Progress Towards the Synthesis of Novel Graphite Derivatives from a Solution Processable Poly-Cyano Precursor Polymer

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Abstract

BEHOF, WILLIAM JAMES. Progress Towards the Synthesis of Novel Graphite Derivatives from a Solution Processable Poly-Cyano Precursor Polymer. (Under the direction of Dr. Christopher B. Gorman.)

In this thesis, the synthetic progress towards the development of a novel potentially conducting ladder polymer, through the direct writing of a soluble precursor polymer, is presented. The proposed ladder polymer was synthesized through three steps; the synthesis of a poly-cyano monomer for polymerization, the synthesis of a poly-cyano precursor polymer, and a one step cascading cyclization of a poly-cyano polymer.

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Progress Towards the Synthesis of Novel Graphite Derivatives from a Solution Processable Poly-Cyano Precursor Polymer

by

William James Behof

A dissertation submitted to the Graduate Faculty of North Carolina State University

in partial fulfillment of the requirements for the Degree of

Doctor of Philosophy

Chemistry

Raleigh, North Carolina 2010

APPROVED BY:

_________________________________ Dr. David A. Schultz

_________________________________ Dr. Lin He

_________________________________ Dr. Alexander Deiters

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Biography

The author was born in the city of Park Ridge, Illinois to James and Judy Behof on March 19, 1982. After graduating from the public primary schools, William attended Grayslake

Community College; he then transferred to the University of Illinois at Chicago (UIC) and graduated with a bachelors of science degree in biochemistry. While attending UIC he

participated in undergraduate research with the advisement of Dr. Duncan Wardrop. In the spring of 2005 he was accepted into the department of chemistry graduate program at North Carolina State University. Before leaving for North Carolina, William married his wife Judy

on July 30th 2005. At NC State he pursued his Doctor of Philosophy degree under the advisement of Dr. Christopher B. Gorman. In his time at NC State William and Judy

welcomed the birth of their first son, Dakota James, on June 07, 2006 and the adoption of their second son, Talon Jackson. At the time of graduation they were expecting the birth of their third son, Austin Reese. William received his Doctor of Philosophy degree in

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Acknowledgements

I must first acknowledge God, without him I would not be here and none of this would be possible.

I would like to think that I could come up with the right words to thank my wife, parents and family, but I cannot find words strong enough to show my love, gratitude and thanks to

them. I could not have done this without my family as they had my back and supported me in whatever I had to do. I have a great gratitude towards my parents for raising me the way they did. Thank you dad for surviving the fall, I couldn’t of have gone through grad school

without you. Judy, I want to thank you for dealing with me on the other end and for helping me survive. A special thanks to my Uncle Bill for giving me my work ethic, teaching me to

measure twice, cut once and to watch out for the brake cleaner. To my Aunt Mary Ellen and Uncle Bill Wade, thank you for encouraging me to go as far as I can go.

I would like to acknowledge Dr. Christopher B. Gorman, who took me into, and supported

me for the past three years on a research assistant grant. You have taught me how to write and overcome my lack of experience in the field of synthetic chemistry. A special thanks to

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A great thanks goes out to my friends and group members at NC State. I greatly appreciate the great deal of time Dr. Kusum Chandra spent tutoring me. This help was invaluable and I would not be the chemist I am today without it. A special thanks to Dr.

Jennifer Ayres for putting up with me in lab. Dr. Joseph Fritz, Dr. Ned Bowen and Dr. David Dickson, from the University of Illinois at Chicago, helped me decide to go to

graduate school. My friends and alliances at NC State, Wesleigh Edwards, Justin Kennemur, Joe DeSousa, Rachel Kudgus, Matt Thompson, Rob Schmidt, Deborah Bromfield, Michelle Clark and Alan Harvell, who all made my time a little bit easier. I would also like to

acknowledge Gorman group members; Dr. Anil Sharma, Eric Tucker, Lebo Xu, Jenelle Willett, Molly Brannock and Dr. Feng Lu for teaching me how to fashion my arguments and

discussions related to our work.

I need to thank Aaron Wallace, Steve Yamnitz and Bill Sanderson (Go VOLS) for helping live as a christian. Steve, thank you for being a best man at my wedding and for all the less

than intelligent adventures we had as children. Aaron, besides being a consistent fishing buddy, there is no way to show my thanks and gratitude to what you and Mel have done for Judy and I.

“How well I have learned that there is no fence to sit on between heaven and

hell. There is a deep, wide gulf, a chasm, and it that chasm is no place for any

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List of Tables

Chapter 2

Table 2-1. Efficacy of aryl organo-boranes as the nucleophile ... 25

Table 2-2. Efficacy of acetonitrile anions as the nucleophile ... 27

Table 2-3. Results of coupling of 22 with 10 under Pd-mediated coupling conditions. ... 38

Table 2-4. Variation of Base ... 41

Table 2-5. Variation of solvent and then further variation of base. ... 44

Table 2-6. Variation of ligand ... 46

Chapter 3 Table 3-1. Synthesis of the A-A monomer with TMSCH2CN ... 64

Table 3-2. Polymerization of 41 and 43 ... 72

Table 3-3. Polymerization of 41 and 43 (continued) ... 73

Chapter 4 Table 4-1. Failed attempts to effect the cascading cyclization under single nucleophile conditions in acid.a ... 102

Table 4-2. Efficacy of ketene-imine intermediates with various nucleophiles ... 109

Table 4-3. Photo-physical data for molecules 67, 68, 69, 70 and 72 ... 115

Appendix B Table B-1. Summary of Crystal Data for (64) x08082 ... 163

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Table B-3. Summary of Crystal Data for (68) x09086 ... 173

Table B-4. Summary of Crystal Data for (69) x09034 ... 178

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List of Figures

Chapter 1

Figure 1-1. Moore’s Law (A prediction that transistor density would double every other

year) ... 3

Figure 1-2. The current photo-lithographic patterning process in which, chips are made. .... 4

Figure 1-3. Electromigration of the gold atoms, which leads to the failure of the metal

connection. ... 5

Figure 1-4. Specialized reactor needed for the synthesis of graphite ... 6

Figure 1-5. Structure of pentance (A); Structure of substituted heptacene (B) ... 7

Figure 1-6. Examples of known precursor ladder polymers and reaction conditions to form a

fully aromatic ladder polymer. ... 8

Figure 1-7. Schematic depiction of direct writing. Conversion of an insulating material

directly into a conducting material upon application of light would require no metallization, strip or lift-off steps. ... 9

Figure 1-8. Fully cyclized ladder polymer end result ... 10

Figure 1-9. Advantages of poly amino-pyridine systems ... 11

Chapter 2

Figure 2-1. Reaction of molecules 9 and 10. (top) After 43 m (bottom) after 2 h. ... 33

Figure 2-2. In-situ formation and reaction of the organo-zinc nucleophile ... 34

Chapter 3

Figure 3-1. 1H-NMR spectrum of 44 (Table 3-3,Entry 6) ... 74

Figure 3-2. 1H NMR (d6-DMSO) of insoluble material. The large peak at 5.0 ppm is due to

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Chapter 4

Figure 4-1. ESI mass spectra illustration the partial and full cyclization of molecule 57 as

well as problematic amide formation ... 99

Figure 4-2. Crystal structure of the products isolated from the reaction of molecule 24 with

