; Proynov, E. I.; Pieniazek, P. A.; Rhee, Y. M.; Ritchie,

J.; Rosta, E.; Sherrill, C. D.; Simmonett, A. C.; Subotnik, J. E.; Woodcock, H. L., III; Zhang,

W.; Bell, A. T.; Chakraborty, A. K.; Chipman, D. M.; Keil, F. J.; Warshel, A.; Hehre, W. J.;

Schaefer, H. F.; Kong, J.; Krylov, A. I.; Gill, P. M. W.; Head-Gordon, M. Phys. Chem.

Chem. Phys. 2006, 8, 3172−3191.

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Chapter 3. A metal-free photoredox mediator based on electrooxidative phenanthroimidazole mediators.

3.1. Mediated electroorganic synthesis

As is highlighted below, electroorganic chemistry provides convenient access to the chemistry of radical ions. Its unique ability to effect charge reversal (umpolung) makes it possible to achieve bond constructions that are otherwise very difficult to accomplish.3

The use of redox mediators to achieve a so-called “indirect electrolysis” offers many advantages compared to a direct electrolysis (vide infra).4 Indirect electrolysis represents a special case of electroorganic synthesis, where the electron transfer (ET) step is shifted from a heterogeneous process occurring at an electrode (a “direct electrolysis”), to a homogeneous process that affords a substance that serves to mediate electron transfer between it and the substrate.5

Consequently, the likelihood of undesired side-reactions is often reduced. For example, the use of para-substituted triarylamines, like tris(p-bromophenyl) amine, and aryl substituted triarylimidazoles such as imid-HHBr (see Scheme 4) for the oxidation of benzylic alcohols

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to the corresponding carbonyl compounds occurred in a manner where potential differences of up to 500 mV were achievable.1,6 For inner-sphere mediators such as TEMPO and DDQ, which involve hydrogen or hydride abstraction, even larger potential differences, sometimes

>1 V, can be overcome.7 The ensuing reactions are typically more selective than those involving outer-sphere electron transfer, since the selectivity is not determined by the potential difference between mediator and substrate but by the chemical reactivity (Scheme

1).

Scheme 1. Outer and inner-sphere mechanisms for mediated electron transfer

The use of electron transfer mediators can also help to avoid electrode passivation resulting from polymer film formation on the electrode surface since direct interaction of the substrate with the electrode surface is avoided. An example depicted in Scheme 2 is the removal of a p-methoxybenzyl ether (PMB) protecting group from 4-phenyl-3-butenol by anodic oxidation (Scheme 2).8

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Scheme 2. Mediated selective deprotection of PMB ethers.

Many new intriguing applications and new types of mediators have been found to meet specific applications,1d including for example, the use of double mediatory systems in biphasic media, enantioselective mediation and heterogeneous electrocatalysis using immobilized mediators, have been introduced.9 Those interested in more detail are referred to the recent comprehensive review by Francke and Little.4

Both single and double mediatory systems exist. Torii et al. have been responsible for many variations.10 One noteworthy example of a double mediatory system consisting of a biphasic medium using an organic solvent and an aqueous electrolyte containing a halide salt (Scheme 3), wherein the active bromine species that is generated anodically reacts with the N-oxyl radical to form the oxoammonium species, which in turn participates in the oxidation of an alcohol to a carbonyl. 11

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Scheme 3. Double mediatory system (Br-/TEMPO) in biphasic electrolyte.

3.2. Triarylimidazole mediators.

Redox catalysts based on the triarylimidazole scaffold, 1, were first developed and characterized electrochemically by Zeng and Little et al.12 As shown in Scheme 4, they are exceptionally easy to synthesize. Most of the triarylimidazoles display three oxidation peaks where the first redox couple is quasi-reversible. By varying the substituents on the aromatic rings, over 600 mV range of accessible potentials can be achieved. For convenience, the structures are abbreviated simply by listing the para substituents in the order R1, R2, and R3.

For example, structure M, where R1 = R2 = H and R3 = OMe, is abbreviated “imid-H H

OMe”.

Scheme 4. Synthesis of triarylimidazoles

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The triarylimidazoles served as effective mediators for the oxidation of electron-rich benzylic alcohols and ethers, converting each to the corresponding carbonyl compounds in the manner portrayed in Scheme 5, as well as in ring opening/Friedel-Crafts heteroarylation of chalcone epoxides, a process occurring best when R2 is electron rich, 12c 32-83% yields with 10 mol% catalyst loading (Scheme 6).

Scheme 5. Triarylimidazole mediated oxidation of benzylic alcohols and ethers.

Scheme 6. Ring opening/Friedel-Crafts heteroarylation of chalcone epoxides.

3.3. Phenanthroimidazoles.

In an effort to eliminate propeller twisting of the aryl rings appended to C4 and C5 of the imidazole framework found in structure 1, and enhance the substituent electronic effects, the ortho-positions of the vicinal aromatic rings were joined to afford the phenanthroimidazoles illustrated in Figure 1.13 The structures are named/abbreviated in the same manner as the triarylimidazoles (vide supra). For example, “phen-H H OMe” refers to structure 2 with R4 = R5 = H, R6 = OMe.

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The computed geometries corresponding to the phenanthroimidazole (phen-H H H) illustrated on the right side of Figure 1, is indeed flatter than the structure of triarylimidazole shown on the left. As shown in Figure 2, the cyclic voltammograms of the resulting phenanthroimidazoles, the redox reversibility is greatly enhanced relative to the triarylimidazole counterpart.12

Figure 1. Structure of triarylimidazole (left) and phenanthroimidazole (right) mediators. Fused carbon-carbon bond is present in red bold. Computed geometries for each 1 2 3 4 5 6 class, when R = R = R = R = R = R =H, were obtained using the B3LYP hybrid functional with 6-31 +G* basis set.

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Figure 2. Cyclic voltammograms of triarylimidazole imid-HHOMe (left) and phenanthroimidazole phen-HHOMe (right). Scan rate: 100 mV s-1 (solid line) and 10 mv s-1 (dashed line).

3.4. Comparing redox mediation with photoredox electron transfer (PET).

As illustrated in Scheme 7, mediated electrochemical processes share many similarities with sensitized photochemical processes. In neither instance is the input energy delivered to the substrate. In electrochemical processes, the mediator is oxidized (or reduced), not the substrate. In photochemical events, the sensitizer accepts the incident radiation, not the substrate. Thus, both processes are “indirect”. For a mediator serving as an oxidizing agent, an electron transfer occurs between the substrate and the Medox to afford the cation radical of the substrate (reactive intermediate) and return the mediator to its resting state, in this case Medred. The reactive intermediate can then undergo one or more follow-up reaction(s) that ultimately afford product(s). Meanwhile, a sensitized photochemical process starts with absorption of light, to afford either a highly reducing or oxidizing excited state capable of facilitating redox-based transformations. For a sensitized photochemical process occurring with a reductive quenching cycle, the excited state sensitizer, Sens*, receives an electron from the substrate to form a cation radical and produce the radical anion of the sensitizer, Sens–•. Subsequent oxidation of Sens–• using a sacrificial oxidant returns to the sensitizer in its neutral ground state.

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Scheme 7. General principle of electro-oxidative mediation (top) and a sensitized

photochemical oxidative process (bottom).

The terms photoredox catalysis and photoinduced electron transfer (PET) are often used to describe this photoredox activation mode.14 Sensitized photochemical processes have drawn much renewed interest, in part because photoredox chemistry has enabled the development of a wide variety of synthetic transformations.15 Examples include Yoon’s formal cycloadditions16; MacMillan’s work on radical mediated asymmetric alkylations17 and Stephenson’s work on reductive dehalogenation and intramolecular radical addition to indoles, pyrroles via C-H activation and natural product synthesis.18

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3.5. Use of EPR to determine the lifetime of phenanthroimidazole cation radicals. Can they serve as useful photoredox catalysts?

The lifetime of the unsubstituted phenanthroimidazole cation radical, phen-3+• (R1 =

R2 = R3 = H), was investigated by EPR. Figure 3a shows X-band continuous wave electron paramagnetic resonance (cw-EPR) spectra of the unpaired electron (I = 1/2) at varying voltages, cycling between 0.5 V to 1.5 V. The complete appearance and disappearance of

EPR signal indicates a reversible process. The unsplit EPR spectrum shows the radical is delocalized over the aromatic framework.

From the observed exponential decay of the EPR spectrum, the half-life of the radical cation can be calculated to be 44 s, and with rate of decay, assuming (pseudo-) first order kinetics, of 0.93 min-1 (Figure 3b). Based on the long “survival time” of the cation radical, we postulate that phenanthroimidazole mediators should be able to carry out photoredox catalyst via an oxidative quenching cycle where the excited catalyst delivers an electron to becomes a cation radical, and thereby serve as a reducing agent. The cation radical returns to the neutral state by accepting an electron from an amine that serves as a sacrificial oxidant, as noted in Scheme 7.

a b

Half-life: t ½ = 44 s -1 kdec = 0.93 min

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Figure 3. (a) EPR studies of in-situ generated phenanthroimidazole (HHH) cation radical

(b) Half-life of in-situ generated HHH cation radical.

Experimental conditions: c(analyte) = 10-3 M; v = 100 mV S-1; electrolyte: 0.1 M

NBu4ClO4 in CH3CN/CH2Cl2; reference electrode = Ag/AgCl ; working electrode

= Pt; auxiliary electrode = Pt. EPR studies carried out at LIKAT, Rostock by

Professor Dr. Dirk Hollmann. Details are located in the Experimental Section.

3.6. UV properties of phen-HHOMe.

As shown in Figure 4, the absorption spectrum of phen-HHOMe displays only a small shoulder, with  = 3190 M-1cm-1, at 365 nm, the wavelength corresponding to the

LEDs to be used in the experiments described below. Despite the weak absorption, it did not hamper our explorations, as the following discussion illustrates.

Absorbance 1.0 Fluorescence

0.8

0.6

0.4

Intensity

Normalized 0.2

0.0

250 300 350 400 450 500 Wavelength (nm)

Figure 4. Absorption and Fluorescence spectrum of phen-HHOMe.

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3.7. Experimental test … useful photoredox catalyst?

The initial test system chosen for investigation was the reduction of iodobenzene to benzene, employing phen-HHOMe as the photocatalyst. The reaction appeared ideal, since it could be easily monitored by 1H NMR. Quantitative reduction of iodobenzene (1a) to benzene (2a) was achieved in 4 h under 365 nm LED irradiation (light intensity was measured as 1.8 W/cm2)19 in the present of 5 mol% of phenanthroimidazole catalyst phen-

HHOMe and 5 equivalents each of tributylamine as the sacrificial oxidant, and formic acid as a potential proton donor (Scheme 8). The reaction vessel, shown in Figure 5, was cooled using a continuous stream of compressed air.

Scheme 8. Initial reduction of iodobenzene (1a) to benzene (2a) in the presence of phen-

HHOMe.

Figure 5. Representative reaction set-up comprising reaction vial surrounded by 365 nm

LEDs with a tube blowing compressed air past the vessel for cooling.

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To validate that phenanthroimidazole was serving as an organic photoredox catalyst, a series of control experiments were carried out in the absence of light, catalyst, or amine.

The results are shown in Table 1. Since amines are known to be able to serve as proton donors, it is not surprising to discover that formic acid is not required. 20

Reaction conditions: Iodobenzene (1 equiv.), formic acid (5 mol%), tributylamine (5 equiv), Acetonitrile at room temperature for 30 min with irradiation from 365 nm LED (1.8mW/cm2). Yield determined using 1H NMR. Table 1. Control experiments.

3.8. Is the chemistry generalizable?

With a general protocol consisting of the use of a bank of 365 nm LEDs (Fig. 5), 5 mol % of phenanthroimidazole catalyst phen-HHOMe, 5 equiv each of tributylamine, and formic acid, we set out to evaluate the applicability of phen-HHH as a photoredox catalyst toward a library of aryl iodides including electronically activated and deactivated derivatives

(Table 2).

Excellent reactivity was observed with compounds containing electron donating groups (2b, 2c, and 2i-2l). In addition, those containing electron withdrawing ester, acid, bromo, and chloro substituents (2d, 2e-2h) were deiodinated in high yields. The ability to achieve reduction of substrates containing carboxylic acid (2f, 2g, 2h), amine (2k, 2l) and para- and meta- alkene (2i, 2j) exemplifies the mildness of our protocol and its tolerance 115

across many different functional groups. From the synthetic utility viewpoint, it is important to note that the deiodination is selective toward C-I bonds, with C-Br and C-Cl bonds being inert (2d, 2e).

Table 2. Substrate scope of phen-HHOMe catalyzed deiodination reactions. Yield

determined by 1H NMR.

3.9. Cost effective?

Although we utilize higher catalyst loadings (5 mol %) than traditional metal-based

21 photoredox system such as Ir(ppy)3 (1 mol %, for example), calculations based on a cost per reaction basis illustrate that 5 mol% phenanthroimidazole is still over 50% cheaper than the rare-earth metal catalyst as is detailed in the Experimental Section.

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3.10. Qualitative rates as a function of aryl substituent.

The effect of a para-substituent on the deiodination was studied qualitatively in order to gain insight concerning the radical vs anion character of the intermediate(s). Since the sigma orbital in which the odd electron (radical) or electron pair (anion) occupies is orthogonal to the -framework, the influences will be inductive. We reasoned that substituent effects would be much smaller for a radical than an anion. This was borne out by performing simple density functional calculations of the B3LYP/6-31+G* variety. Note

Table 3. The energy was determined for both radical and the anion when X = CN and when

X = OMe. In each instance, the energy of the anion was much lower than the radical, the difference favoring the anion being most pronounced when X = CN. In the latter case, the difference was ~ 40 kcal/mol, while when X = OMe, it was ~ 23 kcal/mol. From this information, and assuming that the structure and energy of the transition structures resemble that of the intermediate radical and anion, one can predict that the reaction will occur fastest when X is inductively withdrawing.

Table 3. Difference in energies between anion and anion radicals. Density function of B3LYP/6-31+G* used.

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Experimentally, the relative rates were assessed by comparing the extent conversion after 30 minutes for the series of p-substituted aryl iodides pictured in Table 4. The rates appear to fall into three groups viz., 79, 49 and 43, and 33 and 34% conversion. The fastest occurred when X was an inductively withdrawing carbomethoxy group (entry 1), and slowest when X was inductively donating (methyl and methoxy, entries 4 and 5). In accord with the calculations, these results implicate formation of an anion since an electron withdrawing group stabilizes the anion to a far greater extent than it does the corresponding radical when X = CN compared with X = OMe (vide supra).

Table 4. Effect of para- substituent on the deiodination

3.11. Further mechanistic studies: isotope incorporation

Realizing that in the absence of amine, no conversion is observed, we initiated mechanistic investigations in the presence of deuterated amine that were intended to obtain insight into the following questions:

(1) Does formic acid serve as a proton donor and the source of the new aryl-H bond?

(2) Can the sacrificial reductant (the amine) play a dual role and also serve as an H-donor?

To address these points, experiments were conducted using deuterated formic acid,

DCO2D, and deuterated amine. Since the deuterated form of n-Bu3N is not commercially 118

available, we elected to use Et3N-d15 in its place. The results shown in Table 5 clearly demonstrate that (a) in the absence of acid, Et3N-d15 serves as the D-source in the product

(entry 1). Thus, the amine can play a dual role, and does so in the absence of acid (Scheme

9). 20

Scheme 9. Oxidation of tributylamine to an aminium ion via either an EC or an ECE

pathway.

(b) In the presence of both deuterated amine and deuterated formic acid, complete incorporation is achieved, though the percent conversion diminishes from 46 to 16 %

(compare entries 1 and 2); (c) In the presence of deuterated amine and formic acid, HCO2H, deuterium is not incorporated. Yet, a 61% conversion to the H-containing product is achieved (entry 3).

Table 5. Photoreduction in the presence and absence of formic acid and formic acid-d2.

From these results, we conclude that both the amine and formic acid are capable of serving as the proton donor. In the absence of formic acid, the amine serves as a sacrificial

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reductant and as a proton donor. Finally, the percent conversion is much larger when

HCO2H is used in place of DCO2D (compare entries 2 and 3) thus implying that there is an isotope-related rate difference in the protonation step – a kinetic isotope effect.

3.12. Mechanistic hypothesis.

As illustrated in Scheme 10, photoexcitation of phenanthroimidazole mediator

(MED) leads to (MED*). The latter reduces the substrate, ArI, to form radical anion (ArI)–• and (Med)+•. Conversion of the radical anion to Ar• and iodide, followed by reduction using the sacrificial amine generates the aryl anion, Ar–, whose subsequent protonation with formic acid delivers the product. Meanwhile, the amine also reduces (Med)+• and returns the mediator to the neutral form, ready to undergo excitation once again.

Scheme 10. Proposed mechanism for the deiodination reaction.

3.13. Broadening the scope.

Encouraged by the results described above, we explored the possibility of achieving intramolecular radical cyclizations onto a pendant alkenyl side chain (Scheme 11). This idea has previously been investigated independently by the groups of Suga and Stephenson. 22, 23

The Suga chemistry is especially relevant, it being initiated using an electrochemically generated fluorenyl radical anion to cleave the aryl-halogen bond.

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We examined two reactions shown in Scheme 11. The fact that respectable isolated yields were obtained using the reaction conditions described above suggests that radical cyclization occurs more rapidly than reduction by the sacrificial amine to form an aryl anion.

The latter, of course, would not undergo cyclization.

Scheme 11. Photoinduced deiodination followed by cyclization.

3.14. Concluding remarks.

In conclusion, we have developed a highly reducing, organic photocatalytic platform based on the phenanthroimidazole framework electrochemical mediator. Mechanistic experiments were conducted providing strong evidence of an oxidative-quenching cycle with deuterium studies supporting the primary source of hydrogen atoms being the formic acid.

The chemistry displays broad applicability for the generation of carbon-centered radical intermediates via the deiodination of aryl iodides. The chemistry offers an inexpensive, metal-free alternative to current methods for the reductive cleavage or aryl iodides.

Most importantly, the work described in this chapter clearly illustrates that a single structure can play dual roles viz., electrochemically as an oxidant, and photochemically as a reductant. Similarly, we believe that a structure that behaves electrochemically as a reducing agent, can serve as a photo-oxidant. How general are these ideas? We believe they are.

Time will tell.

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References

1 a) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R.

Green Chem. 2010, 12, 2099–2119. b) Schäfer, H. J.; Harenbrock, M.; Klocke, E.; Plate, M.;

Weiper-Idelmann, A. Pure Appl. Chem. 2007, 79, 2047–2057. c) Sperry, J. B.; Wright, D. L.

Chem. Soc. Rev. 2006, 35, 605-621. d) Steckhan, E. Angew. Chem. Int. Ed. Engl. 1986, 25,

683-701. e) Utley, J. Chem. Soc. Rev. 1997, 26, 157-167.

2 a) Hammerich, O., Speiser, B., Eds. Organic Electrochemistry 5th ed.; CRC Press: New

York, 2015. b) Fry, A. J. Synthetic Organic Electrochemistry, Wiley: New York, 1989.

3 Little, R. D.; Moeller, K. D. Interface, 2002, 11, 36-42.

4 Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492.

5 Simonet, J.; Pilard, J.-F.in Organic Electrochemistry, 4th ed; Lund, H.; Hammerich, O.,

Eds.; Marcel Dekker: New York, 2001; 1163–1225.

6 (a) Zhang, N.-T.; Zeng, C.-C.; Lam, C. M.; Gbur, R. K.; Little, R. D. J. Org. Chem.

2013, 78, 2104-2110.

7 Utley, J.; Rozenberg, G.; J. Appl. Electrochem. 2003, 33, 525-532.

8 Steckhan, E. Top. Curr. Chem. 1987, 142, 1-69 and references cited therein.

9 (a) Savéant, J.-M. Chem. Rev. 2008, 108, 2348–2378. (b) Savéant, J.-M. Elements of

Molecular and Biomolecular Electrochemistry, Wiley-Interscience, Hoboken, N.J, 2006. (c)

Costentin, C.; Drouet, S.; Robert, M.; Savéant, J.-M. J. Am. Chem. Soc. 2012, 134, 11235–

11242. (d) Zhang, N.-T.; Zeng, C.-C.; Lam, C. M.; Gbur, R. K.; Little, R. D. J. Org. Chem.

