Structural Effects on Encapsulation as Probed in Solution - Based and Surface - Confined Redox - Active Core Dendrimers

Abstract

Chasse, Tyson Lee. Structural Effects on Encapsulation as Probed in Solution - Based and

Surface - Confined Redox-Active Core Dendrimers. (Advised by Professor Christopher B.

Gorman)

The purpose of this research was to study structure – property relationships of iron sulfur

core [Fe4S4(S-Dend)4]2- dendrimers. Previous studies have demonstrated that biasing dendrimer architecture increases the effective encapsulation of redox-active, paramagnetic,

Fe4S4 clusters. To further examine structure-property relationships of iron-sulfur core

dendrimers, studies were carried out to 1) probe the relationship between dendritic

architecture and encapsulation via the study of solution-based and surface-confined

constitutional isomers differing only in their benzyl substitution patterns, and 2) studying the

effects of counterion concentration and permeability on the electronic properties of

iron-sulfur core dendrimer thin films.

Three pairs of isomeric, iron-sulfur core dendrimers were synthesized. Each isomer pair was

distinguished by a 3,5-aromatic substitution pattern (extended) versus 2,6-aromatic

substitution pattern (backfolded). Several observations were made supporting the hypothesis

that the iron-sulfur cluster cores were encapsulated more effectively in the backfolded

microenvironment. Furthermore, heterogeneous electron-transfer rates for the backfolded

molecules were attenuated compared to the extended molecules. From diffusion

measurements obtained by pulsed field gradient spin-echo NMR and chronoamperometry,

the backfolded dendrimers were found to be smaller than the extended dendrimers.

Comparison of longitudinal proton relaxation (T1) values also indicated a smaller, more

compact dendrimer conformation for the backfolded architectures. These findings indicated

that dendrimer size was not the major factor in determining electron-transfer rate. Instead,

the effective electron-transfer distance, determined by the relative core position and mobility,

is most relevant for encapsulation.

In addition to solution studies, the electrochemical behavior of thin films composed of

redox-active, iron-sulfur core dendrimers were studied as a function of the type of counterion

available during reduction and re-oxidation. The rate of permeation/migration of counterions

into the film appeared to be the bottleneck to electron transfer through the film. As the

dendrimer is essentially non-polar, decreasing the relative polarity of the counterion

Biography

Acknowledgements

First and foremost, I would like to acknowledge my family and friends. It was the

friendships, love and guidance that you gave me throughout my life that has helped me get

where I am today. You have all touched my life in some way and I am a better person for

having had all of you in my life. Unfortunately, I can’t include everyone, but there are a few

who deserve a special thank you.

My friends that I met here at NC State were directly proportional to my sanity throughout

graduate school. They were always there to talk, whether it was science related or not, and

made life more enjoyable. The Saturday morning football crew was my first social

interaction and turned out to be where I met a lot of my good friends. Scot Bodnar and I

were true “Hall Ball” competitors and helped relieve the stress of chemistry and research. I

achieved a new level of witty banter that I never thought possible from daily conversations

with Ryan Fuierer. Finally, a thanks to my lab mate in Chris Cameron for our debates about

sports and science.

I truly have been blessed to find a best friend in Marcie Tinkham, who I was lucky enough to

marry. Her support and patience has been more than I ever thought possible. My education

and future has not come without sacrifices along the way, but Marcie never looked back on

indebted to her. I love you and I thank you for always being there for me as a wife and as a

friend.

My grandparents will always have a special place in my heart. They were a large part of my

childhood and taught me life lessons that I will always live by. Their love and support has

been incredible even though my future has taken me 1,000 miles away from them. It was

difficult moving away, but I always knew that they were happy and proud of me no matter

where I ended up.

Last but definitely not least, my parents. My father passed away when I was young but not

before he instilled in me the importance of being a great person. His attention to detail taught

me to put forth my best effort into everything I do. This was a great lesson not only in my

science career, but in my daily life. I was fortunate enough to have a stepfather in William

Allen. He was not only a father figure to me but also a great friend. He has really defined

the meaning of perseverance by earning a B.S. degree while working a full time job and still

being a wonderful family man. And finally, I would like to thank my mom. I have the

utmost respect for her and her ability to be a single parent and continuously steer me in the

right direction. She always wanted the best for and from me. Her love and support has

shaped me into the man I am today. Without her guidance, I can be sure that you would not

I acknowledge Dr. Chris Gorman for many lessons learned about being a professional as well

as a scientist. His guidance throughout my graduate career has been extremely helpful.