36 wt% HBr/HOAc, the alternatively cyclized molecule 64 (Left) and partially

cyclized trimer 65 (Right) ... 101

Figure 4-3. UV-Vis absorption spectrum of molecules 67-70 and 72 in CH3CN (left). .... 113 Figure 4-4. Emission spectra of molecules 67-70 in CH3CN (left) and UV-Vis, emission and

excitation spectra of molecule 69 in CH3CN (right). ... 114

Figure 4-5. Cyclic voltammetry of molecules 67, 68 and 69 thin films on the platinum

electrode in propylene carbonate containing 0.1M TBAPF6. Scanned from +1.5

V to -2.0 V vs. Ag+/AgNO3 reference for 2 cycles, scan rate = 100 mV s-1. .... 116

Figure 4-6. TGA scan of 70 from 0oC to 600oC ... 118

Figure 4-7. Structure of molecule 68 (top left), ORTEP drawing of molecule 68 showing

naming and numbering scheme (top right). Ellipsoids are at the 50% probability level, (bottom left) ace to edge stacking of 68, dimerization through hydrogen

bonding (bottom right). ... 121

naming and numbering scheme (top right). Ellipsoids are at the 50% probability level, (bottom left) Stacking of molecule 69, Dimerization through hydrogen

bonding (bottom right). ... 122

naming and numbering scheme (top right). Ellipsoids are at the 50% probability level, (bottom left) Stacking of molecule 76, (bottom right) Dimerization through

hydrogen bonding. ... 123

Appendix A

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Figure A-2. Temperature profiles of neat toluene, toluene with SiO2 and with Si during

irradiation at 100 watts for 2 minutes. ... 147

Figure A-3. IR temperature photographs and orientations in microwave cavity: A) vertical

photograph of position B (side picture shown for clarity) under 100W in toluene; C) vertical photograph of position D under irradiation at 100W in toluene. ... 148

Figure A-4. Si and SiO2 wafer orientation in the microwave vial sample holder. ... 150 Figure A-5. Thickness of PMMA brushes on both Si (Black) and SiO2 (Red) after

microwave irradiation for 2 m in toluene/methyl methacrylate 1:1 v/v. ... 151

Figure A-6. AFM micrographs, 10µm x 10µm, of SiO2 (A) and Si (B) wafers after

irradiation at 100 watts for 30 seconds in toluene/methyl methacrylate 1:1 v/v 152

Figure A-7. Graph indicating the effect of wattage on brush thickness after 2 minutes of

growth for PMMA. ... 153

Figure A-8. Graph indicating the effect of wattage on brush thickness after 2 minutes of

growth for PMMA. ... 154

Appendix B

Figure B-1. ORTEP drawing of (64) x08082 showing naming and numbering scheme. Ellipsoids are at the 50% probability level and hydrogen atoms were drawn with arbitrary radii for clarity. ... 162

Figure B-2. ORTEP drawing of (65) x08100 molecule A showing naming and numbering scheme. Ellipsoids are at the 50% probability level and hydrogen atoms were drawn with arbitrary radii for clarity. ... 166

Figure B-3. ORTEP drawing of (65) x08100 molecule B showing naming and numbering scheme. Ellipsoids are at the 50% probability level and hydrogen atoms were drawn with arbitrary radii for clarity. ... 167

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Figure B-5. ORTEP drawing of (68) x09086 molecule B showing naming and numbering scheme. Ellipsoids are at the 50% probability level and hydrogen atoms were drawn with arbitrary radii for clarity. ... 172

Figure B-6. ORTEP drawing of (69) x09034 molecule A showing naming and numbering scheme. Ellipsoids are at the 50% probability level and hydrogen atoms were drawn with arbitrary radii for clarity. ... 176

Figure B-7. ORTEP drawing of (69) x09034 molecule B showing naming and numbering scheme. Ellipsoids are at the 50% probability level and hydrogen atoms were drawn with arbitrary radii for clarity. ... 177

Figure B-8. ORTEP drawing of (76) x09060 showing naming and numbering scheme. Ellipsoids are at the 50% probability level and hydrogen atoms were drawn with arbitrary radii for clarity. ... 181

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List of Schemes

Chapter 1

Scheme 1-1. ... 13

Scheme 1-2. ... 14

Scheme 1-3. ... 15

Scheme 1-4. ... 16

Chapter 2 Scheme 2-1. ... 23

Scheme 2-2. ... 26

Scheme 2-3. ... 28

Scheme 2-4. ... 30

Scheme 2-5. ... 31

Scheme 2-6. ... 32

Scheme 2-7. ... 36

Scheme 2-8. ... 37

Scheme 2-9. ... 43

Chapter 3 Scheme 3-1. ... 62

Scheme 3-2. ... 63

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Scheme 3-4. ... 66

Scheme 3-5. ... 67

Scheme 3-6. ... 69

Scheme 3-7. ... 70

Scheme 3-8. ... 71

Scheme 3-9. ... 76

Chapter 4 Scheme 4-1. ... 92

Scheme 4-2. ... 93

Scheme 4-3. ... 94

Scheme 4-4. ... 95

Scheme 4-5. ... 96

Scheme 4-6. ... 97

Scheme 4-7. ... 98

Scheme 4-8. ... 104

Scheme 4-9. ... 106

Scheme 4-10. ... 107

Scheme 4-11. ... 107

Scheme 4-12. ... 108

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Scheme 4-14. ... 117

Appendix A

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List of Abbreviations and Terms