2013, 78, 2104–2110.

122

10 a) Torri, S.; Liu, P.; Bhuvaneswari, N.; Amatore, C.; Jutand, A. J. Org. Chem. 1996,

61, 3055-3060. b) Jutand, A. Chem. Rev. 2008, 108, 2300-2347.

11 Inokuchi, T.; Matsumoto, S.; Torii, S. J. Org. Chem. 1991, 56, 2416–2421.

12 (a) Zeng, C.-C.; Zhang, N.-T.; Lam, C. M.; Little, R. D. Org. Lett. 2012, 14, 1314-

1317. (b) Zhang, N.-T.; Zeng, C.-C.; Lam, C. M.; Gbur, R. K.; Little, R. D. J. Org. Chem.

2013, 78, 2104-2110. (c) Lu, N.-N; Zhang, N.-T.; Zeng, C.-C.; Hu, L.-M.; Yoo, S. Y.; Little,

R. D. J. Org. Chem. 2015, 80, 781-789.

13 Francke, R.; Little, R. D. J. Am. Chem. Soc. 2014, 136, 427-435.

14 a) Escudero, D. Acc. Chem. Res. 2016, 49, 1816-1824. b) McCullough, J. J. Chem.

Rev. 1987, 87, 811-860. c) Hasegawa, M. Chem. Rev. 1983, 83, 507-518.

15 (a) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322–

5363; (b) D. M. Schultz and T. P. Yoon, Science, 2014, 343, 1239176; (c) J. M. R.

Narayanam and C. R. J. Stephenson, Chem. Soc. Rev. 2010, 40, 102; (d) D. A. Nicewicz and

T. M. Nguyen, ACS Catal. 2014, 4, 355–360.

16 (a) Hurtley, A. E.; Lu, Z.; Yoon, T. P. Angew. Chem. Int. Ed. 2014, 53, 8991-8994. (b)

Tyson, E. L.; Farney, E. P.; Yoon, T. P. Org. Lett. 2012, 14, 1110-1113. (c) Skubi, K. L.;

Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035-10074.

17 Nicewicz, D. A.; MacMillan, D. W.C. Science, 2008, 322, 77-80.

18 (a) Narayanam, J. M. R.; Stephenson, C. R.J. Chem. Soc. Rev. 2011, 40, 102-113. (b)

Keylor, M. H.; Matsuura, B. S.; Stephenson, C. R. J. Chem. Rev. 2015, 115, 8976-9027.

19 Discekici, E. H.; Treat, N. J.; Poelma, S. O.; Mattson, K. M.; Hudson, Z. M.; Luo, Y.;

Hawker, C. J.; Read de Alaniz, J. Chem. Commun. 2015, 51, 11705-11708.

123

20 Chow, Y. L.; Danen, W. C.; Nelsen, S. F.; Rosenblatt, D. H. Chem. Rev. 1978, 78,

243-274.

21 Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.; Stephenson, C. R. J. Nature

Chemistry, 4, 2012, 854-859.

22 Mitsudo, K.; Nakagawa, Y.; Mizukawa, J.-I.; Tanaka, H.; Akaba, R.; Okada, T.; Suga,

S. Electrochim. Acta. 2012, 82, 444-449.

23 Staveness, D.; Bosque, I.; Stephenson, C. R. J. Acc. Chem. Res. 2016, 49, 2295-2306.

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A metal-free photoredox mediator based on electrooxidative phenanthroimidazole mediators

Experimental section

General Reagent Information

All reactions were carried out under an argon atmosphere unless otherwise noted. All commercially obtained reagents were used as received unless otherwise noted. All reactions were performed at room temperature (ca. 23 oC), unless otherwise noted. Acetonitrile was purchased from Fisher Scientific and used as received.

General Analytical Information

Nuclear magnetic resonance spectra were recorded on a Varian 400 MHz, a Varian 500

MHz, or a Varian 600 MHz instrument. All 1H NMR experiments are reported in δ units, parts per million (ppm), and were measured relative to the signals for residual chloroform

(7.26 ppm) in the deuterated solvent, unless otherwise stated. All 13C NMR spectra are reported in ppm relative to deuterochloroform (77.23 ppm), unless otherwise stated, and all were obtained with 1H decoupling. For quantitative NMR a 15-second relaxation delay parameter.

Light Source

LED strips (365 nm) were purchased from Elemental Led (see www.elementalled.com) and used as shown below. Reaction vials were placed next to the 365 nm lights. The contents were vigorously stirred while compressed air was directed toward the vial to

125

facilitate cooling and ensure that the reactions occurred photochemically and with no thermal component. The light intensity was measured to be 1.8 W/cm2.

Scheme 1. General scheme for the synthesis of phenanthroimidazole mediators:

The following procedure was adopted from Francke and Little. 1

A mixture of phenanthrene-9,10-quinone of choice (2.50 mmol), benzaldehyde (2.50 mmol), ammonium acetate (5.00 mmol) and NaH2PO4 (0.75 mmol) in 20 mL ethanol was heated to 150 °C in a thick-walled glass tube with a screw-on Teflon top. After stirring for 6 h, the reaction mixture was cooled to room temperature. Compounds 1a, 1b and 1d precipitated during the reaction, and also after cooling. In these cases, the solid was filtered off, washed with saturated K2CO3 solution, and water. The crude products were triturated with CHCl3 and dried at 90 °C in vacuum to obtain pure samples.

A mixture of the crude product (2 mmol), NaH (3 mmol) and methyl iodide (3 mmol) in

15 mL of dry DMF was stirred overnight at room temperature under an argon atmosphere.

After completion of the reaction, 25 mL of ammonium hydroxide solution (10%) was added

126

to the mixture. The precipitated product was filtered off, washed with water and recrystallized from toluene/ethyl acetate.

2‐(4‐Bromophenyl)‐1‐methylphenanthro[9,10‐d]imidazole (phen-HHBr). 1

Yield: 87% (light-yellow solid). Known compound.

+ Eox: 1.01 V; Eox1/2: 0.6 V (vs Ag/Ag , equals to 0.90 V vs SCE).

1 H NMR (600 MHz, DMSO-d6): δ 13.53 (s, 1H), 8.86 (d, J = 8.3 Hz, 1H), 8.82 (d, J =

8.1 Hz, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.5 Hz, 2H), 7.81

(d, J = 8.5 Hz, 2H), 7.79 – 7.70 (m, 2H), 7.68 – 7.60 (m, 2H).

13C NMR (151 MHz, DMSO-d6): δ 148.5, 137.5, 132.4, 130.0, 128.4, 128.3, 128.2,

128.0, 127.6, 127.5, 127.3, 125.9, 125.7, 124.5, 124.2, 122.9, 122.8, 122.4, 122.3.

2‐(4‐Methoxyphenyl)‐1H‐phenanthro[9,10‐d]imidazole (phen-HHOMe). 1

Yield: 89% (white solid). Known compound.

+ Eox: 0.88 V; Eox1/2: 0.81 V (vs Ag/Ag , equals to 1.11 V vs SCE).

1H NMR (600 MHz, DMSO-d6): δ 13.29 (s, 1H), 8.86 (d, J = 8.3 Hz, 1H), 8.83 (d, J =

8.3 Hz, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.54 (d, J = 7.9 Hz, 1H), 8.26 (d, J = 8.7 Hz, 2H), 7.75

127

(dd, J = 7.6 Hz, 7.6 Hz, 1H), 7.72 (dd, J = 7.6 Hz, 7.6 Hz, 1H), 7.65 – 7.60 (m, 2H), 7.17 (d,

J = 8.8 Hz, 2H), 3.87 (s, 3H).

13C NMR (151 MHz, DMSO-d6): δ 160.6, 149.7, 137.3, 128.1, 127.9, 127.9, 127.8,

127.5, 127.4, 125.5, 125.4, 124.5, 124.1, 123.5, 122.9, 122.3, 114.8, 55.8.

Spectroelectrochemical - EPR Measurements 2

In situ X-band EPR spectra were recorded at 300 K with a Bruker EMX CW-micro spectrometer equipped with an ER 4119HS-WI high-sensitivity optical resonator. The EPR measurements were performed using a custom-made EPR flat cell. 2 Controlled potential measurements were carried out using a three-electrode arrangement with Pt grids as working electrode and counter electrode as well as a AgCl-coated silver wire as quasi-reference electrode (all potentials are reported with respect to this reference system). Each electrode was connected using PTFE-coated Pt wires (Adinstrument). The measurements were performed with an analyte concentration of 1 mM in an electrolyte consisting of 0.1 M

NBu4ClO4 in CH3CN/CH2Cl2 (4:1) using an Autolab PGSTAT 201 potentiostat (Metrohm).

Price of starting material of phenanthroimidazole 3

Price of starting materials of triarylimidazole 3

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Price of common transition metal photo catalyst4

83.5 USD/1 g 284.5 USD/250 mg 129 USD for/100 mg (2.06 mmol) (0.38 mmol) (0.11 mmol) (anhydrous basis)

General Procedure for deiodination of Ar-X

A vial equipped with a magnetic stir bar and fitted with a Teflon screw cap septum was charged with substrate (0.1 mmol), phen-HHOMe (1.4 mg, 5 mol %), formic acid (19 μL,

0.5mmol), tributylamine (119 μL, 0.5 mmol), and acetonitrile (1 mL). The reaction mixture was degassed with bubbling argon. The vial was vigorously stirred and placed in front of the

365 nm LEDs while cooling with compressed air to maintain ambient temperature. The reaction yield was determined by 1H NMR.

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Air

flow

Figure S1. Representative reaction set-up comprising reaction vial surrounded by 365 nm

LEDs with a tube blowing compressed air toward the reaction vial for cooling.

Control Experiments

Table 1. Control experiments.

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Scheme 2. Substrate for the deiodination reaction.

Table 2. Photoreduction of 1c to 2c with deuterated reagents.

Excited State reduction Potential

With a broad substrate scope and the potential of this metal free photoredox system established, the physical aspects were studied in more detail, in particular the high excited state reduction potential, given by:

E1/2* = Eox1/2 - hc/max

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where E1/2* is the excited state reduction potential, Eox1/2 is the ground state oxidation potential, h is Planck’s constant, c is the speed of light and max is the photoluminescence maximum. While the ground state oxidation potential of HHBr (Eox 1/2 = 0.898 vs. SCE) is slightly higher than that of Ir(ppy)3 (Eox 1/2 = 0.77 V vs. SCE), the photoluminescence maximum of phen-HHBr, max = 262 nm vs max = 500 nm for Ir(ppy)3.

The radiation wavelength is 365 nm and E1/2* phen-HHBr is calculated to be -2.49

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1-(Allyloxy)-4-iodobenzene (1i). 5

To a solution of 4-iodophenol (1.00 g, 4.54 mmol) in acetone (20.0 mL) was added

K2CO3 (942 mg, 6.82 mmol) and ally bromide (0.436 mL, 4.36 mmol) and the solution was heated to reflux and stirred for 1 h. The solution was cooled to rt, MeOH (10.0 mL) was added and the solution was stirred for a further 15 min before being diluted with EtOAc

(50.0 mL), washed with H2O (3 x 50.0 mL) and brine (3 x 50.0 mL), dried over MgSO4, filtered and concentrated under reduced pressure giving 1i (1.16 g, 4.46 mmol, 98%) as a colourless oil, Rf 0.78 (petroleum ether/EtOAc, 4:1).

1 H NMR: (400 MHz, CDCl3)  7.56 (2H, d, J = 9.1), 6.71 (2H, d, J = 9.1), 6.04 (1H, ddt,

J = 17.2, 10.5, 5.3), 5.41 (1H, dd, J = 17.2Hz, 1.6Hz), 4.52 (2H, d, J = 5.3).

13 C NMR: (100 MHz, CDCl3)  158.5, 138.2, 132.8, 117.5, 117.2, 82.9, 68.8.

1-(Allyloxy)-2-iodobenzene (11a). 6

Allyl bromide (1.6 mL, 18 mmol) was added neat to a solution of 2-iodophenol (3.3 g,

15 mol), anhydrous K2CO3 (6.2 g, 45 mmol), and DMF (50 mL). The reaction was stirred for

24 h at 25 OC, poured into water, and extracted with hexane (4X). The hexane extracts were combined and washed with H2O (3X), 10% NaOH, 3% Na2S2O3, and brine. The hexane layer was dried over MgSO4, filtered, and concentrated to afford a colorless oil, 80% yield.

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1 H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8Hz, 1H), 7.30-7.26, (m, 1H), 6.81 (d, J =

10Hz, 1H), 6.72 (m, 1H), 6.03-6.10 (m, 1H), 6.53 (d, J = 20 Hz,1H), 6.32 (d, J = 10, 1H),

4.60 (m, 2H).

13 C NMR (100 MHz, CDCl3): δ157.1, 139.5, 132.6, 129.4, 122.7, 117.6, 112.5, 86.7, 69.7.

3-Methyl-2,3-dihydrobenzofuran (11b). 7

1 H NMR (500 MHz, CDCl3):  7.16 (d, J = 7.5 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.88

(td, J = 7.5 and 1 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 4.68 (t, J = 8.8 Hz, 1H), 4.07 (dd, J =

7.5 and 8.8 Hz, 1H), 3.55 (m, 1H), 1.34 (d, J = 7 Hz, 3H).

13 C NMR (125 MHz, CDCl3): 159.8, 132.4, 128.1, 123.9, 120.6, 109.6, 78.5, 36.6, 19.3.

1-(But-2-enyloxy)-2-iodobenzene (12a).8

Bromo-1-propene (1.54 mL, 18 mmol) was added neat to a solution of 2-iodophenol (3.3 g,

15 mol), anhydrous K2CO3 (6.2 g, 45 mmol), and DMF (50 mL). The reaction was stirred for

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1 H NMR (500 MHz, CDCl3):  7.28-7.23 (m, 1H), 6.81-6.67 (m 2H), 5.93-5.85 (m, 1H),

5.75-5.68 (m, 1H), 4.51 (d, J = 10Hz, 2H), 1.75 (d, J = 5Hz, 3H).

13 C NMR (125 MHz, CDCl3):  157.3, 139.5, 130.1, 129.3, 125.6, 122.5, 112.7, 86.8,

69.8, 17.9.

3-Ethyl-2,3-dihydro-benzofuran (12b). 9

1 H NMR (500 MHz, CDCl3):  7.18-7.11 (m, 2H), 6.88-6.78 (m, 1H), 4.63 (t, J = 8.8

Hz, 1H), 4.22 (dd, J = 7.5 and 8.8 Hz, 1H), 3.55 (m, 1H), 1.85-1.77 (m, 1H), 1.65-1.57 (m,

1H), 0.98 (d, J = 7 Hz, 3H).

13 C NMR (125 MHz, CDCl3):  160.0, 130.9, 128.1, 124.3, 120.2, 109.4, 76.5, 43.4, 27.6,

11.4

1 Francke, R.; Little, R. D. J. Am. Chem. Soc. 2014, 136, 427-435.

2 Hollmann, D.; Rockstroh, N.; Grabow, K.; Bentrup, U.; Rabeah, J.; Polyakov,

M.;Surkus, A.-E.; Schuhmann, W.; Hoch, S.; Brückner, A. ChemElectroChem, 2017, 4,

2117-2122.

3 Price are based on the Sigma Aldrich web site.

https://www.sigmaaldrich.com/catalog/product/aldrich/156507 http://www.sigmaaldrich.com/catalog/product/aldrich/b5151 http://www.sigmaaldrich.com/catalog/product/aldrich/a88107

4 Prices are based on the Sigma Aldrich web site. http://www.sigmaaldrich.com/catalog/product/aldrich/733202

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http://www.sigmaaldrich.com/catalog/product/aldrich/688096 http://www.sigmaaldrich.com/catalog/product/aldrich/754730

5 Denton, R. M.; Scragg, J. T.; Saska, J. Tetrahedron Letters, 2011, 52, 2554-2556.

6 Curran, D. P.; Totleben, M. J. J. Am. Chem. Soc. 1992, 114, 6050-6058.

7 Schweitzer-Chaput, B.; Boess, E.; Klussmann, M. Org. Lett. 2016, 18, 4944-4947.

8 Lhermet, R.; Durandetti, M.; Maddaluno, J. Beilstein, J. Org. Chem. 2013, 9, 710-716.

9 Curran, D. P. ; Totleben, M. J. J. Am. Chem. Soc. 1992, 114, 6050–6058.

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Chapter 4. Reductive coupling carried out in a flow microreactor.

4.1. Organic electrochemistry

Organic electrochemistry uses electrons from electrical current as a redox reagent for the selective introduction and removal of electrons from organic molecules.1 The redox process modifies the polarity of known functional groups in an umpolung (polarity inversion) that renders electron-poor sites rich, and electron-rich sites poor.2 For example, reduction of an -unsaturated carbonyl compound leads to a radical anion where the - carbon possesses nucleophilic rather electrophilic character (Scheme 1).3 This provides opportunities for the formation of new bonds between sites formally possessing the same polarity.

Scheme 1a. Umpolung from single electron transfer.

Scheme 1b. The umpolung character of organic electrochemistry. Intramolecular

cyclizations.

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Electrochemical processes are conducted under what is referred to as either “constant current” (CC) or “controlled potential” (CP) conditions.4,5 Constant current is often preferred because it is less expensive to implement, since it does not require the acquisition of a potentiometer, is amenable to scale up, and the reaction times are often “short”. To maintain a constant current, the potential must change, becoming more negative or positive, depending upon whether a reduction or an oxidation is being investigated. Meanwhile, the use of controlled potential frequently allows one to selectively reduce/oxidize a particular functional group (electrophore).

Controlled potential methods allow one to set the potential to a value corresponding to that of the electrophore, which is similar to the use of a light filter to allow one to irradiate a particular chromophore selectively in a photochemical process. And, just as one obtains a

UV spectrum to determine the appropriate filter prior to conducting photolysis, so one obtains the analogous cyclic voltammogram (CV) corresponding to the material to be studied electrochemically. It shows the current response as a function of potential.

4.2. Cathodic carbon-carbon coupling

There are many reactions that can be and have been referred to as “electroreductive cyclizations”.5 The “Little group” applied the acronym “ERC” to those processes wherein an electron-deficient alkene that is tethered to an acceptor (e.g., an aldehyde, ketone, nitrile, etc.) undergoes an electrochemically promoted reductive cyclization leading to the formation of a new sigma bond between the -carbon of the alkene and the acceptor unit. Scheme 2 illustrates this, as well as electrohydrodimerization (EHD) and electrohydrocyclization

(EHC) transformations.

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Scheme 2. Schematic formulations of the EHD, EHC, and the ERC reactions.

Since these reductive coupling reactions first appeared in the literature, several non- electrochemical variants have been devised, most notably those involving the use of one electron reductants tributyltin hydride and samarium diiodide.6 Other intriguing variations

7 8 9 use catalytic Ni(COD)2 in the presence of diethylzinc, vanadium (II), Mg in methanol, and

Zn/TMSCl.10

The electrohydrocyclization (EHC) reaction first appeared in the literature in 1966.11

It was developed in the research group headed by Manuel M. Baizer at Monsanto as a spin- off of studies conducted there involving the electrochemical -coupling of acrylonitrile

(electrohydrodimerization, EHD, Schemes 2, 3), an industrial process rendered exceptionally important by its utility in the production of Nylon 6-6. The process has been extended to numerous olefins,12 and has been applied in mixed couplings and intramolecular cyclizations.13, 14 Both the EHC and EHD reactions have been the subject of intense study for many decades.15

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Scheme 3. Electrohydrodimerization of acrylonitrile to adiponitrile.

As illustrated in Scheme 2, electrohydrocyclization (EHC) involves the intramolecular coupling of two electron-deficient alkenes tethered to one another. Reduction leads to the formation of an adduct wherein the -carbons are joined by a new sigma bond.