From multiple chats about research and science, to discussions about Maine and “lobstah’s,”

he has been not only an advisor but also a colleague. He has had a great influence on my

Table of Contents

LIST OF FIGURES

LIST OF TABLES

LIST OF SCHEMES

1. DENDRITIC ENCAPSULATION: AN ELECTRONIC

PROPERTIES PERSPECTIVE

1.1 ORIGIN OF DENDRIMERS

1.2 DENDRIMER SYNTHESIS: CONVERGENT VS. DIVERGENT 1.3 DENDRIMER ENCAPSULATION

1.3.1. DETECTION OF ENCAPSULATION: PHOTOPHYSICAL PROPERTIES

1.3.2. DETECTION OF ENCAPSULATION: ELECTROCHEMICAL PROPERTIES

1.4 DENDRIMER APPLICATIONS 1.4.1. ELECTRONIC MATERIALS 1.4.2. BIOLOGICAL MODELS

1.5 IRON-SULFUR (FE4S4) CORE DENDRIMERS

1.6 PERSPECTIVES OF DISSERTATION RESEARCH 1.7 REFERENCES

2. SYNTHESIS AND CHARACTERIZATION OF

CONSTITUTIONAL ISOMERS OF BENZYL-ETHER

IRON-SULFUR CORE DENDRIMERS

2.1 INTRODUCTION

2.2 RESULTS AND DISCUSSION

2.2.1. GENERAL SYNTHETIC METHODS 2.2.1.1. General Method for Halogenation

General Method for Chlorination (SOCl2)

General Method for Chlorination (CCl4/PPh3)

General Method for Bromination (CBr4/PPh3)

General Method for Bromination (PBr3)