Abbreviations, Symbol or Term Explanation

ΦF Quantum yield of fluorescence

Å Angstrom

AIBN 2,2’-azobisisobutyronitrile

Ag+/AgNO3 Silver/Silver Nitrate reference electrode

aq Aqueous

bp Boiling Point

bs Broad singlet

Br Bromine

Brine Saturated solution of sodium chloride

Bu Butyl

n-BuLi n-butyllithium

o_C _{Degree(s) Celsius}

13_C_NMR _{Carbon-13 nuclear magnetic resonance}

spectroscopy

cm-1 Reciprocal centimeters

COSY Correlation Spectroscopy

CV Cyclic Voltammetry

δ Chemical shift in ppm from tetramethylsilane

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DCM Dichloromethane

dd Doublet of doublets

DMAP 4-(N,N-dimethylamino) pyridine

DMF Dimethylformamide

DMSO Dimethylsulfoxide

dba Dibenzylideneacetone

dt Doublet of triplets

EAS Electronic absorption spectra

EBG Estimated Band Gap

Equiv Equivalents

Et Ethyl

Et2O Diethyl ether

EtOAc Ethyl Acetate

EtOH Ethanol

eV Electron Volts

g Grams

GC Gas Chromatography

GPC Gel permeation chromatography

h Hours

H+ Proton or protic acid

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HOAc Acetic Acid

Hex Hexanes

1_{H NMR} _{Proton nuclear magnetic resonance spectroscopy}

HPLC High performance liquid chromatography

HMDS Hexamethyldisilazide

HOMO Highest Occupied Molecular Orbital

HRMS High resolution mass spectrometry

H2SO4 Sulfuric Acid

Hz Hertz

i-Pr Isopropyl

IR Infrared Spectroscopy

J Coupling constant

λMAX The lowest energy transition

λONSET Emission The emission peak onset

λONSET Absorption The λMAX peak onset

L Liter

LDA Lithium diisopropylamide

LiTMP Lithium tetramethylpiperidide

LUMO Lowest Unoccupied Molecular Orbital

µ Micro

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M Molar

m Multiplet

M+ Parent molecular ion

MeCN or CH3CN Acetonitrile

MeOH Methanol

mg Milligrams

MHz Megahertz

m Minutes

mL Milliliters

mmol Millimole

mol Mole

Mn Number average molecular weight

Mp Melting point

Mw Weight Average molecular weight

N Normal

n Degree of polymerization

NBS N-bromo succinimide

NH4OAc ammonium acetate

NMP N-methylpyrrolidinone

nm Nanometer

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PDI Poly-dispersity index

Ph Phenyl

ppm Parts per million

Pr Propyl

q Quartet

R Alkyl group

rt Room temperature

s Singlet

t Triplet

TBAPF6 Tetrabutylammoniumhexafluorophosphate

TBDMS Tertbutyldimethylsilyl

TGA Thermal gravitametric analysis

THF Tetrahydrofuran

TIPS Tri-iso-propylsilyl

TMS Trimethylsilyl

V Volts

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Chapter 1

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1.1 Size Reduction and Moore’s Law

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Figure 1-1. Moore’s Law (A prediction that transistor density would double every other year)

1.2 Photolithography

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method. Due to the thickness of both the thin film and the photo-resist, patterning thin lines creates low aspect ratios which results in mechanically and electrically unstable structures. The aspect ratio also decreases with the number of times the chip gets washed and etched.

Figure 1-2. The current photo-lithographic patterning process in which, chips are made.

1.3 Electromigration

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through a wire. While electromigration does not affect the most recent chips, multiple fans are required to keep these devices cool and decrease the likelihood of device failure. However, as feature sizes are reduced, failure due to electromigration will become more and more likely.

Figure 1-3. Electromigration of the gold atoms, which leads to the failure of the metal connection.

1.4 Organic Conducting Materials

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conductivity of copper (5.8x105 (S/cm)).15 Graphite, however, has a conductivity of 2.2x103 (S/cm)15,16 and doped poly(acetylene) has shown conductivities as high as 3.6x102 (S/cm).17,18 These are figures of merit that may be difficult to match or exceed, however. Fused ring graphitic or aromatic ladder materials also have the potential to maximize the density of intermolecular packing compared to typical, conjugated organics because they are fused and thus required to be planar. In addition, these systems are computationally shown to have properties that are similar to highly conducting materials, e.g. zero band gap.19

Graphite, however, is not a material that is amenable to patterning even though it is used in many other applications.20-25 Graphite is not melt or solution processable, and only a few techniques are reported for its synthesis.26,27 The best known method to produce graphite uses a nickel catalyst at 750-900 K in a ethylene/oxygen rich atmosphere (Figure 1-4).24 Although the reported procedure is the mildest, it is not compatible with nanometer-scale patterning.

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The synthesis of small oligomer acenes (fused linear carbon chains) was explored to avoid the processing problems associated with graphite. Small molecule linear acenes, e.g. pentacene (Figure 1-5, A), have been synthesized as an alternative to graphite and show very impressive properties (hole mobilites upward of 5 cm2/V*s).28-31 However, only substituted hexacene and heptacene (Figure 1-5, B) have been synthesized, as un-substituted linear acenes have not been isolated due poor solubility and stability.28 The synthesis of longer acene systems is increasingly difficult because of the needed substitution.

TIPS

A B

Figure 1-5. Structure of pentance (A); Structure of substituted heptacene (B)

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We hypothesize that this solid-state conversion might be performed locally to create patterns, as discussed in more detail in the next section. A candidate precursor conversion requires mild chemistry that does not involve local heating or harsh reagents, which might facilitate unwanted side reactions. Ideally, a photo-chemically initiated process could most likely be adapted to established photolithography procedures.

R₁ R₁ R₂ R₂ n n R₁ R₂ R₂ R₁ R₁ R₂ R₂ R₁ N N N N BocHN R(O)C C(O)R n _N N N N N N R R n NHBoc

CF₃CO₂H

ZnCl₂

115oC

Figure 1-6. Examples of known precursor ladder polymers and reaction conditions to form a fully aromatic ladder polymer.

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1.5 Direct Writing

Although the ladder polymers described above require conditions that are too harsh for nanometer-scale patterning, they suggest a very useful idea for patterning. The precursor polymer is typically soluble in organic solvents while the ladder polymer is not. It is not only of convenience that the precursor polymer and the ladder polymer have two different solubilities in organic solvents, but also allows the user to write patterns onto materials in a much more efficient way. The soluble precursor polymer can be coated onto a substrate and, upon local laser irradiation38,39 or other type of conversion,40-44 it would be converted to the insoluble, desired, conductive material. The starting precursor could then be washed away.

Figure 1-7. Schematic depiction of direct writing. Conversion of an insulating material directly into a conducting material upon application of light would require no metallization, strip or lift-off steps.

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waste generated.45 This method has been tested with metallo-polymers and resulted in 12 nm structures with high aspect ratios.45

1.6 Proposed Ladder Polymer

As fused, sp2 hybridized materials have several advantages over non-fused polymers, we have chosen to pursue the synthesis of a novel ladder material from a soluble precursor polymer. The proposed poly-amino-iso-quinoline ladder polymer is illustrated in Figure 1-8. As expressed before, the proposed ladder polymer is anticipated to have high conductivity due to the extended conjugation throughout the material. This hypothesis is supported by computations illustrating that fused amino-iso-quinolines are capable of being either n and p-type materials46 with electron mobilities close to that of other carbon acenes.47

N HN N HN N HN NH

X

R R R R

CN

n

Figure 1-8. Fully cyclized ladder polymer end result

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(N-NH) units (Figure 1-9, C).55 Third, the electronic properties can be tuned through protonation,56 and deprotonation (Figure 1-9, D).10,57

Ligands Metal Atoms Ligands N N N N N N N N N N N N 4 N N

C₆H₁₃

N N

C₆H₁₃

C₆H₁₃ CSA H H A _B C _D N N N N H H H H

Figure 1-9. Advantages of poly amino-pyridine systems

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Scheme 1-1.

CN A

CN

B

N HN N HN N N NH₂

X

R R R R

CN

n

CN CN CN CN CN

R R R

X CN

R CN

CN

n

Tautomerization Polymerization

Precursor Polymer

Ladder Polymer A-B Monomer

N HN N HN N N NH

X

R R R R

CN

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1.7 Perspectives and Goals of Dissertation Research

The long term goal of this project is the development of a novel, potentially conducting, material through the direct writing of a soluble precursor polymer. In this thesis, the synthesis of a soluble precursor polymer is presented. In addition, optimal ring closing conditions for discrete oligomers of the aforementioned precursor polymer are also reported.

Since the proposed reactions are relatively unexplored, several challenges exist with the synthetic route presented in Scheme 1-1. The three challenges that are addressed here are:

1. Optimization of a model coupling in application to a polymerization

2. Synthesis of an highly acidic poly-cyano precursor through an anionic polymerization 3. Development of a route for the efficient ring closure of poly-cyano oligomers

Chapter 2 discusses possible and optimal coupling reactions for the precursor polymer and illustrates that highly electron deficient mono-aryl, di-aryl and bis-diaryl acetonitriles can be synthesized effectively using either a nucleophilic aromatic substitution (NAS) or a palladium-mediated coupling pathway (Scheme 1-2). It is shown that the synthesis of di-aryl acetonitriles most conveniently proceeded via NAS while palladium-mediated coupling is required to prepare the bis-diaryl acetonitrile efficiently. These reactions were extremely sensitive to steric and ligand electronic effects.