Saturation of one or both of the C=C  bonds can be an important side reaction.

Both the EHC and ERC reactions have been applied toward the total and partial total synthesis of several natural products, including those portrayed in Figure 1 and described below.

Figure 1. Total and partial total synthesis of natural products using the ERC and EHC reactions. The first total synthesis of the “silver leaf disease” causative agent sterpurene (4) capitalized upon an EHC reaction (1a to 2) to construct the A-ring and set the stage for further development of the remaining framework (Scheme 4). 15b

Scheme 4. Synthetic scheme toward the framework of sterpurene (4) via an EHC pathway.

Electroreductive cyclization (ERC) is a transformation that leads to formation of a new sigma bond between the -carbon of an electron-deficient center and a carbonyl

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acceptor unit. A formal total synthesis of the anti-tumor anti-fungal metabolite quadrone

(10) elegantly and efficiently used the two ERC reactions highlighted in Scheme 6.16 In each instance, isolated yields routinely exceeded 85%.

Scheme 5. Outline of synthetic path leading to quadrone (10) includes two ERC pathways.

(-)-C10-Desmethyl arteannuin B, a substance that can be converted to derivatives of the anti-malarial agent artemisinin using known methodology,17 was approached from two viewpoints,18 one electrochemical, the other not. The ERC step converted enone 12 to the bicyclic hydroxy ester 13 in 78-95% yield. The overall yield, from 11 to product 13, for this route was 17% (Scheme 6).

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Scheme 6. Outline of synthetic pathway leading to the total synthesis of (-)-C10-desmethyl

arteannuin B.

Meanwhile, a route to the structure labeled “phorbol skeleton” in Scheme 8, the tricyclic core of the potent tumor promoter19 phorbol featured the use of both inter- and intramolecular reductive coupling strategies including the formation of 15 via an ERC reaction (14 to 15, Scheme 7).20

Scheme 7. Convergent route to the tricyclic core of the phorbol ester.

4.3. Mediated ERC and EHC reactions

The report by Miranda, Wade, and Little of electroreductive cyclization and electrohydrocyclization using nickel (II) salen as a mediator utilized a 0.1 M of n-Bu4NBr in acetonitrile as supporting electrolyte and solvent, 0.02 M substrate and 6 mol% nickel (II) salen catalyst.21 A mercury pool working electrode (cathode) was used initially. Thereafter, a reticulated vitreous carbon (RVC) electrode was utilized, thereby avoiding the toxic properties of mercury. Cyclohexene was added to the anode chamber to trap the Br2 generated there. A controlled potential electrolysis (CPE) was used, the applied potential corresponding to that for the reduction of nickel salen, not the substrate. The electrolysis converting 20a to 20b occurred in 4 h and consumed the theoretical 2F/mol of charge.

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Scheme 8. Ni(II) salen mediated electrohydrocyclization of 20a to 20b.

Table 1. Mediated reductive coupling with Ni(II) salen with Hg pool and RVC electrodes.

4.4. Mechanism of the ERC reaction

A reductive cyclization requires the addition of two electrons and two protons in addition to the cyclization step itself. Little, Fry, and Leonetti studied the electroreductive cyclization mechanism using linear sweep voltammetry (LSV) along with both chemical and electrochemical arguments to determine the mechanism.22 In principle, cyclization could have proceeded via a radical anion, a radical, or a carbanion. Substrate 22a was utilized to differentiate between radical and carbanion cyclization pathways (Scheme 9). Thus, by

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virtue of the location of the pendant alkene and aldehyde containing chains, the structure provided equal opportunity for either a 5-exo, trig radical cyclization onto the pendant alkene, or a 5-exo, trig cyclization of a carbanion onto the pendant aldehyde.

Scheme 9. Hydroxy ester 21a and lactone 21b that result from carbanion closure onto the carbonyl providing additional evidence that the Electroreductive Cyclization does not proceed via radical cyclization. Of the a priori hundreds of options, it was determined that the five-step sequence, abbreviated ePdcp (vide infra), occurs in the following manner:

(1) addition of the first electron to form a radical anion (the transformation abbreviated with the letter e), (2) a rate determining protonation (P), followed by (3) the addition of a second electron (d), and subsequent (4) cyclization of a carbanion. The mechanism terminates with (5) the addition of a second proton. Scheme 10 illustrates the sequence for the cyclohexyl ketone, 22a. Of particular note was the discovery that the cyclization occurred via a carbanion rather than a radical anion.

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Scheme 10. Reductive cyclization mechanism of -keto-,-unsaturated ester 23a.

4.5. Sustainability issues

Despite the efficiency of the cyclization reactions illustrated above, we realized that improvements needed to be made in order to address environmental and safety concerns.

Clearly, mercury can no longer be used. This we have addressed by switching to various carbon based electrodes such as glassy carbon, reticulated vitreous carbon (RVC),20 carbon felt and the like. In addition, we also needed to meaningfully address the waste issues associated with the use of a supporting electrolyte. Previous efforts have frequently used large amounts of supporting electrolyte that ultimately needed to be separated and either reused or discarded. For example, in the total synthesis of sterpurene (1a, Scheme 4), ~ 4.6 g of substrate 1a saw the use of 54 g of Et4NOTs, the supporting electrolyte, at a concentration of 0.9 M. The heavy load of one-time-use supporting electrolyte creates difficulties in separating the product during workup, and waste, each of which potentially discourages one from even trying electrochemical methods.

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Former group member, Seung Joon Yoo, devised one elegant solution involving the formation and utilization of a supporting electrolyte surrogate that can be recovered and reused.23 It is based upon formation of a composite dispersion between the solid polyionic

® species PDDA(Tf2N) and Super-P carbon black, an inexpensive and readily available form of conducting carbon. Once the two are mixed in an organic solvent and the resulting mixture sonicated for one hour using a simple laboratory sonicator, a black dispersion results. Figure 2 illustrates the dispersion which is stable in that form for at least two years.

The stability is likely due to the existence of cation-pi interactions.24 Use of the recoverable and reusable dispersion afforded excellent results by groups located in the US and China,25

Scheme 11. Synthetic scheme of the PDDA(Tf2N)/CN composite dispersion.

Figure 2. A vial containing PDDA(Tf2N)/CB composite dispersion in acetonitrile.

4.6. New avenues

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We foresaw the opportunity to explore another potential solution to the problem of waste production, one calling for the use of a microflow reactor.26 The results for cathodic cyclization reactions using a flow cell fabricated at UCSB are described below.

4.7. Flow Microreactors

A microreactor is a specially designed chemical reactor with micrometer to millimeter scale channels/tubing through which the substrate passes. It often employs a pump for continuous runs and may combine flows of liquid/gas, gas/gas or liquid/liquid.27

Flow microreactors have been applied in industrial electrochemistry since the mid-20th century. For example, in 1960 Beck and Guthke constructed a disc-stack capillary flow cell with a channel width of 0.2 – 1.0 mm to produce anisaldehyde, a product of commercial interest to

BASF(Figure 3).28

Figure 3. Schematic view of an undivided electrochemical capillary gap cell as used by

Beck and Guthke.

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4.8. Advantages of flow vs batch systems

Flow systems benefit from a large electrode interfacial area, short diffusion distance between electrodes, and adjustable residence time. By combining electrochemistry with a flow microreactor, it leads to few advantages of flow over batch type processes include:

1. A large electrode surface-area-to-volume compared to batch-type reactors;

2. the ability to control residence times,

3. the short distance between the electrodes reduces ohmic drop and improving

conductivity

4. short diffusion distances, and

5. ease of scale up and recyclability

4.9. Selected Application of Flow Microreactor in Electrochemistry

Since Beck and Guthke’s design of the flow reactor illustrated in Figure 3, researchers have developed a host of others. In 1990, Löwe et al. developed an electrochemical flow microreactor with a distance of 75 m between the working and counter electrodes that permitted the electrooxidation of 4-methoxy-benzaldehyde to proceed without the addition of any supporting electrolyte.29

Scheme 12. Anodic oxidation of 4-methyoxytoluene to 4-methoxybenzaldehyde dimethyl acetal. A flow microreactor was applied by Pletcher and coworkers to N-heterocyclic carbene (NHC)-mediated anodic amidation of aldehydes to the corresponding amides.27h,30

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Electrolysis carried out without using supporting electrolyte and the paired electrosynthesis of 2,5-dimethoxy-2,5-dihydrofuran from furan has been studies in a flow apparatus by Atobe et al.,31 and Kolbe electrolysis of di- and trifluoroacetic acid with electron-deficient alkenes, aromatics and heteroaromatics have been investigated in a flow system by Wirth and coworkers.32

In an addition, a versatile and powerful “cation pool” method has been developed by

Yoshida and Suga and their co-workers.33 The system generates carbocation by anodic oxidation at low-temperature. In combination with continuous flow, the method enables the manipulation of unstable carbocations and their reactions with a host of different nucleophiles. The system can also be integrated with FTIR to allow monitoring of the reaction progress and IR characterization.

Yoshida et al. also reported an easily assembled microsystem to achieve a flow- through, and electrolyte-free anodic methoxylation of organic substrates such as p- methoxytoluene.34 In the system, two carbon fiber electrodes were separated by a spacer at micrometer distances, and a diaphragm was used to prevent mixing of anodic and cathodic solutions.

Atobe and Fuchigami et al. reported a micro-flow reactor that ensures the flow is stable and laminar.35 As shown in Figure 4, two solutions are introduced through separate inlets. In this manner, a stable liquid-liquid interface can be formed, and mass transfer between input streams occurs only via diffusion. Substrate and nucleophile solutions are introduced through the inlets. Hence substrates can be oxidized to generate carbocations, while oxidation of nucleophiles can be avoided. The carbocations generated at the anode rapidly diffuse to the bulk electrolytic solution and react with nucleophiles to afford

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products. This approach allows one to bypass concerns regarding the simultaneous oxidation of the nucleophiles, thereby increasing the scope of the chemistry.

Figure 4. Parallel laminar flow in a micro-flow reactor with anodic substitution reaction.

4.10. Cathodic coupling in a flow reactor.

A simple home-made flow reactor was built in the UCSB Department of Chemistry and Biochemistry machine shop. The case is made of chemically inert Teflon TM into which are fitted the electrodes. The dimension of electrodes are 3 x 2 cm2 and the gap in between them is 1 mm. The reaction mixture was injected into the cell against the gravity (bottom-up) in order to fill all the space in between the electrodes (Figure 5).

Figure 5. Home-made flow microreactor (left). Graphite anode with TeflonTM O-ring. On the right, the nickel cathode.

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Figure 6. Home-made flow microreactor with the stainless steel case in which the TeflonTM cell is housed.

Figure 7. Schematic diagram of a flow microreactor.

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Figure 8. Flow microreactor in use.

We elected to explore the cathodic coupling of electron deficient alkenes in the flow microreactor, particularly EHC and ERC reactions. Initial studies focused upon the electrohydrocyclization reaction of gem methyl substituted -unsaturated diester 1a.

Dimethyl malonate was used as the proton donor, while Et4NOTs dissolved in acetonitrile was used as the supporting electrolyte. Initially, a syringe pump was used to inject materials into the reactor. The results obtained using this approach are summarized as entries 1-6 of

Table 3. Thereafter, the MPLC pump illustrated in Figure 5 was used and found to be superior to the syringe pump protocol (vide infra).

Some of the reaction parameters were optimized using 1a. We began by reducing the concentration of the supporting electrolyte from the value first reported in the literature (0.9

M) to 0.2 M. As indicated in entry 1 of Table 3, a 30 % yield of 1b was obtained, as determined by 1H NMR. With this encouraging result, together with the fact that only starting material and product were present after stopping the reaction, the reaction mixture was reinjected into the reactor, using a syringe pump. We were gratified to observe that a 93 152

% yield was achieved using 0.2 M of supporting electrolyte after 3 passes through the flow reactor (Table 3, entry 2). Comparably high yields were obtained when the concentration of the supporting electrolyte was further reduced to 0.09 M (Table 3, entry 3), a value that is ten times lower that that used in a batch reactor.

Air bubbles were often found to build up at the outlet of the cell when a low flow rate of 5 mL/h was used (syringe pump injection), thereby leading to an increase in cell resistance. This was easily rectified by increasing the flow rate, thereby forcing the bubbles to more rapidly leave the cell. Thus while bubbles were observed at 5 mL/h, a 72 % yield of

1b was obtained using a flow rate of 15 mL/h and an even lower concentration of supporting electrolyte, viz., 0.01 M Et4NOTs (Table 3, entry 4). A 61 % yield was obtained when the concentration of supporting electrolyte further decreased to 0.002 M (Table 3, entry 6). This represents a 450-fold reduction in the load of supporting electrolyte compared to literature,

15b and nicely highlights the reduction of waste and cost.

Different cathode materials were tested for using 1a for the electrohydrocyclization.

It was found that nickel and stainless steel were the best cathode material for the reductive cyclization with 93% and 94% yield respectively (entry 1 and 2 of Table 4). Copper lead alloy is not as effectively as nickel and stainless steel and resulted in 72% yield (entry 3 of

Table 4).

With the optimized conditions for syringe pump use in hand, we applied them to substrate 24a. Its product was not separable from dimethyl malonate and thus BHT was used as the proton donor. In each case of dimethyl malonate and BHT, the yields were not satisfactory (28% and 13 %).

The problem of bubble formation was relieved by increasing the flow rate and using a syringe pump, but the problem has yet to be fully resolved. The formation of air bubbles

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was no longer a problem when a recycling MPLC pump (Figure 8) was used at a flow rate of

20 mL/min or 1200 mL/h. This increased flow rate also proved beneficial in that a 79 % yield of product was obtained after only 15 min of reaction time (entry 7 of Table 3), compared with a 61 % yield after 15 min when the flow rate was 15 mL/h.

Reaction conditions: Nickel cathode (3 cm x 2 cm), graphite anode (3 cm x 2 cm), 0.1 mmol substrate, Et4NOTs as supporting electrolyte in 10 mL CH3CN, dimethyl malonate (2 equiv.); yield determined by 1H NMR. Table 3. Optimization of load of supporting electrolyte and flow rate.

Reaction conditions: Cathode (3 cm x 2 cm), graphite anode (3 cm x 2 cm), 0.1 mmol substrate, Et4NOTs as supporting electrolyte in 10 mL CH3CN, dimethyl malonate (2 equiv.); yield determined by 1H NMR. Syringe pump, flow rate: 15 mL/hr, 3 cycle. Table 4. Results obtained using different cathode materials.

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Reaction conditions: Nickel cathode (3 cm x 2 cm), graphite anode (3 cm x 2 cm), 0.1 mmol substrate, Et4NOTs as supporting electrolyte in 10 mL CH3CN, dimethyl malonate (2 equiv.); Syringe pump with flow rate 15 mL/h. Yield determined by 1H NMR, Syringe pump, flow rate 15 mL/h, 1 cycle. Table 5. Syringe pump runs.

4.11. Further optimization of reaction conditions.

Substrate 26a was chosen for further optimization studies because it is readily available and easy to obtain in useful quantities. Its synthesis begins with commercially available methyl 2-oxocyclopentanecarboxylate, acrolein, and triethylamine in ether at room temperature for 2 hour and is followed by a Wittig reaction to afford the unsaturated keto ester 26a, 36 as illustrated in Scheme 13.

Scheme 13. Synthesis of 26a in one pot, two step with commercially available starting

materials.

With 75 mA of applied current and 15 min reaction time, a 66% yield of the [3.3.0] adduct 26b was obtained (Table 6, entry 1) via an ERC reaction. Attempts to prolong the reaction time at 75 mA applied current, led to the formation of a white/pale yellow non-

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conducting layer on the graphite anode and high cell resistance (Figure 9). The resistive layer prevented further reaction from occurring. The coating is believed to be formed by the polymerization of acetonitrile.37 Thus, by using 75 mA of applied current and assuming a fixed cell resistance, the oxidation potential of acetonitrile (+ 1.6 V vs 0.01 M Ag/AgNO3), is easily attained making polymerization a likely annoyance.

Non conducting layer

(white/pale yellow in

color) on graphite (black

in color). Figure 9. White non-conducting layer on graphite after electrolysis.

In an effort to reduce the formation of the non-conducting layer on the graphite anode, isobutyronitrile was used. We reasoned that the bulky radical cation formed after oxidation would be more difficult to polymerize than acetonitrile. Nevertheless, a lower yield (58%) resulted in 15 min of reaction time (entry 2) and the non-conducting layer still appeared thereby preventing further reaction from occurring.

Next, the applied current was reduced from 75 to 50, 30 and 30 mA (Table 6, entries

1, 5, 6 and 7). Gratifyingly, the reactions were not inhibited due to formation of the non- conducting layer on the anode. The yields progressively increased when monitored at 15, 30, and 60 minutes, eventually rising to 89% and 85% for reactions carried out at 50 and 40 mA, respectively. This is a marked improvement compared to the 66% yield obtained using 75 mA (entry 1).

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Different proton sources were also explored (entries 8 and 9). Methanol and acetonitrile containing 1 % water were examined. As shown in entries 3 and 5 of Table 5, the outcomes were abysmal. Bubbling due to the reduction of protons to form hydrogen gas was believed to be the major competitive reaction that led to the low yields. The use of formic acid also led to hydrogen evolution and a low yield (entry 8). Finally, BHT proved unsatisfactory (entry 9). Ultimately, we concluded that dimethyl malonate was the proton donor of choice.

Reaction conditions: Nickel cathode (3 cm x 2 cm), graphite anode (3 cm x 2 cm), 0.1 mmol substrate, 2mM Et4NOTs in 10 mL CH3CN, dimethyl malonate (2 equiv.), yield determined by 1H NMR. Table 6. Use of substrate 26a to further optimize reaction conditions.

4.12. Scope

Based upon the studies described above, we conclude that the optimal conditions use a nickel cathode with a graphite anode (3 cm x 2 cm), 0.1 mmol substrate, 2 mM Et4NOTs in 10 mL CH3CN, dimethyl malonate (2 equiv.) as supporting electrolyte, a MPLC pump for recycling of the substrate with 20 mL/min flow rate, and either 75 mA or 40 mA applied

157

current. With these conditions in hand, and to demonstrate further the utility of the flow reactor, we carried out electrolysis of the substrates illustrated in Table 6, focusing upon both EHC and ERC reactions.

In general, the use of 40 mA applied current with prolonged reaction times afforded higher yields compared to the 75 mA, 15 min runs, except for substrates 23a and 24a. In the latter instances the yield of the ERC reactions were low, ranging from 24 to 44% yield. The reason for the diminished yield is not clear.

The ERC reactions of the trans- and cis-enoates 26a and 27a afforded the same bicyclo[3.3.0] framework 26b and in excellent yields (>85%) using 40 mA of current. That the geometric isomers afforded the same stereoisomeric product is consistent with the ERC reaction mechanism discussed previously (vide infra). Thus, cyclization proceeds via a carbanion, and after the geometric distinction has been lost. The transformation is illustrated in Scheme 14. The scheme also accounts for the stereochemistry present in the product,

26b. Thus attack of the homoenolate from the underside of the ketone carbonyl unit (its Si face) occurs in a manner wherein the CH2CO2Me unit orients away from the existing ring.

158

Scheme 14. Pathway to account for the stereochemical outcome of the electroreductive

cyclization of 26a and 27a to the bicyclic adduct 26b.

Electrohydrocyclization of unsaturated esters (1a, 19a) afforded good to excellent yields at both 75 mA and 40 mA of applied current, the latter proving superior, affording

>80% of each EHC adduct (Table 6, entry 1 and 2). Electroreductive cyclization to afford 6- member rings proved more efficient than closure to the 5-member ring as is exemplified by entries 2, 3, and 6 of Table 6. Significantly, the electroreductive cyclization also works well for the formation of the bicyclic systems (entry 2-4). Electroreductive cyclization of the unsaturated nitrile 25a and unsaturated t-butyl ester 24a proceded slowly in both 75 mA and

40 mA runs.