2.2.1.2. General Method for Coupling Reaction

2.2.1.4. General Method for Deprotection 2.2.1.5. General Method for Ligand Exchange 2.3 EXPERIMENTAL COMPOUND DATA

2.4 REFERENCES

3. ELUCIDATION OF PHYSICAL PROPERTIES OF

CONSTITUTIONAL ISOMER IRON-SULFUR CORE

DENDRIMERS IN SOLUTION

3.1 INTRODUCTION

3.2 RESULTS AND DISCUSSION

3.2.1. DETERMINATION OF THERMODYNAMIC REDOX POTENTIAL AND KINETICS OF HETEROGENEOUS ELECTRON-TRANSFER

3.2.1.1. Cyclic Voltammetry

3.2.1.2. Osteryoung Square Wave Voltammetry

3.2.2. MOLECULAR SIZE AND ITS RELATION TO ELECTRON-TRANSFER RATE

3.2.2.1. Chronoamperometry

3.2.2.2. Pulsed Field Gradient Spin-Echo Nuclear Magnetic Resonance 3.2.3. FURTHER PROBING OF SIZE AND MOBILITY VIA NMR

RELAXATION MEASUREMENTS 3.2 CONCLUSION

3.3 EXPERIMENTAL

3.4.1. DETAILS OF THE ELECTROCHEMICAL ANALYSIS 3.4.1.1. Cyclic Voltammetry

3.4.1.2. Osteryoung Square Wave Voltammetry 3.4.1.3. Chronoamperometry

3.4.1.4. Pulsed Field Gradient Spin-Echo 1H-NMR

3.4.1.5. Inversion Recovery (T1 Relaxation Measurements) 3.4 REFERENCES

4. ELUCIDATION OF REDOX-PROPERTIES OF

CONSTITUTIONAL ISOMER IRON-SULFUR CORE

DENDRIMER THIN FILMS

4.1 INTRODUCTION

4.2 RESULTS AND DISCUSSION 4.2.1. THIN FILM PREPARATION

4.2.2. THIN FILM VS. SOLUTION COMPARISON

4.2.3. BACKFOLDED VS. EXTENDED THIN FILM COMPARISON 4.2.4. DETERMINATION OF KINETIC PROPERTIES

4.3 EXPERIMENTAL

4.3.1. MATERIALS/CHEMICALS

4.3.2. PREPARATION OF FILMS AND ELECTRODES 4.3.3. ELECTROCHEMICAL ANALYSIS

4.3.3.1. Apparatus

4.3.3.2. Electroanalysis of Films 4.4 REFERENCES

5. THE EFFECTS OF COUNTERION ON THE RATE OF

ELECTRON TRANSFER IN DENDRIMER THIN FILMS

5.1 INTRODUCTION

5.2 RESULTS AND DISCUSSION

5.2.1. SYSTEMATIC COUNTERION STUDY 5.2.1.1. Excluding Electrolyte Pre-Soak 5.2.1.2. Including Electrolyte Pre-Soak

5.2.2. ELECTROLYTE IONIC STRENGTH EFFECTS 5.3 CONCLUSION

5.4 EXPERIMENTAL

5.4.1. MATERIALS/CHEMICALS

5.4.2. PREPARATION OF FILMS AND ELECTRODES 5.4.3. ELECTROCHEMICAL ANALYSIS

5.4.3.1. Apparatus 5.4.3.2. Film Thickness

5.4.3.3. Electroanalysis of Films 5.5 REFERENCES

List of Figures

CHAPTER 1

FIGURE 1.1 ILLUSTRATION OF DENDRIMER PRIMARY STRUCTURE. COMPONENTS ARE SHOWN WITH PROPER RELATIVE

ARRANGEMENT AND ORIENTATION

FIGURE 1.2 DIVERGENT (LEFT) AND CONVERGENT (RIGHT)

DENDRIMER SYNTHETIC SCHEMATICS. GRAPHIC FROM FRECHET ET AL

FIGURE 1.3 ILLUSTRATION OF ELECTRON TRANSFER BETWEEN REDOX ACTIVE MOLECULES (LEFT) AND REDOX ACTIVE MOLECULES SURROUNDED (ENCAPSULATED) BY ORGANIC MATERIAL (RIGHT)

FIGURE 1.4 ILLUSTRATION OF THE IDEALOGICAL USE OF DENDRIMERS AS CHARGE TRAPPING UNITS TO CREATE A UNIMOLECULAR

BINARY MEMORY SYSTEM. UNENCAPSULATED REDOX

MOLECULES (LEFT) ALLOW CHARGE TRANSFER BETWEEN SITES, SCRAMBLING INFORMATION, WHILE ENCAPSULATING DENDIMERS TRAP CHARGE CREATING A BINARY SYSTEM OF 0’S (UNCHARGED) AND 1’S (CHARGED)

FIGURE 1.5 GENERATIONS 0-4 OF “FLEXIBLE”

4,4’-BIS(HYDROXYPHENYL)PENTANOL REPEAT UNIT DENDRIMERS (G0 – G4 FLEX)

FIGURE 1.6 GENERATIONS 0-4 OF “RIGID” 3,5-DISUBSTITUTED

GID) PHENYLACETYLENE REPEAT UNIT DENDRIMERS (G0 – G4 RI

FIGURE 1.7 HETEROGENEOUS ELECTRON TRANSFER RATES FOR THE “FLEXIBLE” AND “RIGID” DENDRIMERS PLOTTED AS A FUNCTION OF MOLECULAR WEIGHT

FIGURE 1.8 HETEROGENEOUS ELECTRON TRANSFER RATES FOR THE “FLEXIBLE” AND “RIGID” DENDRIMERS PLOTTED AS A FUNCTION OF THE MOLECULAR RADIUS OF GYRATION

CHAPTER 2

FIGURE 2.1 STRUCTURES OF THE CONSTITUTIONAL ISOMERIC DENDRIMER PAIRS. EACH DENDRIMER HAS THE FORM

(nBu4N)2{Fe4S4D4}, WHERE D INDICATES A DENDRON SUBSTITUTED INITIALLY WITH A FOCAL AROMATIC THIOL. FOR EACH

MOLECULE, FOUR IDENTICAL LIGANDS ARE ATTACHED TO THE IRON-SULFUR CORE (DENOTED BY A CIRCLED D)

CHAPTER 3

FIGURE 3.1 POTENTIAL WAVEFORM OF CYCLIC VOLTAMMETRY (POTENTIAL SWEEP)

FIGURE 3.2 CYCLIC VOLTAMMOGRAMS OF EACH EXTENDED (DOTTED) AND BACKFOLDED (SOLID) DENDRIMER ISOMER PAIR (1 mM

DENDRIMER, 100 mM TEAF IN DMF, SCAN RATE OF 50 mV/S)

FIGURE 3.3 PLOTS DISPLAYING LINEAR BEHAVIOR OF CURRENT VERSUS THE SQUARE ROOT OF SCAN RATE. THIS LINEAR RELATIONSHIP INDICATES A FREELY DIFFUSING SPECIES