Scheme 1-2.

X

CN CN CN

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In Chapter 3, the synthesis of a novel poly-(cyano)-precursor polymer through a palladium catalyzed coupling is reported (Scheme 1-3). The synthesis of the polymer is possible through a short and efficient synthesis of the monomerwhere the critical step is the selective NAS of an ethyl cyanoacetate anion. The precursor polymer was synthesized in modest yield and molecular weight. In addition, it is also illustrated that optimal conditions from the previous study (Chapter 2) may not be directly applicable to the polymerization.

Scheme 1-3.

CN CN CN

C₆H₁₃ C₆H₁₃ Br

CN Br

CN CN

C₆H₁₃

n

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Scheme 1-4.

N HN N

C₄H₉ NH₂

CN CN CN CN

N N

Br NH₂ H₂N Br

36 wt% HBr/HOAc

n-BuLi

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1.8 References

(1) Intel. http://www.intel.com/research/silicon/mooreslaw.htm

(2) Intel. http://www.intel.com/pressroom/kits/quickreffam.htm#Celeron (3) Intel. http://www.intel.com/pressroom/archive/releases/20040830net.htm (4) Intel.

http://www.intel.com/technology/architecture-silicon/32nm/index.htm?iid=tech_sil+32nm

(5) Monceaux, C. Masters Thesis, North Carolina State University, 2004. (6) Pang, X.; Kriman, A. M.; Bernstein, G. H. J. Electrochem. Soc.2002, 149, G103-G108.

(7) Schneider, G.; Hambach, D.; Niemann, B.; Kaulich, B.; Susini, J.; Hoffmann, N.; Hasse, W. Appl. Phys. Lett.2001, 78, 1936-1938.

(8) Durkan, C.; Schneider, M. A.; Welland, M. E. J. Appl. Phys.1999, 86, 1280-1286.

(9) Shiraishi, K.; Rajca, A.; Pink, M.; Rajca, S. J. Am. Chem. Soc.2005, 127, 9312-9313.

(10) Tal, S.; Blumer-Ganon, B.; Kapon, M.; Eichen, Y. J. Am. Chem. Soc.2005, 127, 9848-9854.

(11) Payne, M. M.; Parkin, S. R.; Anthony, J. E. J. Am. Chem. Soc.2005, 127, 8028-8029.

(12) Zhang, C. Y.; Tour, J. M. J. Am. Chem. Soc.1999, 121, 8783-8790.

(13) Jadhav, A. V.; Gulgas, C. G.; Gudmundsdottir, A. D. Eur. Polym. J. 2007, 43, 2594-2603.

(44)

(16) Jaszczak, D. J. A. http://www.phy.mtu.edu/~jaszczak/graphprop.html (17) Chiang, C. K.; Fincher, C. R.; Park, Y. W.; Heeger, A. J.; Shirakawa, H.; Louis, E. J.; Gau, S. C.; Macdiarmid, A. G. Phys. Rev. Lett.1977, 39, 1098-1101.

(18) Chiang, C. K.; Druy, M. A.; Gau, S. C.; Heeger, A. J.; Louis, E. J.;

Macdiarmid, A. G.; Park, Y. W.; Shirakawa, H. J. Am. Chem. Soc.1978, 100, 1013-1015. (19) Bendikov, M.; Duong, H. M.; Starkey, K.; Houk, K. N.; Carter, E. A.; Wudl, F. J. Am. Chem. Soc.2004, 126, 7416-7417.

(20) Baughman, R. H. Science2006, 312, 1009-1010.

(21) Lee, J.; Kim, J.; Hyeon, T. Adv. Mater.2006, 18, 2073-2094.

(22) Makarova, O. V.; Mancini, D. C.; Moldovan, N.; Divan, R.; Tang, C. M.; Ryding, D. G.; Lee, R. H.; Science2003, 182-186.

(23) Miller, T. M.; Kwock, E. W.; Baird, T.; Hale, A. Chem. Mat.1994, 6, 1569-1574.

(24) Phillips, J.; Shiina, T.; Nemer, M.; Lester, K. Langmuir2006, 22, 9694-9703. (25) Schueller, O. J. A.; Brittain, S. T.; Marzolin, C.; Whitesides, G. M. Chem. Mat.1997, 9, 1399-1406.

(26) Brooks, J. D.; Taylor, G. H. Nature1965, 206, 697-699.

(27) Zakhidov, A. A.; Baughman, R. H.; Iqbal, Z.; Cui, C. X.; Khayrullin, I.; Dantas, S. O.; Marti, I.; Ralchenko, V. G. Science1998, 282, 897-901.

(28) Anthony, J. E. Chem. Rev.2006, 106, 5028-5048.

(29) Duong, H. M.; Bendikov, M.; Steiger, D.; Zhang, Q. C.; Sonmez, G.; Yamada, J.; Wudl, F. Org. Lett.2003, 5, 4433-4436.

(30) Tang, M. L.; Mannsfeld, S. C. B.; Sun, Y. S.; Becerril, H. A.; Bao, Z. N. J. Am. Chem. Soc.2009, 131, 882-883.

(45)

(32) Forrester, A. R.; Irikawa, H.; Thomson, R. H.; Woo, S. O.; King, T. J. J. Chem. Soc., Perkin Trans. 11981, 1712-1720.

(33) Kawaguchi, K.; Nakano, K.; Nozaki, K. J. Org. Chem.2007, 72, 5119-5128. (34) Rumynskaya, I. G.; Romanova, E. P.; Agranova, S. A.; Frenkel, S. Y. Acta Polym.1991, 42, 250-253.

(35) Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. J. Am. Chem. Soc.1997, 119, 4578-4593.

(36) Goldfinger, M. B.; Swager, T. M. J. Am. Chem. Soc.1994, 116, 7895-7896. (37) Yamaguchi, S.; Swager, T. M. J. Am. Chem. Soc.2001, 123, 12087-12088. (38) Kordas, K.; Bali, K.; Leppavuori, S.; Uusimaki, A.; Nanai, L.; Science2000, 399-404.

(39) Lee, C. W.; Kim, Y. B.; Lee, S. H. Chem. Mat.2005, 17, 366-372. (40) Asakura, T.; Yamato, H.; Matsumoto, A.; Murer, P.; Ohwa, M. J. Photopolym. Sci. Technol.2003, 16, 335-345.

(41) Ogura, T.; Higashihara, T.; Ueda, M. J. Photopolym. Sci. Technol.2009, 22, 429-435.

(42) Salavagione, H. J.; Miras, M. C.; Barbero, C. Macromol. Rapid Commun.

2006, 27, 26-30.

(43) Shirai, M.; Suyama, K.; Okamura, H.; Tsunooka, M. J. Photopolym. Sci. Technol.2002, 15, 715-730.

(44) Wang, M. X.; Jarnagin, N. D.; Lee, C. T.; Henderson, C. L.; Yueh, W.; Roberts, J. M.; Gonsalves, K. E. J. Mater. Chem.2006, 16, 3701-3707.