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a Reaction conditions: Nickel cathode & graphite anode (3 cm x 2 cm), constant current electrolysis. Flow rate: 20 mL/min, 2 mM Et4NOTs in 10 mL acetonitrile as solvent Table 6. Substrate scope.

4.13. Limitation of reaction scale.

The limitation of the scale of the flow reactor was explored. It is noteworthy that one can use a 2mM concentration of supporting electrolyte and operate the microflow system on

160

a ~100 mg scale and produce 70% yields of the ERC adduct 26b in just one hour. In contrast a literature report by Miranda, Wade, and Little, 21 a 200 mg preparative scale electroreductive cyclization of 20a to 20b mediated by Ni (II) salen required more than 4 hour of reaction time and 0.1 M of supporting electrolyte.

Passivation of the anode is the major limiting factor insofar as scaleup is concerned.

In order for the reaction to continue, the graphite anode has to be replaced or cleaned before continuing the electrolysis after 1 hour of reaction time.

Reaction condition: Nickel cathode & graphite anode (3 cm x 2 cm), constant current electrolysis. Flow rate: 20 mL/min, applied current 75 mA, 2 mM Et4NOTs in 10 mL

Acetonitrile as solvent

Table 7. Limitation of reaction scale – passivation.

4.14. Paired electrolysis without addition of proton donor or base

To make full use of the electrolysis, a paired electrolysis of two substrates,1c, 1i 1a and

28a, was explored. The use of a syringe pump at 15 mL/h flow rate with 75 mA applied current (Scheme 15) led to a 44% yield of 1a. While the reduction was taking place at the cathode, the oxidation of p-methoxybenzyl alcohol (28a) was occurring at the anode to afford a 50% yield of aldehyde 28b (Table 8, entry 1). By pairing 28a with 1a, the reactions

161

could be carried out in the absence of a proton donor. Thus, a more cost efficient and environmental friendly process was achieved. Unfortunately, the problem of passivation still existed.

Scheme 15. Paired electrolysis coupling an EHC reaction with the oxidation of p-

methoxybenzyl alcohol

Scheme 16. Paired electrolysis of 26a and 29a geraniol.

In another effort to solve the problem of passivation, geraniol (29a), a substance that has a higher oxidation potential (>1.4 V) than p-methoxybenzyl alcohol (28a) was used and paired with the ERC reaction of 26a (MPLC pump).38 A 50% yield of the cyclized product

26b was obtained. Unfortunately less than 5% of geraniol 29a underwent oxidation (Table 8, entry 2).

Next, substrate the EHC reaction of 1a was paired with p-methoxybenzyl alcohol and in a separate experiment, geraniol. Using an MPLC pump, high yields of cyclization product were observed (>86%) compared to the syringe pump run (entries 3 and 4). Yet, the yield of anodic reaction was not satisfactory (< 25%). This might due to the low oxidation potential of acetonitrile (~1.6 V vs Ag/Ag+) which competes with the oxidation of the alcohol. Similar passivation patterns were observed on the graphite anode.

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When MeOH was used as the solvent (entry 5), more bubble formation was observed as reduction of methanol to methoxide occurred competitively. A lower yield of EHC product 1b was obtained (37%). Once again, the passivation problem was not solved. The use of methanol did not improve the oxidation even though the reduction of methanol resulted in a basic environment suitable for the conversion of p-methoxybenzyl alcohol to its conjugate base and therefore rendering it easier to oxidize.

Reaction condition: Reaction condition: Nickel cathode & graphite anode (3 cm x 2 cm), constant current electrolysis. 2 mM Et4NOTs in 10 mL acetonitrile as solvent a 75 mA applied current, flow rate 15 mL/h, syringe pump. b 40 mA applied current, flow rate 20 mL/min, MPLC pump, 30 min of reaction time c 40 mA applied current, flow rate 20 mL/min, MPLC pump, 10% MeOH in acetonitrile as solvent, 30 min.

Table 8. Paired electrolysis.

4.15. Conclusion

In summary, a simple, inexpensive, home-made and designed flow reactor was made and proved for several cathodic cyclization reactions of the ERC and EHC varieties. One major advantage of using the microflow reactor for the cathodic cyclization is the need to use much less supporting electrolyte while still maintaining moderate to high yields. Its use permitted us to lower the supporting electrolyte load by a factor of 450 without scarifying the conductivity and yield. Thus, a more environmental friendly approach has been developed, one that promises to be of value in future endeavors.

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1 (a) Fry, A. Electochem. Soc. Interface 2009, 28-33. (b) Yan, M.; Kawamata, Y; Baran,

P. S. Chem. Rev. 2017, 117, 13230-13319. (c) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J.

G.; Palma, A.; Vasquez-Medrano, R. Green Chem. 2010, 12, 2099–2119. (d) Schäfer, H. J.;

Harenbrock, M.; Klocke, E.; Plate, M.; Weiper-Idelmann, A. Pure Appl. Chem. 2007, 79,

2047–2057. (e) Sperry, J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605-621. (f) Steckhan,

E. Angew. Chem. Int. Ed. Engl. 1986, 25, 683-701. (g) Utley, J. Chem. Soc. Rev. 1997, 26,

157-167. (h) Steckhan, E. Top. Curr. Chem. 1987, 142, 1-69 and references cited therein. i)

Moeller, K. D. Chem. Rev. 2018, 118, 4817-4833.

2 Little, R. D.; Moeller, K. D. The electrochemical society Interface, Winter 2002.

3 (a) House, H. O.; Huber, L. E.; Umen, M. J. J. Am. Chem. Soc., 1972, 94, 8471-8475.

(b) Bowers, K. W.; Giese, R. W.; Grimshaw, J.; House, H. O.; Kolodny, N. H.; Kronberger,

K. Roe, D. K. J. Am. Chem. Soc. 1970, 92, 2783-2799.

4 Hammerich, O., Speiser, B., Eds. Organic Electrochemistry 5th ed.; CRC Press: New

York, 2015

5 Little, R. D.; Schwaebe, M. K. Reductive cyclizations at the cathode. In

Electrochemistry VI: Electroorganic Synthesis Bond Formation at Anode and Cathode;

Steckhan, E., Ed.; Topics in Current Chemistry 185; Springer: Berlin, 1997; 1-48.

6 (b) Enholm, E. J.; Cottone, J. S. O-Stannyl Ketyl Radicals. In Radicals in Organic

Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 2,

Chapter 3.4, pp 221-232 and references therein. (c) Molander, G. A. Samarium(II) Mediated

Radical Reactions. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-

VCH: Weinheim, Germany, 2000; Vol. 1, Chapter 2.1, pp 153-182 and references therein.

164

7 (a) Wang, L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang, X.; Krische,

M. J. J. Am. Chem. Soc. 2002, 124 (32), 9448-9453. (b) Montgomery, J.; Oblinger, E.;

Savchenko, A. V. J. Am. Chem.Soc. 1997, 119 (21), 4911-4920. (c) Mahandru, G. M.; Liu,

G.;

Montgomery, J. J. Am. Chem. Soc. 2004, 126 (12), 3698-3699. (d) Montgomery, J.

Angew. Chem., Int. Ed. 2004, 43 (30), 3890-3908. (e) Cossy, J. Bull. Chim. Soc. Fr. 1994,

131 (3), 344-56.

8 Inokuchi, T.; Kawafuchi, H.; Torii, S. J. Org. Chem. 1991, 56 (16), 4983-5.

9 Lee, G. H.; Choi, E. B.; Lee, E.; Pak, C. S. J. Org. Chem. 1994, 59, 1428-1443.

10 Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 24 (28), 2821-2824.

11 Anderson, J. D.; Baizer, M. M.; Petrovich, J. P. J. Org. Chem.1966, 31 (12), 3890-7.

12 Baizer, M. M.; Anderson, J. D. J. Electrochem. Soc. 1964, 111, 2, 223-226.

13 (a) Baizer, M. M.; Anderson, J. D.; Wagenkncht, J. H.; Ort, M. R.; Petrovich, J. P.

Electrochim. Acta. 1967, 12, 1377-1381.

14 Schafer, H. J. Angew. Chem. Int. Ed. Engl. 1981, 20, 911-934. And the references therein

15 (a) Organic Electrochemistry, 4th ed.; Nielsen, M. F., Utley, J. H. P., Lund, H.,

Hammerich, O., Eds.; Dekker: New York, 2001; pp 795-882. (b) Moëns, L.; Baizer, M. M.;

Little, R. D. J. Org. Chem. 1986, 51 (23), 4497-8. (c) Amputch, M. A.; Little, R. D.

Tetrahedron 1991, 47 (3), 383-402. (d) Utley, J. H. P.; Little, R. D.; Nielson, M. F. in

Organic Electrochemistry, 5th ed; Hammerich, O., Speiser, B., Eds.; CRC Press: New York,

2015; 621-704.

165

16 (a) Sowell, C. G.; Wolin, R. L.; Little, R. D. Tetrahedron Lett. 1990, 31, 4, 485 – 488.

(b) Electrochemistry VI: Electroorganic Synthesis: Bond Formation at Anode and Cathode;

Topics in Current Chemistry No. 185; Steckhan, E., Ed.; Springer: Berlin, Germany,

Germany, 1997.

17 Lansbury, P. T.; Nowak, D. M. Tetrahedron Lett. 1992, 33, 1029- 1032.

18 Schwaebe, M.; Little, R. D. J. Org. Chem. 1996, 61, 3240 – 3244.

19 Naturally Occurring Phorbol Esters; Evans, F. J., Ed.; CRC Press: Boca Raton, FL,

1986. (b) Berenblum, I. In Risk Factors and Multiple Cancer; Stoll, B., Ed.; John Wiley and

Sons: New York, 1984. (c) Wender, P. A.; Koehler, K. F.; Sharkey, N. A.; Dell ’Aquila, M.

L.; Blumberg, P. M. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 4214.

20 Carroll, G. L.; Little, R. D. Org. Lett. 2000, 2, 18, 2873 – 2876.

21 Miranda, J. A.; Wade, C. J.; Little, R. D. J. Org. Chem. 2005, 70, 8017-8026.

22 Fry, A. J.; Little, R. D.; Leonetti, J. J. Org. Chem. 1994, 59, 5017-5026.

23 Yoo, S. J.; Li, L.-J.; Zeng, C.-C.; Little, R. D. Angew. Chem. Int. Ed. 2015, 54, 3744-

3747.

24 (a) Fan, F. Y.; Woodford, W. H.; Li, Z.; Baram, N.; Smith, K. C.; Helal, A.;

McKineley, G. H.; Carter, W. C.; Chiang, W.-M. Nano Lett. 2014, 14, 2210-2218. (b)

Dubuta, M.; Ho, B.; Wood, V. C.; Limthongkul, P.; Brunini, V. E.; Carter, W. C.; Chiang,

Y.-M. Adv. Energy Mater. 2011, 1, 511-516.

25 (a) Harold, S. Waldvogel, S. R.; Little, R. D.; Yoo, S. J. Electrochimica

Acta, 2016, 196, 735-74. (b) Li, L.-J.; Jiang, Y.-Y.; Lam, C. M.; Zeng, C.-C., Hu, L.-M.;

Little, R. D. J. Org. Chem. 2015, 80, 11021-11030. (c) Qian, W.; Texter, J.; Yan, F. Chem.

Soc. Rev. 2017, 46, 1124-1159.

166

26 Yoshida, J.-I. The Electrochemical Society Interface 2009, summer

27 (a) Matlosz, M., Ehrfeld, W., Baselt, J. P., Eds. Microreaction Technology; IMRET 5:

Proceedings of the Fifth International Conference on Microreaction Technology; Springer:

Berlin, 1998; (b) Haswell, S. J.; Fletcher, P. D. I.; Greenway, G. M.; Skelton, V.; Styring, P.;

Morgan, D. O.; Wong, S. Y. F.; Warrington, B. H. In Automated Synthetic Methods for

Specialty Chemicals; Royal Society of Chemistry: Cambridge, U.K., 1999; p 26. (c) Manz,

A., Becker, H., Eds. Microsystem Technology in Chemistry and Life Sciences; Springer:

Berlin, 1999. (d) Ehrfeld, W.; Hessel, V.; Löwe, H. Microreactors: New Technology for

Modern Chemistry; Wiley−VCH: Weinheim, Germany, 2000. (e) Jensen, K. F.

Microreaction Engineering − Is Small Better? Chem.Eng. Sci. 2001, 56, 293−303. (f)

Haswell, S. J.; Middleton, R. J.; O’Sullivan, B.; Skelton, V.; Watts, P.; Styring, P. The

Application of Micro Reactors to Synthetic Chemistry. Chem. Commun. 2001, 391−398. (g)

Atobe, M.; Tateno, H.; Matsumura, Y. Chem. Rev. 2018, 118, 4541-4572. (h) Pletcher, D.;

Green, R. A.; Brown, R. C. D. Chem. Rev. 2018, 118, 4573-4591.

28 (a) Beck, F.; Guthke, H. Entwicklung Neuer Zellen für Elektroorganische Synthesen.

Chem. Ing. Tech. 1969, 41, 943−950. (b) Ziogas, A.; Kolb, G.; O’Connell, M.; Attour, A.;

Lapicque, F.;Matlosz, M.; Rode, S. Electrochemical Microstructured Reactors: Design and

Application in Organic Synthesis. J. Appl. Electrochem. 2009, 39, 2297−2313.

29 Löwe, H.; Ehrfeld, W.; Electrochimica Acta 1999, 44, 3679-3689.

30 Green, R. A.; Pletcher, D.; Leach, S. G.; Brown, R. C. D. Org Lett. 2015, 17, 3290-

3293.

31 Horii, D.; Atobe, M.; Fuchigami, T.; Marken, F. Electrochem. Commun. 2005, 7, 35–

39.

167

32 Arai, K.; Watts, K.; Wirth, T. ChemistryOpen 2014, 3, 23-28.

33 (a) Suga, S.; Okajima, M.; Fujiwara, K.; Yoshida, J.-I. J. Am. Chem. Soc. 2001, 123

(32), 7941-7942. (b) Yoshida, J.-I.; Suga, S. Chem. Eur. J. 2002, 8 (12), 2650-2658. (c)

Yoshida, J.-I. The Electrochemical Society Interface 2009, summer

34 Horcajada, R.; Okajima, M.; Suga, S.; Yoshida, J. Chem. Commun. 2005, 1303–1305.

35 Horii, D.; Fuchigami, T.; Atobe, M. J. Am. Chem. Soc. 2007, 129, 11692-11693.

36 (a) Lee, G. H.; Choi, E. B.; Lee, E.; Pak, C. S. J. Org. Chem. 1994, 59, 1428-1443. (b)

Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821-2824.

37 (a) Eizo, O.; Kyoichi, M.; Goro, S. Bull. Chem. Soc. Jpn, 1966, 39, 1182-1185. (b)

Millich, F. Chem. Rev. 1972, 72, 101-113.

38 (a) Arteaga, J. F.; Ruiz-Montoya, M.; Palma, A.; Alonso-Garrido, G.; Pintado, S.; guez-Mellado, J. R. Molecules, 2002, 17, 5126-5138. (b) Shibuya, H.; Murakami, N.;

Shimada, F.; Kitagawa, I. Chem. Pharm. Bull. 1991, 39, 1302-1304. (c) Palmisano, G.;

Ciriminna, R.; Pagliaro, M. Adv. Synth. Catal 2006, 348, 2033-2037.

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Reductive coupling carried out in a flow microreactor.

Experimental section

General Reagent Information

All commercial reagents were used as received unless otherwise noted. All reactions were performed at room temperature (ca. 23 oC), unless otherwise noted. Acetonitrile was purchased from Fisher Scientific and used as received. Silica gel 60 F254 TLC plates were used for monitoring of reaction progress and the course of column chromatography. Silica gel (600 mesh) was used for flash column chromatography using the combination of ethyl acetate and petroleum ether as eluent. Glass chromatography columns of size 0.5-1 inch diameter were used, the size depending on the amount of material to be separated.

General Analytical Information

Nuclear magnetic resonance spectra were recorded on a Varian 400 MHz, a Varian

500 MHz, or a Varian 600 MHz instrument. All 1H NMR data are reported in δ units, parts per million (ppm), and were measured relative to the signals for residual chloroform (7.26 ppm) in the deuterated solvent, unless otherwise stated. All 13C NMR spectra are reported in ppm relative to deuterochloroform (77.23 ppm), unless otherwise stated, and all were obtained with 1H decoupling. For quantitative NMR a 10-second relaxation delay parameter.

Power Source

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A DC power supply, Arksen 303 D, was used (Figure 1). The current was adjusted to the desired settings and the instrument was set to shut down automatically when the voltage reached 32 V.

Figure 1. DC power supply used.

Electrodes

Electrodes (graphite, stainless steel, nickel, and copper lead alloy) were made in the

UCSB Department of Chemistry and Biochemistry machine shop by Mr. Bruce Dunson. The electrodes were washed with water, dichloromethane and acetonitrile and allowed to air dry after every use.

General method for the electrolysis

The electrodes were rinsed with acetonitrile before use. Prior to an electrolysis, a solution of pure acetonitrile solution was passed through the flow cell in order to ensure that no leakage was occurring and the absence of bubbles. The electrodes were washed with acetonitrile, water and acetone and allowed to air dry after use.

An acetonitrile solution containing starting material (20 mM), supporting electrolyte

(generally 2 mM at concentrations specified in Table 3 in the main text), and proton donor

(when used) was prepared and placed in a round-bottomed flask. Teflon TM tubes (1.75 mm

170

inner diameter) were used to transfer and recycle solution from the round-bottomed flask and the flow reactor.

Circulation of the reaction mixture was achieved using an MPLC pump (FMI Lab

Pump Model RP-SY), with a setting of 9 (flow rate of 20 mL/min, confirmed by calibration).

The solution was circulated through the cell prior to starting an electrolysis in order to ensure that the electrodes were wet and that no bubbles remained. After ~ 5 minutes circulation to ensure that the cell did not leak, the power was turned on and adjusted to the desired current.

Figure 2. Flow cell in use.

Synthesis of substrates used in flow experiments.

Substrates were synthesized by following the routes illustrated in Schemes 1 – 4.

Scheme 1. Synthesis of 1a.

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(a) O3, -78 °C, MeOH/CH2Cl2; (b) cat TsOH; (c) Me2S, rt (90% for steps a-c); (d) Ph3P=CHCO2Me, CH2Cl2, rt; (e) CF3CO2H, CH2Cl2/H2O (1:1.2, v/v), 12 h rt (77% combined yield for steps d and e); (f) NaH, (EtO)2POCH2CN, THF, 0 °C (78%, steps f and e); (g) O3, -78 °C, CH2Cl2; (h) Ph3P=CHCO2Me, MeOH, -78 °C to rt (30%, two steps) Scheme 2. General scheme for the synthesis of 19a, 20a, 25a.

(a) O3, -78 °C, MeOH/CH2Cl2; (b) cat TsOH; (c) Me2S, rt (90% for steps a-c); (d) Ph3P=CHCO2t-Bu, CH2Cl2, rt; (e) CF3CO2H, CH2Cl2/H2O (1:1.2, v/v), 12 h rt (77% combined yield for steps d and e) Scheme 3. General scheme for the synthesis of 24a.

Scheme 4. Synthesis of 26a via a one pot, two step sequence.

Dimethyl (E,E)-5,5-dimethyl-2,7-nonadienedioate (1a). 1

172

To a solution of oxalyl chloride (12.2 mL, 0.14 mmol) in dry dichloromethane and cooled to -70 oC, was added over five minutes, dimethyl sulfoxide (19.6 mL, 0.277 mmol).

The resulting mixture was stirred for 15 min prior to the addition of 1,5-dihydroxy-3,3- dimethylpentane (7.61 g, 0.058 mmol) over 5 min as a solution in CH2Cl2 (30 mL). After stirring for 1 h at -70 oC, triethylamine (80.3 mL, 0.576 mmol) was added and the reaction mixture was allowed to warm to 0 oC. The resulting white salt was dissolved by adding 400 mL of dry CH2Cl2 whereupon methyl (triphenylphosphoranylidene) acetate (48.1 g, 0.144 mmol) was added in one portion. The resulting mixture was refluxed for 21 h and the clear yellow solution was concentrated in vacuo and poured into 500 mL of saturated NaCl, extracted with CH2Cl2 (5 x 200 mL) and dried over MgSO4. Concentration in vacuo afforded a red-brown oil which was dissolved in a minimum amount of hexane prior to chromatography on silica gel eluting with 10% ethyl acetate in hexane in quantitative yield.