(45) Clendenning, S. B.; Aouba, S.; Rayat, M. S.; Grozea, D.; Sorge, J. B.; Brodersen, P. M.; Sodhi, R. N. S.; Lu, Z. H.; Yip, C. M.; Freeman, M. R.; Ruda, H. E.; Manners, I. Adv. Mater.2004, 16, 215-219.

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(47) Eng, M. P.; Albinsson, B. Angew. Chem.-Int. Edit.2006, 45, 5626-5629. (48) Berry, J. F.; Cotton, F. A.; Lei, P.; Lu, T. B.; Murillo, C. A. Inorg. Chem.

2003, 42, 3534-3539.

(49) Gaillard, S.; Elmkaddem, M. K.; Fischmeister, C.; Thomas, C. M.; Renaud, J. L. Tetrahedron Lett.2008, 49, 3471-3474.

(50) Gong, H. Y.; Zhang, X. H.; Wang, D. X.; Ma, H. W.; Zheng, Q. Y.; Wang, M. X. Chem.-Eur. J.2006, 12, 9262-9275.

(51) Hasan, H.; Tan, U. K.; Lin, Y. S.; Lee, C. C.; Lee, G. H.; Lin, T. W.; Peng, S. M. Inorg. Chim. Acta2003, 351, 369-378.

(52) Lee, M. H.; Cho, B. K.; Yoon, J.; Kim, J. S. Org. Lett.2007, 9, 4515-4518. (53) Vellis, P. D.; Mikroyannidis, J. A.; Lo, C. N.; Hsu, C. S. J. Polym. Sci., Part A: Polym. Chem.2008, 46, 7702-7712.

(54) Wan, Y. J.; Niu, W. J.; Behof, W. J.; Wang, Y. F.; Boyle, P.; Gorman, C. B. Tetrahedron2009, 65, 4293-4297.

(55) Keinan, S.; Ratner, M. A.; Marks, T. J. Chem. Phys. Lett.2004, 392, 291-296. (56) Hancock, J. M.; Jenekhe, S. A. Macromolecules2008, 41, 6864-6867.

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Chapter 2 Optimization of Applicable Coupling Conditions to

the Synthesis of the Precursor Polymer

Behof, W. J.; Brannock, M.C.; Morrison, G.; Gorman, C.B. “Synthesis of a Poly-Cyano

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2.1 Introduction

As part of a research program in the synthesis of cyano-containing polymers, we became interested in synthesizing oligomers and polymers with the general repeat unit shown in

Scheme 2-1 (Middle). The diaryl methane subunit can be formed through a benzyl/phenyl

linkage as shown in Scheme 2-1. Scheme 2-1 also shows the two logical bond

deconstructions that could potentially give rise to this linkage. The substituent on the aryl

group could be nucleophilic (M) while the substituent at the benzylic position would then be the leaving group (LG) (Scheme 2-1, top). Alternatively, the substituent positions could be

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Scheme 2-1. M Nu CN CN CN + CN E R R LG

CN CN CN

R R LG E CN CN CN + CN Nu R R M

CN CN CN

R R

CN

CN CN CN

R R

CN CN CN

R R n n m m n m

Precursor Polymer

Previous attempts by Gorman group members to synthesize the precursor polymer

(Scheme 2-1), were unsuccessful. These results lead us to believe the coupling reaction was

ineffective.1 Therefore, a two-step strategy was developed to find an effective coupling approach. First, a quick assessment of commercially available or easily synthesized leaving

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Herein, we illustrate the efficacy of organo-boranes, organo-lithiums, acetonitrile anions and benzyl anions as nucleophilic partners in the coupling shown in Scheme 2-1. Of all the

methods attempted, use of benzyl anion nucleophiles appeared to be most effective. Thus,

both a nucleophilic aromatic substitution and a palladium mediated pathway using the benzyl anion nucleophiles were optimized. Choice of base, solvent, and catalyst/ligand will be

shown to be key parameters to optimize for a successful coupling. Finally, an optimal, high yielding route will be illustrated.

2.2 Results and Discussion

2.2.1 Assessment of Various Nucleophile and Electrophile Combinations

The first task is to explore potential couplings, which are applicable to the synthesis of the

precursor polymer, with commercially available starting materials. This is needed because there is a vast amount of reported reactions concerning C-C bond formation. The nucleophilic partners that will be explored herein are: organo-boranes, organo-lithiums,

acetonitrile anions and aryl acetonitrile anions.

2.2.1.1 Organo-borane nucleophiles

Organo-borane nucleophiles are of interest because of their functional group tolerance and mild conditions for coupling reactions that utilize them. Nobre et al. illustrated the cross

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acids, at both elevated and room temperature.2 The conditions reported in that work were used as a starting point to test the coupling between benzyl bromide 2 and the aryl boronic

acid 1 (Table 2-1). Variations in temperature, time and heating method on the efficacy of the

coupling were also investigated.

Table 2-1. Efficacy of aryl organo-boranes as the nucleophile

CN

Br B(OH)₂

CN CN CN CN

+

CN

1 2 3

Entry NB Pg # Pd:Lig Heating Temp (oC) Time (h) Yield [%] of 3a

1 WJB-IV-11 0.01/0.02 Ther. 80 19 16

2 WJB-IV-96 0.02/0.04b Ther. 25 72 0 b,c 3 WJB-IV-97 0.02/0.04 Mic. 130 3 min 0b,c,3

Conditions and Reagents: toluene, K3PO4, Pd(OAc)2, PPh3. aIsolated yield, bMolecule 2

decomposed, yields of 3 were estimated by TLC and NMR to be very low.

A modest 16% yield of molecule 3 was isolated under the reported conditions (entry 1).

However, debromination of molecule 2 was observed as a major side product by NMR and

thin layer chromatography (TLC). The temperature of the reaction was reduced in order to minimize the de-bromination of molecule 2 (entry 2). Although, there was no decomposition

of molecule 2, there was also no formation of molecule 3. The large loss of molecule 2 at

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low yields.4,5 This coupling was not explored further. In addition, it is suspected that molecule 2 should only be used at room temperature or lower to minimize debromination.

2.2.1.2 Organo-lithium nucleophiles

Aryl lithium nucleophilic reagents were tested because of their high nucleophilicity, potential to react via a non-palladium mediated pathway, and presumed reactivity at low

temperatures. Pirrung et al. reported the efficient synthesis of di-aryl methanes through,

in-situ generated and electron deficient, aryl lithium reagents with benzyl halides.6 However, when these conditions were applied to the coupling of molecule 1 with the in-situ generated aryl lithium of 4, molecule 3 was isolated only in modest yield (Scheme 2-2).

Scheme 2-2.