1 H NMR (600 MHz, CDCl3)  6.93-6.87 (m, 1H), 6.88-5.77 (d, 2H, J =18 Hz), 3.63 (s,

3H), 2.08-2.06 (d, 2H, J = 12 Hz), 0.91 (s, 3H).

13 C NMR (126 MHz, CDCl3) δ 166.6, 145.6, 123.5, 77.3, 77.1, 76.8, 51.4, 44.6, 34.6,

26.9.

(E)-8-Oxo-oct-2-enoic Acid Methyl Ester (20a). 2

3 6,6-Dimethoxyhexanal (5.0 g, 31 mmol) was dissolved in 65 mL of CH2Cl2 and

(carbomethoxymethylene)triphenylphosphorane (25.0 g, 77.5 mmol) was added in one portion at room temperature. The reaction mixture was stirred for 3.5 h, and TLC analysis

(30% Et2O in hexane) indicated that conversion to the unsaturated ester was complete. A

173

solution of trifluoroacetic acid (8 mL) and water (75 mL) was added to form a biphasic mixture. The reaction was monitored by TLC (30% Et2O in hexane), and upon completion of hydrolysis of the acetal (3 h), the organic phase was separated. The organic phase was washed with saturated aqueous NaHCO3 (6 x100 mL) and water (3 x 75 mL) and was dried over MgSO4. Upon removal of the solvent under reduced pressure, the crude oil was purified by column chromatography over silica gel (30% Et2O in hexane) to give the title compound

(4.06 g, 23.87 mmol, 77% yield).

1 H NMR (400 MHz, CDCl3)  5.79 (m, 1H), 5.00 - 4.91 (m, 2H), 4.35 (t, J = 5.8 Hz,

1H), 3.30 (s, 6H), 2.04 (m, 2H), 1.59 (m, 2H), 1.43 - 1.30 (m, 4H);

13 C NMR (100 MHz, CDCl3) δ 202.5, 104.4, 52.9, 43.9, 32.4, 24.3, 22.0.

Dimethyl 1,7-octadiene-1,8-dicarboxylate (19a). 4

To a 5-mL round-bottomed flask topped with a serum cap was added 66.8 mg (0.2 mmol) of (carbomethoxytriphenylphosphoranylidene)acetate in 1.5 mL of acetonitrile at room temperature. 2-(3-Oxopropyl)cyclohexanone (15.4 mg, 0.1 mmol) in 85 L of acetonitrile was added and stirring was continued. The reaction was monitored by TLC. The solvent was removed in vacuo and the solid was repeatedly washed with ether. The ether layer was concentrated in vacuo to afford 25 mg of a yellow oil. The yellow oil was dissolved in ethyl acetate (20 mL) and extracted with water (20 mL x 3) and saturated NaCl solution (20 mL). The resulting organic layer was dried with MgSO4 and was chromatographed over silica gel by using 10% ethyl acetate in hexane to afford 0.085 mmol product (85% yield).

174

1 H NMR (400 MHz, CDCl3) 6.95 (dt, J = 15.7, 6.9 Hz, 2H), 5.82 (dt, J = 15.7, 0.7 Hz,

2H), 3.72 (s, 6H), 2.20 (m, 4H), 1.50 (m, 4H);

13 C NMR (CDCl3)  166.9, 148.8, 121.2, 51.3, 31.8, 27.4.

Methyl (E)-5-(2-oxocyclopentyl)-2-pentenoate (23a). 5

To a 5-mL round-bottomed flask topped with a serum cap was added 33.4 mg (0.10 mmol) of (carbomethoxytriphenylphosphoranylidene)-acetate in 0.75 mL of acetonitrile at room temperature. 2-(3-Oxopropyl)cyclohexanone (15.4 mg, 0.1 mmol) in 85 L of acetonitrile was added and stirring was continued. The reaction was monitored by TLC. The solvent was removed in vacuo and the solid was repeatedly washed with ether. The ether layer was concentrated in vacuo to afford 25 mg of a yellow oil. The yellow oil was dissolved in ethyl acetate (20 mL) and extracted with water (20 mL x 3) and saturated NaCl (20 mL). The resulting organic layer was dried with MgSO4 and was chromatographed over silica gel by using 10% ethyl acetate in hexane to afford 0.085 mmol product (85% yield).

1 H NMR (500 MHz, CDCl3)  6.94 (dt, 1 H, J = 6.9, 15.6 Hz), 5.85 (dt, 1H, J= 15.6, 1.4

-Hz), 3.70 (s, 3 H), 2.69-2.65 (m, 1H), 2.44-2.41 (m, 2H), 2.31-2.30 (m, 1H), 2.20-2.05 (m,

3H), 1.87-1.86 (m, 1H) 1.67-1.62 (m, 2 H), 1.36-1.33 (m, 1 H).

13 C NMR (126 MHz, CDCl3)  211.3, 166.8, 147.2, 122.5, 51.4, 39.5, 42.0, 33.7, 32.1,

27.8, 25.1.

175

(E)-7-Oxo-hept-2-enoic acid tert-butyl ester (24a).6

5,5-Dimethoxypentanal (4.53 g, 31 mmol) was dissolved in 65 mL of CH2Cl2 and

Ph3PC=CO2tBu(carbomethoxymethylene)triphenylphosphorane (29.1 g, 77.5 mmol) was added in one portion at room temperature. The reaction mixture was stirred for 3.5 h, and

TLC analysis (30% Et2O in hexane) indicated that conversion to the unsaturated ester was complete. A solution of trifluoroacetic acid (8 mL) and water (75 mL) was added to form a biphasic mixture. The reaction was monitored by TLC (30% Et2O in hexane), and upon completion of hydrolysis of the acetal (3 h), the organic phase was separated. The organic phase was washed with saturated aqueous NaHCO3 (6 x100 mL) and water (3 x 75 mL) and was dried over MgSO4. Upon removal of the solvent under reduced pressure, the crude oil was purified by column chromatography over silica gel (30% Et2O in hexane) to give the title compound (4.06 g, 23.87 mmol, 77% yield).

1 H NMR (600 MHz, CDCl3) d 9.78 (1H, t, J = 1.4), 6.83-6.78 (1H, dt, J = 15.6, 7.0 Hz),

5.77-5.74 (1H, dt, J = 15.6, 1.6Hz), 2.49-2.46 (2H, dt, J = 1.4,7.2 Hz), 2.24-2.20 (2H, m),

1.82-1.77 (2H, m), 1.48, (9H, s)

13 C NMR (151 MHz, CDCl3) δ 201.7, 165.8, 146.2, 124.0, 80.2, 43.0, 31.1, 28.1, 20.4.

(E)-8-Oxo-oct-2-enenitrile (25a). 7

A suspension of NaH (0.71 g of 60% in mineral oil, 18.6 mmol) in dry THF (27 mL) was cooled to 0 °C over an ice bath. Diethyl (cyanomethyl)phosphonate (2.96 mL, 18.6 mmol)

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was added dropwise via syringe. The reaction mixture was warmed to room temperature and was stirred for 1 h after which time hydrogen gas evolution had ceased and the suspension had become a homogeneous solution. 6,6-Dimethoxyhexanal (2.0 g, 12.4 mmol) was dissolved in THF (5 mL) and was transferred to the reaction vessel dropwise at room temperature. After 3 h, TLC (30% Et2O in hexane) indicated that conversion to the unsaturated nitrile was complete. The reaction was concentrated in vacuo, and the crude mixture was dissolved in CH2Cl2 (30 mL) and a solution of trifluoroacetic acid (3.2 mL) and water (40 mL) was added to form a biphasic mixture. The reaction was stirred overnight.

The organic layer was separated and then was washed with NaHCO3 (3 x 15 mL) and saturated NaCl solution (3 x 15 mL) and was dried over MgSO4. The solvent was evaporated, and the crude product was purified by column chromatography (50% Et2O in hexane) to afford the (E)-isomer in a 78% yield (1.325 g, 9.67 mmol).

1 H NMR (400 MHz, CDCl3) δ 9.68 (t, J = 1.6 Hz, 1H), 6.93 (dt, J = 16.4, 7.2 Hz, 1H),

6.44 (dt, J = 11.2, 7.6 Hz, 1H), 5.34-5.28 (m, 2H), 2.46-2.37 (m, 3H), 2.20 (m, 1H, J = 7.2

Hz), 1.60 (m, 2H), 1.45 (m, 2H).

13 C NMR (100 MHz, CDCl3) δ 201.8, 201.7, 155.1, 154.2, 117.2,115.7, 99.9, 99.8, 43.2,

43.1, 32.8, 31.3, 27.3, 26.8, 21.2, 21.0.

Methyl (Z)-and (E)-S-[2-(Methoxycarbonyl)-l-oxocyclopent-2-yl]-2-pentenoate (26a and 27a). 8

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A mixture of methyl 2-oxocyclopentanecarboxylate (3.13 g, 20.0 mmol), acrolein (1.68 g, 30.0 mmol), and triethylamine (0.5 mL) in ether (30 mL) was stirred for 2 h at room temperature under the nitrogen atmosphere. The reaction mixture was concentrated in vacuo to afford a pale orange oil. The residue was dissolved in ethanol (30 mL) and methyl

(tripheny1phosphoranylidene)-acetate (8.02, g, 24.0 mmol) was added at room temperature.

After 1 h, the reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate and extract with water (20 mL x 3), saturated NaCl solution (20 mL) and dried with MgSO4. The organic layer was then concentrated in vacuo and the isomers separated by flash column chromatography (silica gel) with 30% ethyl acetate in hexane to give 27a (1.73 g, 6.4 mmol, 32%) and 26a (3.34 g, 12.2 mmol, 61 %) as colorless oils. TLC (silica gel) Rf

0.45 (hexane/EtOAc (3/1)).

For 26a (trans):

1 H NMR (500 MHz, CDCl3) δ 6.94-6.88 (m,1H), 5.84-5.81 (d, 1H, J = 15Hz), 3.71 (s,

3H), 3.70 (s, 3H), 2.57-2.52 (m, 1H), 2.47-2.40 (m, 1H), 2.30-2.23 (m, 2H), 2.20-2.13 (m,

1H), 2.10-1.84 (m, 4H), 1.72-1.68 (m, 1H), 1.63 (s, 1H).

13 C NMR (126 MHz, CDCl3) δ 214.2, 171.1, 166.8, 147.8, 121.5, 59.8, 52.6, 51.5, 37.8,

33.2, 32.1, 27.6, 19.6.

For 27a (cis):

1H NMR (500 MHz, CDCl3)  6.21-6.16 (m, 1H), 5.77-5.74 (m, 1H), 3.69 (s, 3H), 3.67

(s, 3H), 2.65-2.50 (m, 2H), 2.58-2.52 (m, 2H), 2.43-2.37 (m, 1H), 2.11-2.04 (m, 1H), 2.04-

1.92 (m, 3H)

13 C NMR (126 MHz, CDCl3) δ 214.5, 171.1, 166.5, 148.8, 119.9, 60.2, 52.6, 51.0, 37.9,

32.8, 32.4, 24.5, 19.6. 178

Dimethyl 2,2'-(4,4-dimethylcyclopenta-1,2-diyl)diacetate (1b). 1a

Colorless liquid isolated by column chromatography using 30% ethyl acetate in hexane as eluent. Rf 0.45 (30% ethyl acetate in hexane).

1 H NMR (CDCl3, 500 MHz)  3.66 (s, 6H), 2.50-2.45 (m, 2H), 2.21-2.15 (m, 2H), 2.07-

2.00 (m, 2H), 1.77-1.73 (m, 2H), 1.19-1.15 (m, 2H), 1.00 (s, 6H)

13 C NMR (CDCl3, 126 MHz)  173.5, 51.5, 47.7, 46.7, 41.8, 38.9, 37.7, 37.0, 35.1, 30.9.

(2-Methoxycarbonylmethyl-cyclohexyl)-acetic Acid Methyl Ester (19b). 9

Colorless isolated with 30% Et2O in hexane by column chromatography, Rf 0.20 Et2O in hexane; vanillin stain.

1 H NMR (CDCl3, 400 MHz)  3.65 (s, 6H), 2.49 (dd, 2H, J = 3.8, 14.7 Hz,) 3.8, 14.7,

2H), 2.19 (dd, 2H, J = 8.5, 14.9), 1.6-1.8 (m, 6H), 1.25 (m, 4H);

13 C NMR (CDCl3, 100 MHz)  173.8, 51.7, 39.2, 39.2, 39.6, 29.9, 25.9

trans-(2-Hydroxycyclohexyl)-acetic Acid Methyl Ester (20b), 10

Colorless liquid isolated with 30% Et2O in hexane by column chromatography. Rf 0.13

30% ether in hexane.

179

1 H NMR (500 MHz, CDCl3) δ 3.68 (s, 3H), 3.21 (m, 1H), 2.66 (dd, J = 15.2, 6.0 Hz,

1H), 2.19 (dd, J = 15.2, 6.4 Hz, 1H), 1.95 (m, 1H), 1.84 (d, J = 4.8 Hz, 1H) 1.80-1.71 (m,

3H), 1.66 (m, 1H), 1.26 (m, 3H), 1.02 (m, 1H).

13 C NMR (126 MHz, CDCl3) δ 203.4, 173.1, 57.6, 51.8, 39.1, 37.3, 33.0, 26.9, 24.9.

tert-Butyl 2-(2-hydroxycyclopentyl)acetate (24b). 8

The product was not separable from dimethyl malonate, the proton donor, by silica gel chromatography using any combination of hexane, diethyl ether and ethyl acetate.

1 H NMR (600 MHz, CDCl3) δ 3.86-3.81 (m, 1H), 2.61 (br, 1H), 2.38-2.27 (m, 2H),

2.07-1.99 (m, 1H), 1.97-1.87 (m, 2H), 1.75-1.66 (m, 1H), 1.62-1.53 (m, 2H), 1.43 (s, 9H),

1.25-1.14 (m, 1H).

(2-Hydroxy-cyclohexyl)-acetonitrile (20). 8

Colorless liquid isolated with 100% hexane by column chromatography. Not visible under UV or stain.

1 H NMR (400 MHz, CDCl3) 3.29 (m, 1H), 2.62 (dd, J = 17.2, 4.4 Hz, 1H), 2.48 (dd, J

= 17.2, 7.6 Hz, 1H), 2.16 (d, J = 5.2 Hz, 1H), 1.99 (m, 1H), 1.90 (m, 1H), 1.77 (m, 1H), 1.70

(m, 1H), 1.54 (m, 1H), 1.31-1.16 (m, 3H).

13 C NMR (100 MHz, CDCl3) 118.9, 73.0, 41.9, 35.8, 30.3, 25.1, 24.6, 20.6

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Methyl 2-((1S,6aR)-6a-hydroxyoctahydropentalen-1-yl)acetate (23b). 2a

Isolated with 30% ethyl acetate in hexane by column chromatography. Rf 0.30 (30% ether in hexane)

1 H NMR (400 MHz, CDCl3) d 3.69 (s, 3H), 3.42 (br, 1H), 2.47 (m, 2H), 2/30-2//05 (m,

3H), 1.95-1.5 (m, 5H). 1.45-1.15 (m, 3H), 1.10-0.95 (m, 1H).

Trans-8-(methoxycarbonyl)- 2-[(methoxycarbonyl)methyl]-l- hydroxybicyclo[3.3.01,5]-octane (26b). 8

Colorless liquid isolated by 30% ethyl acetate in hexane with column chromatography. Rf

0.30 (30% ether in hexane).

1 H NMR (600 MHz, CDCl3) δ 3,71 (s, 3H) 3.67 (s, 3H), 3.16 (s, 1H), 2.56-2.49 (m, 3H),

2.43-2.29 (m, 4H), 1.90-1.78 (m, 3H), 1.67-1.51 (6H), 1.42-1.36 (m, 1H), 1.36-1.20 (m, 2H)

13 C NMR (126 MHz, CDCl3) δ 176.7, 174.0, 93.0, 61.9, 52.2, 51.7, 46.6, 37.8, 36.2,

35.0, 34.3, 28.8, 24.9.

1 Moëns, L.; Baizer, M. M.; Little, R. D. J. Org. Chem. 1986, 51, 4497-4498.

2 (a) Little, R. D.; Fox, D. P.; Van Hijfte, L.; Dannecker, R.; Sowell, G.; Wolin, R. L.;

Moëns, L.; Baizer, M. M. J. Org. Chem. 1988, 53, 2287-2294. (b) Zhang, Y.; Dlugosch, M.;

Jübermann, M.; Banwell, M.G.; Ward, J. S. J. Org. Chem. 2015, 80, 4828−4833.

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3 (a) Schreiber, S. L.; Claus, R. E.; Regan, J. Tetrahedron Lett. 1982, 23 (38), 3867-

3870. (b) Schreiber, S. L.; Claus, R. E. Organic Syntheses; Wiley & Sons: New York, 1990;

Collect. Vol. 7, pp 168-173.

4 (a) Cope, A. C.; Nealy, D. L.; Scheiner, P.; Wood, G. J. Am. Chem. SOC. 1965, 87,

3130-3135. (b) Allan, R. D.; Gordiner, B. G.; Wells, R. J. Tetrahedron Lett. 1968, 6055-

6056. (c) Stork, G.; Landsman, H. K. J. Am. Chem. SOC. 1956, 78, 5129-5130.

5 (a) Little, R. D.; Fox, D. P.; Van Hijfte, L.; Dannecker, R.; Sowell, G.; Wolin, R. L.;

Moën, L.; Baizer, M. M. J. Org. Chem. 1988, 53, 2287-2294.

6 Yasuhara, T.; Nishimura, K.; Yamashita, M.; Fukuyama, N.; Yamada, K.-I.;

Muraoka,O.; Tomioka, K. Org. Lett. 2003, 5, 1123-1126.

7 (a) Carroll, G. L.; Little, R. D. Org. Lett. 2000, 2 (18), 2873-2876. (b) Carroll, G. L.

Investigation of the Vinylcyclopropane Trimethylenemethane Diradical and Exploration of a

Route to Phorbol Analogs. Ph.D. Thesis, UC Santa Barbara, 2000.

8 (a) Lee, G. H.; Choi, E. B.; Lee, E.; Pak, C. S. J. Org. Chem. 1994, 59, 1428-1443. (b)

Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821-2824.

9 Nelson, N. A.; Paquette, L. A. J. Org. Chem. 1962, 27, 2272-2274.

10 (a) Cros, G.; Costes, J.-P.; De Montauzon, A. Polyhedron 1984, 3 (5), 585-588. (b)

Fox, D. P.; Little, R. D.; Baizer, M. M. J. Org. Chem. 1985, 50, 2202-2204.

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Chapter 5. On the Reactivity of N-Oxyl Radicals in the Presence of

Lewis Acids: Mild and Efficient Oxidation with TEMPO and Scandium

Triflate.

5.1. Introduction

The stable TEMPO free radical (TEMPO = 2,2,6,6-tetramethylpiperidinyl-N-oxyl) is frequently employed in organic reactions, mostly for the oxidation of alcohols,1 and less frequently for oxygen transfer to sulfides2 and C,H-activation of the allylic and benzylic position.3 Furthermore, TEMPO and its derivatives can be used as trapping agents for radicals or strong electrophiles.2,4 Due to its high chemoselectivity, the use of TEMPO in the catalytic oxidation of alcohols is particularly attractive.1c,2 However, typical oxidation protocols involving TEMPO require some quantity of base and the stoichiometric use of a

5 terminal oxidant such as NaOCl or PhI(OAc)2, conditions which are not tolerated by a number of functional groups and that can lead to undesired side-reactions such as chlorination of aromatic rings and overoxidation.6

Milder and more environmentally friendly methods such as aerobic oxidation using transition metal co-catalysts (e. g. with Cu, Ru or Fe metal centers) have been developed.7 A further very promising approach is represented by the use of TEMPO as a redox mediator in electrosynthetic reactions, where the chemical co-oxidant is replaced by electric current.8

However, many of these protocols still require basic conditions in order to trap protons liberated during the oxidation process. In this context, the Hayton group recently reported an efficient method for the oxidation of alcohols using TEMPO in the presence of a Lewis

9 1 acid. A TEMPO and MCl3 (M = Al, Fe) are demonstrated to form a complex MCl3(η -

183

TEMPO) (1, Scheme 1) which can oxidize even secondary alcohols to ketones at room temperature (Scheme 2). The protocol can be considered as complementary to classic

TEMPO oxidations, since the substrates are converted in a neutral environment in absence of base and terminal oxidant.

1 Scheme 1. Synthesis of MCl3(η -TEMPO) complexes.

1 Scheme 2. Oxidation of alcohols using MCl3(η -TEMPO) complexes.

However, the poor stability of the complexes (e.g., structure 1) represents a drawback of this method compared to classical TEMPO oxidation procedures. Due to their susceptibility towards hydrolysis in the presence of small amounts of water, it is necessary to operate under rigorously anhydrous conditions. Moreover, the free Lewis acid, AlCl3, might cause undesired side reactions when acid-labile functional groups are present. In order to increase the stability of the redox-active complex and to create milder reaction conditions, we envisaged the use of scandium triflate as the Lewis acidic component. In contrast to many other Lewis acids commonly used in organic synthesis, Sc(OTf)3 is stable towards water and can be considered as a very mild reagent or catalyst.10 Herein we describe the reactivity of TEMPO in the presence of Sc(OTf)3 and present a mild and straightforward protocol for the oxidation of alcohols.

184

5.2. Oxygen and water stable Sc(OTf)3(η1-TEMPO)

A test reaction using 4-methoxybenzyl alcohol with TEMPO and Sc(OTf)3 in acetonitrile, carried out on an analytical scale in an NMR tube, showed exclusive conversion to the corresponding aldehyde in 1 h (viz., 40% conversion after 1 h). Raising the temperature to 50 °C leads to nearly complete conversion after the same length of time without any side reaction. Notably, the reaction does not require working under inert conditions in contrast to previously elaborated protocols using complex 1.9a

With these encouraging results in hand we were interested in learning more about the nature of the interaction between the oxidant and the Lewis acid. 1H NMR spectroscopy

(CD3CN) of TEMPO and Sc(OTf)3 in a molar ratio of 1:1 revealed three broad resonances at

δ = 5, 2 and −4 ppm (see experimental section Figure 2). These signals integrate for 2, 4 and

12 and can therefore be assigned to the γ-, β- and the methyl protons of the TEMPO unit.

Since these resonances do not correspond to the signals expected for uncoordinated TEMPO

(viz., δ = 14, −17 and −30 ppm in CD3CN, see experimental section Figure 1), we conclude

1 that formation of Sc(OTf)3(η -TEMPO) occurs quantitatively upon the addition of Sc(OTf)3 to the N-oxyl radical, as observed before with Lewis acids of the type MCl3 (M = Fe and Al,

Scheme 1). Additional sharp signals between 0.6 and 1.3 ppm as well as around 8.3 ppm arise in presence of Sc(OTf)3. From this information, we assume that in absence of substrate,

1 Sc(OTf)3(η -TEMPO) is prone to slow disproportionation and follow-up reactions and that the additional signals in the 1H NMR spectrum are attributable to slow decomposition following the complex formation.

185

5.3. Optimization of reaction conditions

With 4-methoxybenzyl alcohol as a substrate, we used 1H NMR at 50 °C to screen five solvents (see Table 1). The choice of solvents is somewhat limited due to the low solubility of Sc(OTf)3 and the corresponding TEMPO adduct in solvents such as CH2Cl2 and

CHCl3. Whereas rapid conversion and the exclusive formation of the aldehyde was observed in CD3CN (entry 4) and acetone-d6 (entries 1 and 5), the use of D2O afforded extremely low reaction rates (16% conversion) and the use of DMSO-d6 leads to no observable conversion

(entries 6). We assume that a lowering of the Lewis acidic character of Sc(OTf)3, either by coordination of solvent molecules to Sc or by strong solvation of DMSO and H2O, is responsible for inhibition of the oxidation. However, control experiments using CD3CN with

2% and 10% D2O (v/v) indicates that the presence of water is tolerated to a certain extent

(entries 2 and 3).

Entr Solvent Conversion (%)* y 1 CD3CN 86 2% (v/v) D O 2 2 67 in CD3CN 10% (v/v) D O 3 2 36 in CD3CN 4 D2O 16

5 Acetone-d6 75

6 DMSO-d6 0 * Determined using 1H-NMR spectroscopy, c(substrate) = 20 mM. Table 1. Effect of the solvent on the reactivity of TEMPO/Sc(OTf)3.

186

In order to further optimize the reaction conditions, we studied the influence of the ratio between TEMPO and Sc(OTf)3 (see Table 2). We found that lowering the amount of

Sc(OTf)3 below one equivalent leads to drastically decreased reaction rates. For example, decreaing the amount of Sc(OTf)3 from 1.0 equivalent to 0.8 equivalent leads to a decrease of yield from 88% to 75% (entry 4 and 8).on the other hand, increasing the amount of

TEMPO from 2.0 equivalent to 2.2 equivalents results in higher yields shows that a slight excess of TEMPO is beneficial and that over 10% excess of TEMPO is not necessary. As a tradeoff between rate and practicality, we decided to use one equivalent of Sc(OTf)3 and 2.2 equivalents of TEMPO throughout this study.

Entry equiv. equiv. Solvent Temp. (oC) Time (hour) Yield (%) Sc(OTf)3 TEMPO 1 0 2 CD3CN 50 16 0 2 2 2 CD3CN 50 18 78 3 2 2 CD3CN 50 18 88 4 1 2 CD3CN 50 16 88 5 1 2.2 CD3CN 50 18 95 6 0.4 2 CD3CN 50 18 41 7 0.8 2 CD3CN r.t. 18 75 8 0.8 2 CD3CN 50 18 78 9 0.8 2.2 CD3CN 40 1 88 10 0.8 2.2 CD3CN 40 24 100 Table 2. Optimization of reaction conditions.

5.4. Substituent studies

Next we explored the reaction of substituted benzylic alcohols under the optimized conditions described thus far. In order to qualitatively explore the influence of the substituents upon the reaction rate, we started with analytical scale experiments (as described above) and observed the course of the reactions over 30 minutes using 1H NMR.

187

As shown in Figure 1, the rate increases as the electron donating character of the substituents increase. Whereas the conversion of 4-OMe and 4-OH-substituted benzyl alcohols is essentially complete after 30 minutes, the conversion of structures with R = H, CH2Cl or F requires prolonged reaction times. Slow conversion is observed in the case of 4-CF3 and 4-

NO2-substituted substrates. In fact, full conversion does not seem to be feasible in reasonable reaction times at a temperature of 50 °C with the given concentration.

Figure 1. Qualitative influence of the substitution pattern on the reaction rate; conditions: 2.2 equiv. TEMPO, 1 equiv. Sc(OTf)3, c(substrate) = 20 mM, T = 50 °C.

For batch size processes we increased the benzaldehyde concentrations from 20 mM to 0.7 M. The reaction course was monitored by TLC. After quenching and work-up (note experimental section), the products were purified using column chromatography over silica gel. For every preparative scale run we obtained good to excellent yields of the corresponding aldehyde (Table 3). Full conversion was obtained with activated benzylic

188

alcohols (entries 1 - 4), and the corresponding products were isolated in 91 – 97% yield. In

2 1 contrast, the reaction of non-activated substrates (R = H, R = H, F and CH2Cl2) remained incomplete even after 3 – 4 h (entries 5 – 8). The isolated yields are lower in these cases (80

– 90%), though still in the good to excellent range. The trifluoromethyl- and nitro- substituted alcohols can be converted to 4-CF3C6H4CHO (3h) and NO2C6H4CHO (3i), respectively. High yields of both compounds are obtained (74% and 90%, see entries 2 8 and

9), although prolonged reaction times are necessary to reach full conversion. This result highlights the potential of the present method, since such deactivated substrates are not

11 oxidized by a number of oxidation agents, including for example DDQ or Mn(OAc)3.

time Conversion Isolated yield Entry R1, R2 (h) (%)* (%) 1 OMe, H 3 100 91 (4a) 2 OH, H 2 100 97 (4b) OMe, 3 4 100 91 (4c) OMe 4 Me, H 2 100 92 (4d) 5 H, H 4 90 90 (4e) CH Cl, 6 2 3.5 81 80 (4f) H 7 F, H 3 89 87 (4g) 8 CF3, H 8 99 91 (4h) 9 NO2, H 11.5 99 90 (4i) 10 SCH3, H 3 100 92 (4j) * Determined using 1H-NMR spectroscopy, c(substrate) = 20 mM. Table 3. Preparative scale oxidation of benzylic alcohols.

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5.5. Substrate Scope

To explore the substrate scope of the chemistry we examined the structures shown in

Table 3. Application of the optimized reaction conditions to 1-phenylethanol (5a) afforded acetophenone (6a) in a 76% isolated yield after 6 h (entry 1). Comparison of the time and conversion between entry 5 of Table 3 and entry 1 of Table 4 indicates a slight retardation, probably due to increased steric shielding of the secondary alcohol. Oxidation of cinnamyl alcohol (5c) affords an 80 % yield of cinnamaldehyde (6c) in only 2 h under the same conditions (entry 2). In contrast to these examples the aliphatic substrate, 3-phenyl-1- propanol (5d), reacts much slower in testament to the importance of either benzylic or allylic activation (entry 3).

Entry Substrate (5) Product (6) Time (h) Isolated yield (%)

1 6 76 (6a)

2 3 92 (6b)

3 2 80 (6c)

4 11.5 23 (6d)

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5 2 86 (6e)

6 1 89 (6f)

7 3 90 (6g)

Table 4. Exploration of the scope of substrates.

1 We were also interested in applying the Sc(OTf)3(η -TEMPO) system to the oxidation of a more complex structure. Therefore, we studied the oxidation of lignin model system 5e (diastereomeric mixture, erythro/threo = 3 : 1) under our optimized reaction conditions (Table 4, entry 4). Compound 5e is often used as a model for the structure of lignin, a biopolymer that is currently a subject of interest due to its potential as a renewable feedstock.12 The β-O-4 connectivity in 5e, which features a primary aliphatic alcohol and a secondary benzylic alcohol, also constitutes a major fraction of the linkages between the aromatic units of the lignin polymer.13 In recent literature it has been reported that benzylic oxidation of β-O-4 lignin models such as 3 results in facile Cα−Cβ bond cleavage, leading to high-value aromatic compounds.14 Fortunately, our protocol exhibits exclusive selectivity towards the oxidation of the benzylic position, while the primary aliphatic hydroxy group remains unaffected. Thus, after 2 h at 50 °C, compound 6e is isolated in 86% yield. Similar results were recently reported by Moody and co-workers in a photochemical reaction using a

15 catalytic system consisting of DDQ and sodium nitrite with O2 as the terminal oxidant.

Interestingly, 9,10-dihydroanthracene is rapidly converted to anthracene (entry 5), a result that suggests that electron transfer between substrate and oxidizing agent does not

191

necessarily have to proceed via initial bond formation as in the classic TEMPO oxidation.

1 Since bond formation between the hydrocarbon and a Sc(OTf)3(η -TEMPO) complex is rather unlikely, we conclude that the sequence is initiated either by single electron transfer or by proton-coupled electron transfer from substrate to oxidant. However, we cannot exclude the possibility that the alcohol oxidation follows a different mechanism that involves initial complex formation between hydroxy-O and the Lewis acid.

Scheme 1. Proposed mechanism for the oxidation of 9,10-dihydroanthracene 5f to anthracene 6f.

192

Scheme 2. Proposed mechanism for the oxidation of benyl alcohols.

5.6. Conclusion

In conclusion we have successfully tuned the stability of previously developed

1 MX3(η -TEMPO) system by replacing AlCl3 with Sc(OTf)3. The use of this modified reagent system enables the oxidation of a variety of alcohols in a highly selective manner under very mild conditions using a straightforward protocol. Due to use of the water-stable Lewis acid

Sc(OTf)3, our method provides complementary reaction conditions to the classic TEMPO- bleach reactions and related methods, where typically a high concentration of base is required. Consequently, our protocol is expected to be suitable for substrates containing

1 base-labile functional groups. Compared to the AlCl3(η -TEMPO) system, a major advantage is that no rigorous exclusion of moisture is necessary. With regard to selectivity, electronic effects play a more important role than steric factors. In particular, the reaction rates for the oxidation of alcohols are in the order 2° benzylic position > 1° benzylic position

> 1° allylic position > 1° aliphatic position. Furthermore, the successful dehydrogenation of

9,10-dihydroanthracene to anthracene suggests that the scope of substrates reaches beyond

193

the oxidation of alcohols. Further studies are needed in order to expand the scope of the chemistry and to obtain further mechanistic insights.

References

1 (a) Zhan, B.-Z.; Thompson, A. Tetrahedron 2004, 60, 2917-2935. (b) Sheldon, R. A.;

Arends, I. W. C. E.; ten Brink, G.-J.; Dijksman, A. Acc. Chem. Res. 2002, 35, 774-781. (c)

Ciriminna, R.; Pagliaro, M. Org. Process Res. Dev. 2009, 14, 245-251.

2 Vogler, T.; Studer, A. Synthesis 2008, 1979-1993.

3 (a) Breton, T.; Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46, 2487-2490. (b)

Li, C.; Zeng, C.-C.; Hu, L.-M.; Yang, F.-L.; Yoo, S. J.; Little, R. D. Electrochim. Acta 2013,

114, 560-566. (c) Richter, H.; García Mancheño, O. Eur. J. Org. Chem. 2010, 4460-4467.

4 (a) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J.

Am. Chem. Soc. 2010, 132, 10012-10014. (b) Pouliot, M.; Renaud, P.; Schenk, K.; Studer,

A.; Vogler, T. Angew. Chem. Int. Ed. 2009, 48, 6037-6040.

5 (a) Adam, W.; Saha-Möller, C. R.; Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499-

3548. (b) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559-

2562. (c) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1998, 64, 293-295.

6 (a) Boger, D. L.; Borzilleri, R. M.; Nukui, S. J. Org. Chem. 1996, 61, 3561-3565. (b)

Ibert, M.; Marsais, F.; Merbouh, N.; Brückner, C. Carbohydrate Res. 2002, 337, 1059-1063.

7 (a) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou, C. S. J. Am. Chem. Soc.

1984, 106, 3374-3376. (b) Gamez, P.; Arends, I. W. C. E.; Reedijk, J.; Sheldon, R. A. Chem.

Commun. 2003, 2414-2415. (c) Dijksman, A.; Marino-González, A.; Mairata i Payeras, A.;

Arends, I. W. C. E.; Sheldon, R. A. J. Am. Chem. Soc. 2001, 123, 6826-6833. (d) Ryland, B.

L.; Stahl, S. S. Angew. Chem. Int. Ed. 2014, 53, 8824-8838. (e) Hoover, J. M.; Ryland, B. L.;

194

Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 2357-2367. (f) Steves, J. E.; Stahl, S. S. J. Am.

Chem. Soc. 2013, 135, 15742-15745.

8 (a) Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492-2521. (b) Ogibin,

Y. N.; Elinson, M. N.; Nikishin, G. I. Russ. Chem. Rev. 2009, 78, 89-140. (c) Semmelhack,

M. F.; Chou, C. S.; Cortes, D. A. J. Am. Chem. Soc. 1983, 105, 4492-4494. (d) Nutting, J.

E.; Rafiee, M. R.; Stahl, S. S. Chem. Rev. 2018, 9, 4834-4885. (e) Hoover, J. M.; Stahl, S. S.

J. Am. Chem. Soc. 2011, 133, 16901-16910.

9 (a) Scepaniak, J. J.; Wright, A. M.; Lewis, R. A.; Wu, G.; Hayton, T. W. J. Am. Chem.

Soc. 2012, 134, 19350-19353. (b) Wright, A. M.; Page, J. S.; Scepaniak, J. J.; Wu, G.;

Hayton, T. W. Eur. J. Inorg. Chem. 2013, 2013, 3817-3820. (c) Nguyen, T.-A. D.; Wright,

A. M.; Page, J. S.; Wu, G.; Hayton, T. W. Inorg. Chem. 2014, 53, 11377-11387.

10 Kobayashi, S. Eur. J. Org. Chem. 1999, 15-27.

11 Cosner, C. C.; Cabrera, P. J.; Byrd, K. M.; Thomas, A. M. A.; Helquist, P. Org. Lett.

2011, 13, 2071-2073.

12 (a) Siedlecka, R.; Skarzewski, J. Synthesis 1994, 401. (b) Siedlecka, R.; Skarzewski, J.

Synlett 1996, 757. (c) Huang, J.-Y.; Li, S.-J.; Wang, Y.-G. Tetrahedron Lett. 2006, 47,

5637-5640. (d) Velusamy, S.; Kumar, A. V.; Saini, R.; Punniyamurthy, T. Tetrahedron Lett.

2005, 46, 3819-3822.

13 Zakzeski, J.; Bruijnincx, P. C. A.; Jongerius, A. L.; Weckhuysen, B. M. Chem. Rev.

2010, 110, 3552-3599.

14 Lapierre, C.; Pollet, B.; Rolando, C. Res. Chem. Intermed. 1995, 21, 397-412.

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15 (a) Rahimi, A.; Azarpira, A.; Kim, H.; Ralph, J.; Stahl, S. S. J. Am. Chem. Soc. 2013,

135, 6415-6418. (b) Nguyen, J. D.; Matsuura, B. S.; Stephenson, C. R. J. J. Am. Chem. Soc.

2013, 136, 1218-1221.

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On the Reactivity of N-Oxyl Radicals in the Presence of Lewis Acids: Mild and

Efficient Oxidation of Alcohols using TEMPO and Scandium Triflate

Experimental Section

Instruments and Reagents

All chemicals were of reagent grade and used as commercially supplied without further purification. 1H NMR and 13C NMR spectra were recorded on a Varian Unity Inova 500

MHz instrument or an actively shielded Varian Unity Inova 600 MHz Spectrometer. Trace amounts of CHCl3 (δ = 7.26 ppm) or CH3CN (δ = 1.94 ppm) in the respective deuterated solvent were used as internal standard. The following abbreviations were used for the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, m = multiplet, br = broad.

Oxidation of alcohol substrates on the analytical scale

The reactions were carried out in a 1 dram glass vials sealed with a screw-on cap fitted with a Teflon insert to avoid contamination. A solution of alcohol substrate (0.01 mmol), scandium triflate (0.01 mmol, 1 equiv.), and TEMPO (0.022 mmol, 2.2 equiv) in 0.5 mL

o CD3CN or another deuterated solvent was stirred at 50 C. Proton NMR analysis was carried out at room temperature without purification or quenching.

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Oxidations on the preparative scale

A mixture of benzylic alcohol substrate (1.45 mmol; note Table 3 of text), scandium triflate (1.45 mmol, 1 equiv), and TEMPO (3.19 mmol, 2.2 equiv.) in 2 mL of acetonitrile was stirred in a thick-walled glass tube equipped with a screw-on Teflon cap at 50 oC. The reactions were monitored using TLC. After the substrate was entirely consumed, 15 mL of aqueous 0.1 M HCl was added. The aqueous layer was then extracted with 15 mL of ethyl acetate. The organic layer was washed with H2O (2 x 15 mL) and brine (15 mL) and dried over magnesium sulfate. After concentration under reduced pressure, the crude product was purified using flash chromatography. The products were characterized using 1H and 13C

NMR spectroscopy, and the spectral data is reported below. Spectral data for known structures accorded with published data.