CN

Br Br

CN CN CN CN CN

+

2 3

4

n-BuLi, THF

Temp= -78oC, 17% Temp= -100oC, 28%

Possible reasons for the low yields include intermolecular lithium halogen exchange, steric

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2.2.1.3 Acetonitrile anion nucleophiles

Carbon-carbon bond formation could proceed through carbanion coupling with a halide

electrophile. Culkin et al. employed acetonitrile anions to synthesize diphenyl acetonitriles from bromo-benzene while showing they have dual functions. First, a single equivalent of acetonitrile anion can act as a nucleophile and form the desired benzyl cyanide. Upon

formation of the benzyl cyanide, a second equivalent of acetonitrile anion can deprotonate the more acidic benzyl proton, creating a benzyl nucleophile which then can undergo another

coupling with molecule 4.7

Table 2-2. Efficacy of acetonitrile anions as the nucleophile

CN CN CN CN

+ Br

H H

CN

4 5 3

Entry NB Pg # Cat Lig Base Solvent Temp(o_{C) Product}a

1 WJB-I-2 Pd2dba3 BINAP NaHMDS DMF 90 0

2 WJB-I-93 Pd(OAc)2 BINAP LiHMDS Toluene 25 0

3 WJB-I-88 Pd2dba3 P(tBu)3 LiHMDS Toluene 25 0

4 WJB-I-89 Pd2dba3 P(tBu)3 LiHMDS Toluene 0 0

Conditions and Reagents: 2 eq. of base, 0.1/0.2 Pd:Ligand. a_{Estimated by both TLC and}

NMR.

Couplings were performed under the conditions reported by Culkin et al. and with slight variations (Table 2-2, Entries 1-3). These yielded no product. Addition of the anion of 5 at

0oC (Entry 4) resulted in the absence of molecules 3 and 4, raising questions about the

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observation is supported by literature reports of nucleophilic attack by acetonitrile anions at the electrophilic aryl cyanide carbon.8-10 Therefore, utilization of acetonitrile anions as a nucleophilic coupling partner was not a practicable route.

2.2.1.4 Benzyl cyanide nucleophiles

Deprotonation of PhCH2CN or o-CNPhCHCN and subsequent use as a nucleophilic

equivalent has had several successful precedents. You and Verkade11,12 illustrated coupling of phenyl acetonitrile anions to aryl halides in the presence of a proazaphosphatrane ligand.

Culkin and Hartwig7,13 showed that the anion of benzyl nitriles could undergo a palladium-mediated coupling to aryl halides and studied the mechanism of this transformation in some detail (Scheme 2-3). Wan et al. has reported couplings between aryl chlorides and phenyl

acetonitrile anions through a nucleophilic aromatic substitution pathway (NAS).14 Therefore we pursued this method further because of these successful precedents and the significant

limitations described with the aforementioned (Section 2.2.1-3) methods.

Scheme 2-3.

CN

R= H, 93% R=t-Bu, 98%

R + K-OtBu, Pd(OAc)2

BINAP or Verkade Cat. Br

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2.2.2 Optimization of Couplings Employing Benzyl Cyanide Nucleophiles

Given the precedents described in Section 2.2.1.4, a cyanobenzyl nucleophile was selected

as the nucleophile for this coupling. Moreover, o-cyanophenyl benzyl nitrile (o -CNC6H5CH2CN) is relatively acidic, (pKa = 19.2 in dimethyl sulfoxide (DMSO)).15 The

resulting carbanion would then be a suitable nucleophile in a carbon-carbon coupling

reaction. The pKa determination of similar molecules containing such groups will be reported below. Furthermore, the arene is relatively electron deficient which renders it a

good electrophile. As reported, Hartwig et al.,6 Satoh et al.14 and Verkade et al.10, 11 employed, with high efficiency, phenyl acetonitrile for monoarylations and acetonitrile for di-arylations.

The examples given above suggest several challenges and potential opportunities in the carbon-carbon bond forming reaction under study here. First, since our proposed arene is so

electron deficient, can simple nucleophilic aromatic substitution compete with palladium-mediated coupling? This question may also be relevant in some of the examples shown above. Second, in the work above, limitations were observed when ortho substituents were

present on the arene electrophile.16 The presence of o-cyano groups in our target might thus be an issue. Third, since the methine proton in the product (e.g. Ph2(CN)CH) should be more

acidic than the proton that must be removed in the starting material (e.g. Ph(CN)CH2), can

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Fourth, are reactions where Ph2(CN)C- (Scheme 2-4, right) acts as a nucleophile

problematic?

Scheme 2-4.

X

CN CN

R R

CN

R CN CN

X

CN CN

R R

CN

R CN CN

2.2.2.1 Nucleophilic aromatic substitution

In the work of Hartwig et al.7,13,17 and Verkade et al.11,12 discussed above, both electron rich and electron deficient aryl halide substrates were explored. In the coupling of interest here, the aryl halide is electron deficient, begging the question as to whether, in this case, a

nucleophilic aromatic substitution (NAS) reaction would be applicable. We tested this in three ways. First, a reaction from the literature was repeated under NAS conditions. Then from this, two new coupling reactions were explored.

First, the NAS pathway was investigated in the case of an electron deficient arene. Culkin and Hartwig reported formation of molecule 8 from p-bromo benzonitrile (6) in 99% yield in

the presence of palladium acetate (Pd(OAc)2) and

2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP).7 You and Verkade reported a similar reaction using p-chloro benzonitrile (7) to achieve molecule 8 in 92% yield in the presence of Pd(OAc)2 and a

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palladium/ligand under the same conditions and obtained 42% (X = Br) and 72% (X = Cl) yield, respectively. Thus, palladium-mediated coupling does result in a higher yield. However, in this case, the results provide evidence for competition between NAS and the

palladium pathway.

Scheme 2-5.

CN

X

CN

NC

6: X= Br

7: X= Cl

8 i or ii

Conditions and Reagents: (CH3)2CHCN, sodium hexamethyldisilazide (NaHMDS),

toluene (i) 6, 100⁰C, 1 h, 42% (ii) 7, 90⁰C 2 h, 72%.

We then turned to the NAS of 2,6-dichloro benzonitrile (9)with o-cyanophenyl acetonitrile

(10).When two equivalents of molecule 10 were reacted withmolecule 9 in the presence of

sodium tert-butoxide (Na-OtBu) (Scheme 2-6), only the mono-coupled product 11 was

obtained in 91% yield. When molecule 11 was isolated and reacted with molecule 10 for a

longer period of time (72 h) and in excess (3.2 equivalents) base, a small amount (13 %) of bis-coupled product 12 was isolated. This reaction was clearly inefficient for the formation

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Scheme 2-6.

CN Cl Cl

CN

CN CN

Cl

11 9

CN CN

CN CN CN

12

CN CN

+

10

i _ii

Conditions and Reagents: (i) Na-OtBu, THF, µW, 155oC, 5 m, 91%; (ii) Na-OtBu, 10,

THF, reflux, 72 h, 13%.

In an attempt to understand why this coupling was inefficient, the reaction was followed by nuclear magnetic resonance (NMR). Molecule 10 (1.4 equiv.) and sodium tert-butoxide (1.2 equiv.) were mixed in d8-tetrahydrofuran (THF). The benzylic peak at 4.15 ppm shifted to

3.45 ppm and broadened considerably as would be expected for deprotonation of molecule

10. Then, 2,6-dichloro-benzonitrile (9) electrophile (1.0 equiv) was introduced. After 43 m,

the NMR spectrum (Figure 2-1, top) showed both nucleophile and electrophile co-existing in

solution with the emergence of new peaks. After 2 h, Figure 2-1, bottom showed no anion

as evidenced by the disappearance of the peak at 5.7 ppm. Moreover, a re-emergence of the

benzyl protons peak at 4.1 ppm was observed. Thus, it was concluded that the anion was gone. Moreover, no methine peak indicative of the products 11 or 12 was observed around

6.2 ppm. Instead, a series of well-separated peaks relatively upfield for aromatic protons were observed. These were assigned to the anion of 11 as the same spectrum could be

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Figure 2-1. Reaction of molecules 9 and 10. (top) After 43 m (bottom) after 2 h.

2.2.2.2 Reduction of basicity through metal complexation

The effects of benzyl anion metal complexation were explored because organo-zinc

reagents are milder carbanions but are still quite nucleophilic. Benefits of milder reagents include a potential shift in the anion equilibrium. Second, the organo-zinc could be less likely to attack the aryl cyanide. After deprotonation of molecule 10 in d8-THF ZnBr2 was

added. The organo-zinc reagent subsequently formed (Figure 2-2), as suggested by the

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density around the aryl ring. This is expected as the C-ZnBr bond should be more covalent than that of a Na+ PhCHCN- salt. However, after heating at 60oC for 2 h there was no formation of molecule 11. Thus, the organo-zinc reagent appeared to be insufficiently

reactive in this case. Additionally, complete deprotonation of the methine proton was observed when molecule 11 was added. Similar experiments performed with CeCl3 in place

of ZnBr2 also failed to yield the desired product.

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2.2.2.3 Palladium-mediated coupling

Given the poor results when attempting to prepare molecule 12 via NAS, palladium

mediated-coupling was explored. Hartwig et al. showed that Pd(OAc)2/BINAP could couple

phenyl acetonitrile anions with p-tBu-bromobenzene.7 These conditions were used as the starting point to optimize the reaction for the formation of molecule 12. Because it is the

second coupling that is challenging, the reaction of molecule 11 with molecule 10 was

explored. The mono iodo and bromo derivatives of molecule 9 are proposed as electrophiles

since palladium-mediated couplings typically are more efficient with aryl bromides and iodides than chlorides. The synthesis of molecule 18 was challenging because even though

molecule 16 could be synthesized from molecule 15 the subsequent conversion to the aryl

cyanide failed (Scheme 2-7).18 This method is currently being explored by other Gorman

group students. Electrophilic aromatic substitution from molecule 14, which was synthesized

from the di-ortho lithium metalation of molecule 13,19 with iodine mono-chloride (ICl) was

ineffective.20 However, molecule 18 could be synthesized from a di-lithium halogen

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Scheme 2-7.

CN TMS TMS

C₆H₁₃ CN

C6H13

13 14

I I

NH2

C₆H₁₃ NH2

C₆H₁₃

16 17 CN I I CH₃ 18 CN Br Br CH₃ 15

Li-TMP, I₂ 88%

I₂, AgNO₃ Quant.

ICl, CH2Cl2

0%

CuSO₄, K₃CuCN₄,

H₂SO₄, NaNO₂, 0%

n-BuLi, I₂ 70%

CN I I

C6H13

CN I I

C₆H₁₃

.

The di-phenyl methane nucleophilic partners 21-23 were synthesized through NAS of

molecules 17, 18 and 20 with molecule 10 (Scheme 2-8). Molecule 20 was synthesized

through bromination of 4-hexyl aniline to form molecule 19. This is then followed by

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Scheme 2-8. CN X X R CN CN CN R X CN CN + NH₂ R Br Br

19: R= C6H13 20: R= C6H13, X= Br, 10% 17: R= CH3, X= Br 18: R= CH₃, X= I

21: R= C6H13, X= Br, 60% 22: R= CH3, X= Br, 92% 23: R= CH₃, X= I, 90%

i ii

Conditions and Reagents: (i) CuSO4, K3CuCN4, H2SO4, NaNO2; (ii). K-OtBu, DMF, µW,

100oC, 100W, 25 m.

Reaction of molecules 22 and 10 under palladium-mediated coupling was then explored.

The results are shown in Table 2-3. A maximum yield of 62% was obtained. Comparison of

entries 1 and 2 in Table 2-3 indicate that use of the aryl bromide indeed does result in a

higher yield. Comparison of entries 2 and 3 indicate that NAS is indeed also less efficient on the aryl bromide compared to palladium mediated coupling. Comparison of entries 3 and 4

indicate that microwave heating was more efficient than thermal heating and gave a much higher yield of product. Moreover, extending the reaction time under thermal heating showed no further increase in yield when the reaction time was increased from 4 h to 6 h.

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Table 2-3. Results of coupling of 22 with 10 under Pd-mediated coupling conditions.

CN CN CN CN CN

Br

CN CN CN CN CN

10 22

24

Entry NB Page # eq. K-OtBu Heat Source Temp (°C) Time % 24a

1 MCB-IV-18 3.2 Microwave 130 5 m 0b

2 GM-I-37 3.2 Microwave 130 5 m 33c

3 WJB-V-2 3.2 Microwave 130 5 m 62

4a MCB-III-70 3.2 Thermal 80 2 h 17

4b MCB-III-70 3.2 Thermal 80 4 h 37

4c MCB-III-70 3.2 Thermal 80 6 h 36

5 MCB-III-54 2.1 Microwave 130 5 m 29

6 MCB-III-55 1.1 Microwave 130 5 m 5

Conditions: 0.3M THF, 1.2 eq. 10, 0.1 eq. Pd(OAc)2, 0.2 eq. BINAP. aValues obtained

from HPLC with an estimated error of ± 5%. bMolecule 9 was used instead of molecule 22. c_{No Pd catalyst or BINAP were added.}

2.2.2.4 Variation of base and effect of cation counterion complexation

The yield of a palladium-catalyzed coupling reaction can be greatly influenced by the base

employed. Furthermore, the data above indicate that excess base is required. This requirement likely results because (1) both molecules 22 and 24 are deprotonated

preferentially to molecule 10 and (2) any equilibrium between molecules 22- or 24- and

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true. You and Verkade showed that the reaction between bromobenzene and benzyl cyanide to form diphenyl acetonitrile could be accomplished in 93 % yield using 1.4 equivalents of sodium hexamethyl disilazide.11,12 The tabulated pKa values of benzyl cyanide and diphenyl acetonitrile are 21.9 and 17.5, respectively.21 Thus, we speculated that there likely was some equilibrium between the anion of the product and that of the starting material in this case.

However, in our case, the o-cyano groups likely had an important influence on the pKa (and more importantly, the relative pKa) values of our starting materials and product.

To determine the relative acidity of the protons on molecules 10, 22 and 24, pKa

measurements in DMSO were performed, by a co-worker Molly Brannock, using the procedure developed by Bordwell et al.22 The pKa of molecule 10 was measured to be19.2.

Molecule 22 had a pKa of 13.6 and molecule 24 had pKa1 and pKa2 values of 13.2. The

similarity of the two pKa values for molecule 24 is consistent with the findings of

Streitwieser where unfused, diprotic structures were determined to have very similar, almost

indistinguishable, pKa values.23 Thus, if the anion of molecule 10 is produced, it is likely in

equilibrium with the anion of molecule 22 and the (di)anion of molecule 24 (Scheme 2-4).

Given the values, this equilibrium is likely to be unfavorable, resulting in the need to use

more than one equivalent of base. This need is in contrast to the results reported by You and Verkade above.