4-Methoxy benzaldehyde

The product was purified using flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 obtained as a colorless oil. H NMR (600 MHz, CDCl3): δ = 9.89 (s, 1H), 7.84 (d, 2H, J =

13 8.8 Hz), 7.00 (d, 2H, J = 8.8 Hz), 3.89 (s, 3H). C NMR (150 MHz, CDCl3): δ = 190.8,

164.6, 132.0, 130.0, 114.3, 55.6.

4-Methyl benzaldehyde

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The product was purified using flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 obtained as a colorless oil. H NMR (600 MHz, CDCl3): δ = 9.94 (s, 1H), 7.75 (d, 2H, J =

13 7.9 Hz), 7.31 (d, 2H, J = 7.8 Hz), 2.42 (s, 3H). C NMR (150 MHz, CDCl3) δ = 191.9,

145.5, 134.2, 129.8, 129.7, 21.8.

4-Hydroxy benzaldehyde

The product was purified using flash chromatography (eluent mixture: hexanes/ethyl

1 acetate = 7:3) and obtained as a colorless oil. H NMR (600 MHz, CDCl3): δ = 9.86 (s, 1H),

13 7.82 (d, 2H, J = 7.2 Hz), 6.98 (d, 2H, J = 7.2 Hz). C NMR (150 MHz, CDCl3): δ = 191.3,

161.8, 132.6, 129.7, 116.2, 105.0.

Benzaldehyde

The product was purified using flash chromatography (eluent: hexanes) and obtained as a

1 colorless oil. H NMR (600 MHz, CDCl3): δ = 10.03 (s, 1H), 7.89 (d, 2H, J = 7.9 Hz), 7.67-

13 7.60 (m, 1H), 7.54 (t, J = 7.6 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 192.3, 136.4,

134.4, 129.7, 129.0.

4-Fluoro benzaldehyde

199

The product was purified using flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 obtained as a colorless oil. H NMR (600 MHz, CDCl3): δ = 9.97 (s, 1H), 7.93 – 7.90 (m,

13 2H), 7.22 (dd, J = 8 Hz, 7.5 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 190.8, 166.7 (d, J =

255 Hz), 133.3, 132.6 (d, J = 9.9 Hz), 116.6 (d, J = 22 Hz).

4-Dichloromethyl benzaldehyde

The product was purified via flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 isolated as a colorless oil. H NMR (600 MHz, CDCl3): δ = 10.03 (s, 1H), 7.89 (d, J = 8.1

13 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 4.64 (s, 1H). C NMR (150 MHz, CDCl3): δ = 191.6,

143.8, 136.2, 130.1, 129.1, 45.3.

4-Trifluoromethyl benzaldehyde

The product was purified using flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 isolated as a colorless oil. H NMR (600 MHz, CDCl3): δ = 10.09 (s, 1H), 7.99 (d, J = 7.8

13 Hz, 2H), 7.79 (d, J = 7.9 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 191.2 (s), 138.8 (s),

135.8 (q, J = 32.7 Hz), 130.1 (s), 126.3 (q, J = 3.8 Hz), 123.6 (q, J = 273.0 Hz).

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4-Nitro benzaldehyde

The product was purified using flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 obtained as a colorless solid. H NMR (600 MHz, CDCl3): δ = 10.14 (s, 1H), 8.37 (d, J = 8.5

13 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 190.2, 140.0, 130.4,

124.3, 102.9.

3,4-Dimethoxy benzaldehyde

The product was purified via flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 isolated as a colorless solid. H NMR (500 MHz, CDCl3); δ = 9.85 (s, 1H), 7.46 (dd, 1H, J =

8.2, 1.9 Hz), 7.41 (d, 1H, J= 1.8 Hz), 6.98 (d, 1H, J = 8.2 Hz), 3.97 (s, 3H), 3.94 (s, 3H). 13C

NMR (125 MHz, CDCl3): δ = 190.9, 154.5, 149.6, 130.2, 126.9, 110.4, 109.0, 56.2, 56.0.

Acetophenone

The product was purified via flash chromatography (eluent: 100% hexane) and isolated

1 as colorless oil. H NMR (600 MHz, CDCl3): δ = 7.96 (d, J = 7.4 Hz, 2H), 7.57 (t, J = 7.4

201

13 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 2.61 (s, 3H). C NMR (150 MHz, CDCl3): δ = 198.1,

137.1, 133.1, 128.5, 128.3, 26.6.

Cinnamaldehyde

The product was purified via flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 isolated as pale yellow oil. H NMR (600 MHz, CDCl3): δ = 9.72 (d, J = 7.7 Hz, 1H), 7.58 -

7.53 (m, 2H), 7.51-7.44 (m, 4H), 6.73 (dd, J = 15.9, 7.7 Hz, 1H). 13C NMR (150 MHz,

CDCl3): δ = 193.7, 152.7, 134.0, 131.2, 129.1, 128.6, 128.5.

3-Phenyl propionaldehyde

The product was purified via flash chromatography (gradient elution with hexanes and ethyl acetate, starting with 100% hexanes and finishing with hexanes/ethyl acetate = 7:3) and

1 isolated as colorless oil. H NMR (600 MHz, CDCl3): δ = 9.83 (s, 1H), 7.31-7.29 (m, 2H),

7.22 – 7.19 (m, 3H), 2.97 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H). 13C NMR (150 MHz,

CDCl3): δ = 201.5, 140.3, 128.6, 128.2, 126.3, 45.2, 28.1.

Anthracene

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The product precipitated from the reaction mixture. After filtration it was purified by

1 recrystallization from hexane and obtained as a colorless solid. H NMR (600 MHz, CDCl3):

δ = 8.43 (s, 2H), 8.01 (dd, J = 6.3, 3.1 Hz, 4H), 7.47 (dd, J = 6.5, 2.9 Hz, 4H). 13C NMR

(150 MHz, CDCl3): δ = 131.6, 128.1, 126.2, 125.3.

1-(3,4-Dimethoxyphenyl)-3-hydroxy-2-(2-methoxyphenoxy)propan-1-one (4)

The starting material was employed as a diastereomeric mixture (erythro/threo = 3:1) and synthesized according to a literature procedure.1 The product was purified via flash chromatography (eluent mixture: hexane/ethyl acetate = 7:3) and obtained as a colorless

1 solid. H NMR (500 MHz, CDCl3): δ = 7.75 (dd, J = 8.4, 1.8 Hz, 1H), 7.61 (d, J = 1.8 Hz,

1H), 7.00 - 6.86 (m, 4H), 6.81 (t, J = 7.6 Hz, 1H), 5.42 (t, J = 5.0 Hz, 1H), 4.08 (d, J = 5.0

Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.84 (s, 3H), 3.03 (s, bs, 1H). 13C NMR (125 MHz,

CDCl3): δ = 195.0, 154.0, 150.2, 149.2, 146.9, 128.0, 123.6, 123.4, 121.2, 117.8, 112.3,

111.0, 110.2, 84.2, 63.7, 56.1, 56.0, 55.8.

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1H NMR spectrum of TEMPO and Sc(OTf)3 in a molar ratio of 1:1

1 Figure 1. H NMR spectrum of TEMPO (500 MHz, CD3CN).

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1 Figure 2: H NMR spectrum of TEMPO in presence of one equiv. Sc(OTf)3 (500 MHz,

CD3CN).

1H and 13C NMR spectra of preparative scale run products

The following spectra are the product spectra from Part 3 oxidations on the preparative scale.

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4-Methoxy benzaldehyde

206

5.2 4-Methyl benzaldehyde

207

4-Hydroxy benzaldehyde

208

Benzaldehyde

209

4-Fluoro benzaldehyde

210

5.6 4-Dichloromethyl benzaldehyde

211

4-Trifluoromethyl benzaldehyde

212

4-Nitro benzaldehyde

213

3,4-Dimethoxy benzaldehyde

214

Acetophenone

215

Cinnamaldehyde

216

3-Phenyl propionaldehyde

217

Anthracene

218

1-(3,4-dimethoxyphenyl)-3-hydroxy-2-(2-methoxyphenoxy)propan-1-one (4)

219

1 Buendia, J.; Mottweiler, J.; Bolm, C. Chem. Eur. J. 2011, 17, 13877-13882.

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Chapter 6. Selective electrochemical C-O bond cleavage of -O-4 lignin model compounds mediated by iodide ion.

Much of this chapter is reproduced with permission from Gao, W.-J.; Lam, C. M.; Sun,

B.-G.; Little, R. D. Tetrahedron. 2017, 78, 2447-2454. Copyright [2017] Elsevier.

6.1. Introduction

Lignin, the second most abundant natural polymer, consists of an oxygenated phenylpropane subunit connected via C-O and C-C bonds. The -O-4 ether bond is the most common linkage and comprising approximately 50% of all subunit bonds of this type.1 Due to its abundance in nature and potential of providing high-valued aromatics with low molecular weight, selective decomposition of lignin is considered as a longstanding aim in sustainable development and green chemistry.2 In principal, the decomposition and fragmentation of lignin can be achieved via cracking, hydrolysis, catalytic reduction and catalytic oxidation.1 Among them, catalytic oxidation has attracted most of the attention since oxidation reactions tend to form more structurally complex platform of aromatic subunits, and possess functionality that could be used to convert lignin directly to fine

3 chemicals. In the context, metal oxides, nitrobenzenes and CoCrO4 have been used for catalytic oxidative cleavage of lignin.4 Recently, new catalytic methods have also been developed, including biocatalysis,5 organometallic catalysis, biomimetic catalysis,6 photocatalysis,7 the use of mesoporous materials8 and vanadium-based catalysis.9

Electrochemistry provides an alternative approach for the decomposition of lignin and lignin model compounds by proposing direct electron transfer between the lignin component and the working electrode, or an indirect process using a redox catalyst. For

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example, Kraft lignin was degraded electrochemically using a Ti/TiO2NT/PhO2 electrode, leading to a 13% reduction in the C-O-C group content and a 44% increase in C=O groups.10

Hempelmann and coworkers studied electro-catalytic oxidative cleavage of lignin in protic ionic liquid (triethylammonium methanesulfonate) by using a working electrode coated with ruthenium-vanadium titanium alloy oxide. The authors observed that the applied potential powerfully influenced the product distribution; higher potentials resulted the formation of molecules with lower molecular weights.11 Recently, Chen and Wan et al. carried out electrochemical depolymerization of lignin in an undivided cell using a RuO2-IrO2/Ti mesh anode and an alkaline electrolyte. The linkage among C9 units (such as p-hydroxybenzene, guaiacyl, and syringyl phenylpropane units) in lignin was found being cleaved; more than 20 kinds of low-molecular weight aromatics were produced and identified by GC-MS and ESI-

MS/MS measurements.12

Figure 1. Representation of the structure of lignin and lignin model compounds, highlighting the -O-4 linkage.

Because of the complexity of lignin, especially its low solubility in most of the common solvents, most of studies of the electrochemical oxidative cleavage of lignin have been performed based on the use of model compounds. Utley and coworkers investigated the

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direct electrooxidative cleavage of non-phenolic lignin model dimers I bearing a secondary benzylic hydroxyl unit (see structure I of Figure 1) and dimers II (a carbonyl unit conjugated with one of the aromatic rings – see structure II) in an alkaline electrolyte using a nickel anode (Figure 1). It was observed that polymerization was the predominant pathway, although aldehydes were formed together with larger amounts of the corresponding carboxylic acids.13 When the preparative scale anodic oxidation of dimer I was performed in methanol containing 0.2 M NaClO4, 3,4-dimethoxybenzaldehyde was the major product, it corresponding to cleavage of C-C bonds. In contrast, model II analogues were not cleaved under the identical conditions.14

Electrochemical cleavages of lignin model compounds in the presence of redox catalysts have also investigated. Employing a triarylamine as an electron carrier, the anodic oxidation of model I compounds in acetonitrile afforded aldehydes (vanillin or syringaldehyde derivatives) as the major products.12 In addition, Takano et al. carried out systematic studies of electro-oxidative reactions of non-phenolic lignin model compounds in the presence of laccase mediators (such as N-hydroxyphthalimide (NHPI), 1- hydroxybenzotriazole (HBT), violuric acid (VLA), 2,2,6,6-tetramethylpiperidine-N-oxyl

(TEMPO) and 2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS)). The authors found that the oxidation of dimers I with NHPI, HBT, VLA, and TEMPO as mediators gave exclusively dimers II, the corresponding C=O products, in high yield, whereas ABTS resulted in C-C cleavage.15 It has been reported that the -O-4 linkage (see the subunit in the frame in Figure 1) is significantly weakened upon oxidation of either the secondary benzylic or the primary hydroxyl unit to a carbonyl group.16 In addition, the dehydrogenative

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cross coupling of propiophenone derivatives and secondary amines could be achieved chemically and electrochemically (Scheme 1).17

Based on these observations, we envisioned that the electrochemical oxidation of model II type structures (e.g., 2-phenoxy-1-arylethanone, III), mediated by halide in the presence of an amine, might produce an N,O-ketal such as IV whose hydrolysis ought to lead to cleavage of the C-O bond. The resulting fragments, e.g., 2-oxo-2-arylacetaldehyde and phenols, may avoid of being overoxidized electrochemically and therefore lead to a higher yield of 2-oxo-2-arylacetaldehyde and phenols (Scheme 1). Herein, we describe our findings in electro-oxidative cleavage of lignin model compounds III in the presence of an iodide mediator.

Scheme 1. Working hypothesis.

6.2. Results and discussion

To demonstrate the feasibility of our idea, we initially carried out constant current electrolysis (CCE) of o-methoxyphenoxy phenylethanone, 1d, in the presence of a secondary

224

amine with a graphite plate as the working electrode. Despite much effort screening amines

(Et2NH, morpholine), redox catalysts (n-Bu4NI, Et4NBr, NaBr) and solvents (CH3CN and

NMP), we invariably obtained complex reaction mixtures from which it proved difficult to isolate and identify the products. In order to clarify the nature of possible products, the aforementioned reaction mixture was analyzed by GC-MS. The presence of acetophenone,

4c, and o-methoxyphenol was confirmed. This result indicates that C-O bond cleavage of

1d did occur (Table 1, entry 1). The C-O bond cleavage of 1d was further confirmed by electrochemical oxidation of 1d in the presence of morpholine. Thus, after 7 F/mol of charge was consumed, 1d was completely consumed and 4c was isolated in 10% yield, along with unidentified product mixtures after column chromatography (Scheme 2 and entry 2 of Table

1).

a Conditions: starting 1d or 1a (0.5 mmol), redox catalyst (0.6 mmol) in 12 mL solvent, graphite anode, iron plate cathode, undivided cell, 6 mA/cm2. b Isolated yield from column chromatography. c The presence of acetophenone 4c, and o-methoxyphenol were confirmed by GC-MS. d Yield determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard.

Table 1. Screening of base, redox catalysts and solvent for the selective cleavage of C-O bond of lignin model 1d and 1aa.

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Scheme 2. Electrochemical cleavage of 1d in the presence of morpholine.

In an effort to identify other product structures and obtain mechanistic insight, we choose 1a as the model substrate. It was observed that the results of the electrochemical oxidation of 1a were influenced by the choice of 1) base, and 2) redox mediators. For example, when 1a was subjected to electrolysis at a constant current of 6 mA/cm2 in methanol in the presence of morpholine (1.2 equiv) with KI as mediator, 4- methoxyacetophenone, 4a, and methyl 2-(4-methoxyphenyl)-2- oxoacetate, 7a, were isolated in 35% and 18% yields, respectively, along with other unidentified mixture (Scheme 3 and entry 3 of Table 1).

Scheme 3. Electrochemical cleavage of 1a in the presence of morpholine.

These results suggest that morpholine functioned only as a base rather than undergoing dehydrogenative cross coupling with the lignin model as portrayed in Scheme 1.

In addition, the use of morpholine leads to low yield of cleavage product and complex mixtures. In order to avoid side reactions, secondary amines should not be used.

226

Next, the electrochemical oxidation of 1a using inorganic bases was performed; once again, product mixtures were obtained. For example, in the presence of NaOH (0.4 equiv), the electrochemical oxidation of 1a in MeOH using NaI (0.6 equiv) as redox mediator

afforded compounds 5a, 6a and 7a with isolated yields of 34%, 13% and 13%, respectively (Scheme 4 and entry 4 of Table 1).

Scheme 4. Electrochemical cleavage of 1a in the presence of NaOH.

When the reaction mixture was treated with acetic acid, products 5a and 6a underwent the expected hydrolysis and the yield of 7a increased to 31%. In addition, when

NaHCO3 was employed as a base, a different product distribution was observed, with the amount of 2a, 3a and 4a being determined as 28%, 9% and 5% (1H NMR yield using 1,3,5- trimethoxybenzne as an internal standard; Scheme 5 and entry 5 of Table 1). Notably, we found that 2a and 3a were produced in 46% and 27% 1H NMR yield, respectively, with a combined 73% yield after 4 F/mol of charge was consumed when the reaction was performed in MeOH without any base (Scheme 6 and entry 6 of Table 1). Therefore, the presence of base is dispensable for the electro-oxidative cleavage of model -O-4 lignin compounds.

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Scheme 5. Electrochemical cleavage of 1a in the presence of NaHCO3.

Scheme 6. Electrochemical cleavage of 1a in neutral MeOH.

The nature of the redox catalyst also influenced the cleavage product distribution. For example, replacing NaI by NaBr, the anodic oxidation of 1a in the presence of NaOH gave a

40% yield of 4a and a 16% yield of 7a (entry 7 of Table 2). When n-Bu4NI was used as a redox catalyst, complex mixtures were observed based on TLC monitoring (entry 8 of Table

2). Based on the results described above, we concluded that the efficient anodic cleavage of model compound 1a calls for using NaI as the mediator and neutral methanol as the solvent.

228

a Conditions: substrate 1a (0.5 mmol) in MeOH (10 mL) containing NaI (0.6 equiv.), 6 mA/cm2 b 1H NMR yield. c 0.3 equiv. of NaI was used. d 0.9 equiv. of NaI was used. e LiClO4 (0.1 M)/CH3OH as supporting electrolyte.

Table 2. Further optimization of reaction conditions.a

With these results in hand, we sought to further optimize the reaction conditions. By using NaI as the redox catalyst and MeOH as solvent, the charge consumption was first screened at 0 oC. When 6 F/mol of charge passed, an 84% yield was observed, the products consisting of 66% of 2a, and 18% of 3a. After passing 8 F/mol and 10 F/mol of charge, 3a was not detected in either case, and 2a was isolated with a lower yield of 46% and 37%, respectively (Table 2, entry 1-4). In addition, monitoring the reaction mixture using HPLC-

MS showed that o-methoxyphenol appeared after passing 2 F/mol of charge. Its HPLC integration area reached a maximum at 6 F/mol, and dropped to 0 after 10 F/mol of charge

229

was passed. A similar tendency was observed for product 2a. The results indicate that the use of excess charge is not compatible with the generation of 2a.

Temperature also influenced the reaction selectivity. For example, when the electrolysis of 1a was performed at room temperature (~25 oC), a total yield of 78% resulted, but with lower reaction selectivity (Table 2, entry 5). Thus, two additional compounds, 5a and 6a, were detected and identified in 11% and 14% yields, respectively, along with the formation of 2a (29%) and 3a (24%). A further increase of the reaction temperature to 40 oC decreased the yield of 2a to 15%, whereas 5a and 6a were isolated in 12% and 23% yield, respectively, in addition to 23% of 3a (Table 1, entry 6). Therefore, we concluded that the use of a lower temperature proves beneficial and leads to improved product selectivity.

The product distribution was also affected by the amount of redox catalyst. As shown in Table 2, when the amount of NaI decreased to 0.3 equiv, from the initial value of 0.6 equiv, a different product distribution was observed, and products 2a and 4a were identified and isolated in 18% and 11% yields respectively (Table 2, entry 7). In contrast, 2a (45%) and

3a (22%) were obtained in a total yield of 67% when the loading of NaI increased to 0.9 equiv. (Table 2, entry 8). We conclude that 0.6 equiv. of NaI constitutes the best loading.