These pKa values may be only partially relevant, however. There are reports that suggest weak bases such as potassium carbonate (K2CO3)24 and dimethylamino pyridine (DMAP)25

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molecules 10, 22 and 24 might be quite different. Indeed, based on computations, Ding et al.

suggest that neutral acids are typically eleven orders less acidic in THF than in DMSO.26 Furthermore, even if the anions of molecules 22 and 24 are produced, they may be innocent

or reactive, particularly depending on the solvent and counter-cation present. The reactivity of carbanions is particularly variable depending on these parameters.27 Thus, some variation of base was explored.

To explore variation of base in an efficient manner, reactions were conducted under otherwise identical conditions and analyzed by HPLC. Both the percentage of unreacted

molecule 22 and the percentage of molecule 24 are given in Table 2-4. Weak bases (entries

1-5) clearly were ineffective. Potassium tert-butoxide yielded the greatest conversion.

Addition of 18-crown-6, however, resulted in little recovered starting material or product. Thus, use of the larger potassium counterion favors product formation but complexation of the potassium tends to produce side products (e.g. loss of starting material without formation

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Table 2-4. Variation of Base

CN CN CN CN CN

Br

CN CN CN CN CN

10 22

pKa (DMSO) = 13.6

24

pKa (DMSO) = 13.2

Yield % ofa

Entry NB Page # Base Recovered 22 24

1 GM-I-61 CsF 93 4

2 GM-I-29 NEt3 100 ndb

3 GM-I-31 Pyridine 97 ndb

4 GM-I-61 Ph2NH 98 1

5 WJB-V-4 Cs2CO3 87 8

6 GM-I-35 NaOMe 47 22

7 GM-I-50 Na-OiPr 53 1

8 GM-I-74 Li-OtBu 100 ndb

9 WJB-V-6 Na-OtBu 74 26

10 WJB-V-2 K-OtBu 15 62

11 MCB-III-53 K-O_18-crown-6tBu/0.1 eq. 3 37

Conditions: 0.3M in THF, 1.2 eq. 10, 3.2 eq. Base, 0.1 eq. Pd(OAc)2, 0.2 eq. BINAP,

130°C, µW, 100W, 5 m. aValues obtained from HPLC with an estimated error of ± 5%.

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2.2.2.5 Variation of solvent / base combinations

As this reaction generates anions that must transmetallate to palladium, and as metalated

nitriles form both complex aggregates with counterions28 and also complex to palladium,7 the choice of counterion and solvent is likely to have a large influence on the efficiency of this reaction. Thus, several solvents were explored for further optimization of the coupling. The

results are presented in Table 2-5. The best conditions found in Section 2.2.2.4 are

reproduced as Entry 1. Inoh et al. used Cs2CO3/DMF to deprotonate p-nitro toluenes (pKa of

20.4 in DMSO),29 yet entries 2 and 3 in Table 2-5 indicate poor conversion and loss of

starting material when DMF was used. When molecule 24 was heated in DMF briefly,

decomposition was observed indicating that DMF is not a suitable solvent for this reaction.

N-Methylpyrrolidone (NMP) was tried as an alternative polar, aprotic solvent (Table 2-5,

entry 4). The desired product was obtained in 20% yield with no starting material recovered.

However, when mixed NMP/THF was used (Table 2-5, entries 5-9), excellent results were

obtained. In 90/10 THF/NMP in the presence of 0.1 eq. 18-crown-6, an 83% yield of product was obtained. Note that, in the presence of NMP, 18-crown-6 increased the reaction yield.

This behavior was not the case in pure THF. In addition, use of aryl iodide 23 as the

electrophile yielded less than optimal results. This is in sharp contrast to the notion that aryl

iodides are better electrophilic partners under palladium mediated catalysis. Use of molecule

21 as the electrophile illustrated that solubility of (di)anion 25 has little effect on the yield

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Scheme 2-9.

CN CN CN CN CN

Br

CN CN CN CN CN

C6H13

21 10 25

K-OtBu, Pd(OAc)₂, BINAP

THF/NMP (90/10), µW 100W, 5 m, 62%

To test the efficiency of a milder base in this solvent system (Table 2-5, entries 10-13),

several other, weaker bases than K-OtBu were explored. The moderate conversion to molecule 24 using potassium hydroxide (KOH) (Table 2-5, entry 10), indicates that KOH

was strong enough for deprotonation, but this base was not efficient. It was suspected that

the formation of water upon the protonation of hydroxide anion might be hindering the further formation of product by inactivating the palladium. To test the effect of water on the yield, reactions containing 0.22, 0.44, and 1.1 equivalents of water were run. Yields were

found to change minimally from 71 % to 77% when 0.22 eq. were added and 77% to 71% when 0.44 equivalents were added, but decreased dramatically from 71% to 39% when 1.1

eq. were added. Carbonate bases were also explored but gave poor yields. The slightly less basic potassium methoxide and potassium iso-propoxide gave no advantage in yield. Furthermore, addition of tert-butyl alcohol (as a buffer) systematically decreased the yield of

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Table 2-5. Variation of solvent and then further variation of base.

Yield % ofa Entry NB Page # Solvent Ratio Base Recovered 22 24

1 WJB-V-2 THF -- K-OtBu 15 62

2 WJB-V-33 DMF -- K-OtBu 14 31

3 GM-I-6 DMF -- Cs2CO3 28 26

4 GM-I-42 NMP -- K-OtBu ndb 20

5 GM-I-30 THF/NMP 90/10 K-OtBu 5 71

6 WJB-V-17 THF/NMP 85/15 K-OtBu 24 65

7 WBJ-V-16 THF/NMP 80/20 K-OtBu ndb 71

8 WJB-V-11 THF/NMP 50/50 K- OtBu ndb 49

9 WJB-V-21 THF/NMP 90/10 K-Oeq. tBu+ 0.1 18-crown-6

ndb₈₃

10 MCB-I-14 THF/NMP 90/10 KOH 84 18

11 GM-I-65 THF/NMP 90/10 Cs2CO3 64 9

12 MCB-III-52 THF/NMP 90/10 K2CO3 93 1

13

MCB-III-51

THF/NMP 90/10

K2CO3 + 0.1

eq.

18-crown-6 94 10

14 MCB-III-91 THF/NMP 90/10 KOCH3 4 47

15 MCB-III-92 THF/NMP 90/10 KOiPr 76 16

16 GM-I-51 THF/HOtBu 75/25 K-OtBu 6 ₇₅

Conditions: 1.2 eq. 10, 3.2 eq. Base, 0.1 eq. Pd(OAc)2, 0.2 eq. BINAP, 130°C, µW, 100W,

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2.2.2.6 Effect of supporting ligand

Additional monodentate and bidentate phosphine ligands were tested for coupling

efficiency as shown in Table 2-6. The bidentate bis-diphenylphosphinoferrocene (dppf) was

used both in the presence and absence of 18-crown-6 (entries 2 and 3 respectively). A slight increase in yield was observed in the absence of 18-crown-6, so subsequent reactions were

run without this additive. Use of the bidentate diphenylphosphinobutane (dppb) and bis-diphenylphosphinoethane (dppe) resulted in similar yields (entries 4 and 5). Three

monodentate ligands were then explored (entries 6, 7, and 8). Tri-cyclohexylphosphine (P(Cy)3) provided the best results. The comparably poor result obtained with P(tBu)3