Notably, when the reaction was repeated in the presence of LiClO4 (0.1 M) as conducting salt, 2a was generated exclusively, while the yield was not improved (Table 2, entry 9).

Since the nature of the electrode can play an important role in an electrolysis, electrode material screening was also carried out. It was observed that both the anode and the cathode affect the reaction. For example, when the graphite working electrode was replaced by a glassy carbon electrode, reaction selectivity decreased and three products (2a,

3a and 4a) with a total yield of 45% were isolated (Table 2, entry 10). In the cases of dimension stable anode (DSA) and Pt, the total yield increased to 73% and 81%,

230

respectively, with 2a and 3a being predominate products (Table 2, entries 11 and 12). On the other hand, when Sn, Al, Ni and graphite were used as the cathode, 2a, 3a and 4a were identified, while their yields were dependent upon the cathode (Table 2, entries 13-15).

Based on the results described above, we conclude that the optimal reaction conditions call for using NaI as the redox catalyst and also as the supporting electrolyte (60 mol %), a graphite plate as the working electrode and an Fe plate as the cathode. The reaction is best performed at 0 oC in an undivided cell using methanol as the solvent without additional conducting salt or added base, and with 6 F/mol of charge.

6.3. Scope.

With the optimal conditions in hand, we then studied the scope and the generality of the protocol by examining other -O-4 lignin model compounds illustrated in Scheme 6. As shown in Table 3, when phenol ether 1b was subjected to electrolysis under the standard conditions, only 2a was obtained albeit in a 36% yield (entry 2). Comparison of this outcome with that obtained using the o-methoxy substituted substrate 1a, reveals that the presence of electron-donating substituents on the phenol ether subunit may benefit the C-O cleavage.

This assumption is further verified when one compares the results of 1c with 1d, in which higher yield was obtained from 1d, the methoxy substituted analog of 1c. Appending two electron donating groups proved either beneficial or deleterious, depending upon their location. For instance, 3,4-dimethoxy phenol ether 1f provided a 68% yield of 2a, along with

9a in 9% yield. In contrast, 2,5-dimethoxy phenol ether 1e, led to only a 14% yield of 2a.

The results imply that the nature of the substituent, as well as its position influences the efficiency and selectivity of C-O bond cleavage.

231

Reaction conditions: substrate (0.25 mmol), 0 oC, charge (Q) = 6 F/mol, NaI (60 mol%), 10 2 mL of CH3OH, 6 mA/cm , graphite anode and Fe plate cathode. Yield were determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard.

Table 3. Electrochemical C-O cleavage of -O-4 lignin model compounds.

232

For alkyl-substituted phenol ethers 1g and 1h, several yields of cleavage product 2a were obtained. However, when 1i was subjected to anodic oxidation under standard conditions, a precipitate formed at the anodic surface and only 9% yield of 4b was detected from the reaction mixture. Eventually, when 1j was used as the substrate, only a trace amount of 2b was found.

On the basis of the results described above, and the well-known electrochemical - hydroxylation of ketones,18 a possible mechanism for the formation of the various cleavage products is proposed and illustrated in Schemes 7 and 8. The chemistry starts with the anodic oxidation of iodide ion to form its oxidation state, I+; meanwhile, the solvent methanol is reduced at the cathode to generate methoxide anion, MeO-. The electrochemically generated methoxide serves as a base to deprotonate the starting 2- aryloxyarylethanone 1 followed by the subsequent reaction with electrochemically in situ generated I+ to generate -iodoketone 8. Addition of the methoxide anion to the carbonyl group of intermediate 8, followed by an intramolecular cyclization leads to intermediate epoxide 9. Subsequent ring-opening of 9 induced by the second equivalent of methoxide anion results in the formation of -hydroxy ketals 10. Once the key intermediate 10 is generated, it undergoes hydrolysis, removing the Ar2OH unit to form ,-dimethoxy aryl acetoaldehyde 2.

233

Scheme 7. Proposed mechanism for the electrochemical formation of 2, 5, 6 and 7.

On the other hand, oxidation of intermediate 10 to corresponding ester 5, followed by trans-esterification and hydrolysis affords product 7; alternatively, ester 5 first undergoes hydrolysis to give intermediate 11, followed by a trans-esterification to generate methyl - oxo arylacetate 7 (see Scheme 7). To account for the formation of compound 3a, we propose that the epoxide 9a initially undergoes a ring-opening process in the presence of methanol to form intermediate 12a, which then loses methanol and undergoes a 1,2-H~ and aryl transfer to form intermediate 15a and finally generate 3a (see Scheme 8).

Scheme 8. Proposed mechanism for the electrochemical formation of 3a from 9a.

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6.4. Conclusions

In summary, a study of electrochemical oxidative cleavage of lignin -O-4 model compounds was conducted. Various electrolytic parameters, including solvent, additive, mediator, charge, temperature and electrode material, were investigated to optimize the reaction conditions. Constant current electrolysis of a series of lignin -O-4 model compounds was achieved in a simple undivided cell, employing catalytic amount of NaI as the redox mediator and supporting electrolyte in methanol. It was found that addition of an amine or an inorganic base as additives was not necessary for this electro-oxidative cleavage.

In addition, complicated reaction mixtures of cleavage products were invariably obtained, the distribution being dependent upon electrolytic parameters while 2,2-dimethoxy-2- arylacetaldehyde was concluded as the main product. Finally, a plausible reaction mechanism was proposed.

References

1 (a) Chatel, G.; Rogers, R. D. ACS Sustain Chem. Eng. 2014, 2, 322-339. (b)Lange, H.;

Decina, S.; Crestini, C. Eur Polym J. 2013, 49, 1151-1173.

2 (a) Zakzeski, J.; Bruijnincx, P. C. A.; Jongerius, A. L.; Weckhuysen, B. M. Chem. Rev.

2010, 110, 3552-3599. (b) Rahimi, A.; Azarpira, A.; Kim, H.; Ralph, J.; Stahl, S. S. J. Am.

Chem. Soc. 2013, 135, 6415-6418. (c) Wong, D. W. S. Appl. Biochem. Biotechnol. 2009,

157, 174-209. (d) Hammel, K. E. Environ. Health Perspectives 1995, 103, 41-43.

3 (a) Forrester, I. T.; Grabski, A. C.; Burgess, R. R.; Leatham, G. F. Biochem Biophys

Res Commun. 1988, 157, 992-999. (b) Bonnarme, P. Jeffries, T. W. Appl Environ Microbiol.

1990, 56, 210-217.

235

4 (a) Leopold, B. Sven Kem Tidskr. 1952, 64, 18-26. (b) Smith, C. Utley, J. H. P.;

Petrescu, M.; Viertler, H. J Appl Electrochem. 1989, 19, 535-539.

5 Springer, S. D.; He, J.; Chui, M.; Little, R.D.; Foston, M.; Butler, A. ACS Sustainable

Chem. Eng. 2016, 4, 3212–3219.

6 Crestini, C.; Crucinelli, M.; Orlandi, M. Saladino, R. Catal Today. 2010, 156, 8-22.

7 Tonucci, L.; Coccia, F.; Bressan, M.; Alessandro, N. Waste Biomass valor. 2012, 3,

165-174.

8 Badamali, S. L.; Luque, R.; Clark, J. H.; Breeden, S. W. Catal Commun. 2013, 31, 1-4.

9 (a) Hanson, S. K.; Wu, R.; Silks, L. A. P. Angew Chem, Int Ed. 2012, 51, 3410-3414.

(b) Sedai, B.; Diaz-Urrutia, C.; Baker, R. T.; Wu, R.; Silks, L. A. P.; Hanson, S. ACS Catal.

2013, 3, 3111-3122.

10 Pan, K.; Tian, M.; Jiang, Z. H.; Kiartanson, B.; Chen, A. Electrochim Acta. 2012, 60,

147-153.

11 Reichert, E.; Wintringer, R.; Volmer, D. A.; Hempelmann, R. phys Chem Chem Phys.

2012, 14, 5214-5221.

12 Zhu, H.; Wang, L.; Chen, Y.; Li, G.; Li, H.; Tang, Y.; Wan, P. RSC Adv. 2014, 4,

29917-29924.

13 Pardini, V. L.; Smith, C. Z.; Utley, J. H.; Vargas, R. R.; Viertler, H. J. Org. Chem.

1991, 56, 7305-7313.

14 Pardini, V. L.; Vargas, R. R.’ Viertler, H.; Utley, J. H. P. Tetrahedron, 1992, 48, 7221-

7228.

236

15 (a) Shiraishi, T.; Sannami, Y.; Kamitakahara, H.; Takano, Y. Electrochim Acta. 2013,

106, 440-446. (b) Shiraishi, T.; Takano, T.; Kamitakahara, H.; Nakatsubo, F. Holzforschung.

2012, 66, 311-315.

16 (a) Cho, D. W.; Parthasarathi, R.; Pimentel, A. S.;Maestas, G. D.; Park, H. J.; Yoon,

U. C.; Dunaway-Mariano, D.; Gnanakaran, S.; Langan, P.; Mariano, P. S. J. Org. Chem.

2010, 75, 6539-6562. (b) Lim, S. H.; Nahm, K.; Ra, C. S.; Cho, D. W.; Yoon, U. C.;

Latham, J. A.; Dunaway-Mariano, D.; Mariano, P. S. J. Org. Chem. 2013, 78,9431-9443.

17 (a) Jiang, Q.; Xu, B.; Zhao, A.; Jia, J.; Liu, T.; Guo, C. C. J. Org. Chem. 2014, 79,

8750-8756. (b) Liang, S.; Zeng, C.-C.; Tian, H. Y.; Sun, B. G.; Luo, X. G.; Ren, F. Z. J.

Org. Chem. 2016, 81, 11565-11573.

18 (a) Elison, M. N.; Feducovich, S. K.; Dorofeev, A. S.; Vereschagin, A. N.; Nikishin,

G. I. Tetrahedron. 2000, 56, 9999-10003. (b) Nikishin, G. I.; Elison, M. N.; Makhova, I. V.

Tetrahedron. 1991, 41, 895-905.

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Selective electrochemical C-O bond cleavage of -O-4 lignin model compounds mediated by iodide ion.

Much of this chapter is reproduced with permission from Gao, W.-J.; Lam, C. M.; Sun,

B.-G.; Little, R. D. Tetrahedron. 2017, 78, 2447-2454. Copyright [2017] Elsevier.

Experimental Section

Instruments and reagents

Analytical thin-layer chromatography was carried out using silica gel 60 F254 precoated plates. Silica gel (600 mesh) was used for flash column chromatography using the combination of ethyl acetate and petroleum ether as eluent. All commercial reagents were used as received. All melting points were measured by an electrothermal melting point apparatus, and are uncorrected. IR spectra were recorded as neat samples for liquid and in

KBr for solids. 1H NMR spectra were recorded with a 400 M spectrometer (400 MHz 1H frequency and 100 MHz 13C frequency). Chemical shifts are given in ppm, and coupling constants are in Hertz. All starting materials were synthesized according to known procedures.1

Typical procedure for the electrochemical cleavage of lignin model compounds

A 50mL beaker-type undivided cell was equipped with a carbon anode and a Fe plate cathode and connected to a DC regulated power supply. Lignin model substrates (0.25 mmol), NaI (0.15 mmol) and 15 mL of CH3OH were added to the cell. The mixture was electrolyzed using constant current conditions (~6 mA/cm2) at 0 oC while stirring. The electrolysis was terminated when 6 F mol-1of charge had been consumed. After the electrolysis, the solvent was removed under reduced pressure. Then the residue was

238

extracted using CH2Cl2 (20 mL x 3). The combined organic phase was washed with water

(15 mL x 3) and dried with Na2SO4. After filtration to remove Na2SO4 and evaporation to remove solvent, the residue was subjected to column chromatography to give the desired products. Alternatively, to the residue was added 1,3,5-trimethoxybenzene as well as 15 mL of CH2Cl2. When CH2Cl2 was removed under reduced pressure, the residue was placed into a vacuum drying oven at 30 oC for over 10 h. The yields of products were calculated by 1H

NMR measurement.

2,2-Dimethoxy-2-(4-methoxyphenyl)acetaldehyde (2a).

1 Isolated as a colorless oil. H NMR (400 MHz, CDCl3):  3.33 (s, 6H), 3.83 (s, 3H), 6.95

13 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 9.32(s, 1H); C NMR (400 MHz, CDCl3): 

50.3, 55.3, 103.0, 113.6, 125.5, 129.0, 160.5, 195.3; IR (KBr) (cm-1): 2954, 2360, 1716,

1607, 1512, 1435, 1257, 1170, 1031, 848, 771; HRMS (ESI) m/z calcd for C11H14O4Na (M

+ Na)+ 233.0784, found 233.0780.

2,2-Dimethoxy-2-phenylacetaldehyde (2b). 1

Isolated as an oil. 1H NMR (400 MHz, CDCl3):  3.35 (s, 6H), 7.40-7.46 (m, 3H), 7.55

(d, J = 7.2 Hz, 2H), 9.37 (s, 1H).

239

2-Methoxy-2-(2-methoxyphenoxy)-2-(4-methoxyphenyl) acetaldehyde (3a).

1 Isolated as a colorless oil. H NMR (400 MHz, CDCl3):  3.45 (s, 3H), 3.83 (s, 3H), 3.94

(s, 3H), 6.79-6.83 (m, 1H), 6.93-7.04 (m, 4H), 7.24-7.27 (m, 1H), 7.64 (d, J = 8.8 Hz, 2H),

13 9.34 (s, 1H); C NMR (400 MHz, CDCl3):  50.9, 55.3, 55.9, 104.8, 112.2, 114.4, 119.5,

120.8, 123.6, 125.5, 129.3, 143.6, 150.7, 160.7, 193.3; IR (KBr) (cm-1): 3445, 2960, 1726,

+ 1681, 1600, 1503, 1261, 1174, 835, 746; HRMS (ESI) m/z calcd for C17H17O5 (M - H)

301.1076, found 301.1080.

1-(4-Methoxyphenyl)ethanone (4a).2

o 1 Isolated as a colorless solid, m.p.: 37-39 C. H NMR (400 MHz, CDCl3):  2.58 (s, 3H),

3.89 (s, 3H), 6.95 (d, J = 9.2 Hz, 2H), 7.96 (d, J = 9.2 Hz, 2H).

1-(2-Methoxyphenyl)ethanone (4b).3

1 Isolated as a colorless oil, H NMR (400 MHz, CDCl3):  2.63 (s, 3H), 3.91 (s, 3H),

6.97-7.03 (m, 2H), 7.46-7.50 (m, 1H), 7.74-7.76 (m, 1H).

240

2-Methoxyphenyl 2,2-dimethoxy-2-(4-methoxyphenyl) acetate (5a).

1 Isolated as a colorless oil. H NMR (400 MHz, CDCl3):  3.37 (s, 3H), 3.63 (s, 3H), 3.83

(s, 3H), 3.95 (s, 3H), 6.77-6.81 (m, 1H), 6.91-7.00 (m, 4H), 7.23-7.27 (m, 1H), 7.71 (d, J =

13 8.8 Hz, 2H); C NMR (400 MHz, CDCl3):  50.7, 53.0, 55.2, 56.1, 102.3, 112.1, 113.8,

117.4, 120.7, 122.7, 128.2, 128.6, 144.1, 150.2, 160.2, 168.9; IR (KBr) (cm-1): 3002, 2952,

2838, 2603, 1753, 1610, 1504, 1457, 1253, 1173, 1106, 749; HRMS (ESI) m/z calcd for

+ C18H19O6 (M - H) 331.1182, found 331.1183.

Methyl 2,2-dimethoxy-2-(4-methoxyphenyl)acetate (6a).4

Isolated as a white oil. 1H NMR (400 MHz, CDCl3):  3.27 (s, 6H), 3.74 (s, 3H), 3.83 (s,

13 3H), 6.91 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H); C NMR (400 MHz, CDCl3): 

50.3, 52.9, 55.2, 101.5, 114.3, 128.1, 128.6, 160.1, 169.6.

Methyl 2-(4-methoxyphenyl)-2-oxoacetate (7a).5

o 1 Isolated as a colorless solid, m.p.: 54 C. H NMR (400 MHz, CDCl3):  3.88 (s, 3H),

3.91 (s, 3H), 6.93 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H); 13C NMR (400 MHz,

CDCl3):  51.9, 55.4, 113.6, 122.6, 131.6, 163.3, 166.9.

241

NMR, IR and HRMS spectra of the isolated fragment structures

1H NMR of 2,2-Dimethoxy-2-(4-methoxyphenyl)acetaldehyde (2a)

13C NMR of 2,2-Dimethoxy-2-(4-methoxyphenyl)acetaldehyde (2a)

242

IR of 2,2-Dimethoxy-2-(4-methoxyphenyl)acetaldehyde

(2a)

HRMS of 2,2-Dimethoxy-2-(4-methoxyphenyl)acetaldehyde (2a)

243

1H NMR of 2,2-Dimethoxy-2-phenylacetaldehyde (2b)1

1H NMR of 2-Methoxy-2-(2-methoxyphenoxy)-2-(4-methoxyphenyl)acetaldehyde

(3a)

244

13C NMR of 2-Methoxy-2-(2-methoxyphenoxy)-2-(4-methoxyphenyl)acetaldehyde (3a)

IR of 2-Methoxy-2-(2-methoxyphenoxy)-2-(4-methoxyphenyl)acetaldehyde (3a)

245

HRMS of 2-Methoxy-2-(2-methoxyphenoxy)-2-(4-methoxyphenyl)acetaldehyde (3a)

1H NMR of 1-(4-Methoxyphenyl)ethanone (4a)2

246

1H NMR of 1-(2-Methoxyphenyl)ethanone (4b)3

1H NMR of 2-Methoxyphenyl 2,2-dimethoxy-2-(4-methoxyphenyl)acetate (5a)

247

13C NMR of 2-Methoxyphenyl 2,2-dimethoxy-2-(4-methoxyphenyl)acetate (5a)

IR of 2-Methoxyphenyl 2,2-dimethoxy-2-(4-methoxyphenyl)acetate (5a)

248

HRMS of 2-Methoxyphenyl 2,2-dimethoxy-2-(4-methoxyphenyl)acetate (5a)

1H NMR of Methyl 2,2-dimethoxy-2-(4-methoxyphenyl)acetate (6a)4

249

13C NMR of Methyl 2,2-dimethoxy-2-(4-methoxyphenyl)acetate

(6a)4

250

1H NMR of Methyl 2-(4-methoxyphenyl)-2-oxoacetate (7a)5

251

13C NMR of Methyl 2-(4-methoxyphenyl)-2-oxoacetate

(7a)5

1 Laskar, D.D.; Prajapati, D.; Sandhu, J.S. Chem. Lett. 1999, 12, 1283-1284.

2 Cunningham, A.; Mokal-Parekh, V.; Wilson, C.; Woodward, S. Org. Biomol. Chem.

2004; 2, 741-748.

3 Liu, S.F.; Berry, N.; Thomson, N.; Pettman, A.; Hyder, Z.; Mo, J. Xiao, J. J. Org.

Chem. 2006, 71, 7467-7470.

4 Antus, S.; Baitz-Gács, E.; Boross, F.; Nógrádi, M.; Sólyom, A. Liebigs Ann Chem.

1980, 8, 1271-1282.

5 Mallinger, A.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 2009, 74, 1124-1129.

252

1 Laskar, D.D.; Prajapati, D.; Sandhu, J.S. Chem. Lett. 1999, 12, 1283-1284.

1 Cunningham, A.; Mokal-Parekh, V.; Wilson, C.; Woodward, S. Org. Biomol. Chem.

2004; 2, 741-748.

1 Liu, S.F.; Berry, N.; Thomson, N.; Pettman, A.; Hyder, Z.; Mo, J. Xiao, J. J. Org.

Chem. 2006, 71, 7467-7470.

1 Antus, S.; Baitz-Gács, E.; Boross, F.; Nógrádi, M.; Sólyom, A. Liebigs Ann Chem.

1980, 8, 1271-1282.

1 Mallinger, A.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 2009, 74, 1124-1129.

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254

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256