FIGURE 3.4 WORKING CURVE SHOWING VARIATION OF PEAK POTENTIAL SEPARATION VERSUS Ψ

FIGURE 3.5 POTENTIAL WAVEFORM OF OSTERYOUNG SQUARE WAVE VOLTAMMETRY (POTENTIAL STEP)

FIGURE 3.6 POTENTIAL WAVEFORM OF CHRONOAMPEROMETRY (POTENTIAL PULSE)

FIGURE 3.7 ILLUSTRATION OF PFGSE 1_{H-NMR. THE ILLUSTRATION ON} THE LEFT DEMONSTRATES THE MAGNETIC FIELD GRADIENT. THE EFFECT OF THIS GRADIENT IS SHOWN ON THE RIGHT AS

DIFFERENCES IN THE MAGNETIC SPIN VECTOR OF MOLECULES IN VARIOUS LOCATIONS WITHIN THE FIELD GRADIENT

FIGURE 3.8 CARTOON ILLUSTRATING THE ROLE OF CORE MOBILITY AND MOLECULAR SIZE ON THE EFFECTIVE ELECTRON-TRANSFER DISTANCE

FIGURE 3.10 A TYPICAL INVERSION RECOVERY EXPERIMENT SHOWING 1_{H-NMR SPECTRA AT MULTIPLE τD}

FIGURE 3.11 BAR GRAPH INDICATING THE RELATIVE T1 VALUES OF TERMINAL AROMATIC PROTONS MEASURED FOR EACH

DENDRIMER (0.1 mM DMF SOLUTION)

FIGURE 3.12 CYCLIC VOLTAMMOGRAMS OF ALL DENDRIMERS AT MULTIPLE SCAN RATES

FIGURE 3.13 OSTERYOUNG SQUARE WAVE VOLTAMMOGRAMS OF ALL DENDRIMERS AT MULTIPLE SCAN RATES

FIGURE 3.14 NMR SPECTRA OF 2B,2B DENDRIMER AT MULTIPLE GRADIENT PULSE STRENGTHS (0.1 mM DENDRIMER IN D7-DMF). GRADIENT STRENGTHS (G/CM) FROM FRONT TO BACK 1.59, 7.95, 14.3, 20.7, 27.0, 33.4, 39.75, AND 47.2 (δ = 5 mS)

CHAPTER 4

FIGURE 4.1 CYCLIC VOLTAMMOGRAMS OF EACH CONSTITUTIONAL ISOMER AS A THIN FILM (DOTTED) AND IN SOLUTION (SOLID). (FILMS – 100 mM TEAPF6 IN 80:20 PROPYLENE GLYCOL/PROPYLENE CARBONATE, SCAN RATE OF 50 mV/S, VS. FC/FC+ EXTERNAL

STANDARD. SOLUTION – 1 mM DENDRIMER, 100 mM TEAF IN DMF, SCAN RATE OF 50 mV/S VS. FC/FC+ EXTERNAL STANDARD)

FIGURE 4.2 CYCLIC VOLTAMMOGRAMS OF EXTENDED (DOTTED) AND BACKFOLDED (SOLID) CONSTITUTIONAL ISOMERS AS THIN FILMS (100 mM TEAPF6 IN 80:20 PROPYLENE GLYCOL/PROPYLENE

CARBONATE, SCAN RATE OF 20 mV/S, VS. FC/FC+ EXTERNAL STANDARD)

FIGURE 4.3 SCHEMATIC OF THE THIN FILM DEPOSTION PROTOCAL. A 5 µL DROPLET WAS PRODUCED AT THE END OF A SYRINGE (LEFT), THE DROP WAS PLACED ON THE PT SURFACE (MIDDLE) AND ALLOWED TO DRY, UNDISTRUBED, TO CREATE A UNIFORM FILM ON THE PT BUTTON SURFACE (RIGHT)

FIGURE 4.4 CYCLIC VOLTAMMOGRAMS OF EXCESSIVELY THIN (TOP) AND THICK (BOTTOM) CONSTITUTIONAL ISOMER FILMS

FIGURE 4.5 CYCLIC VOLTAMMOGRAMS OF DENDRIMER THIN FILMS DEPOSITED FROM DENDRIMER/THF SOLUTION CONCENTRATIONS OF 500 µM, 1 mM AND 2 mM

FIGURE 4.6 CYCLIC VOLTAMMOGRAMS OF DENDRIMER THIN FILMS DEPOSITED FROM A 2 mM DENDRIMER/THF SOLUTION OF 1, 2 AND 5

– 5 µL DROP QUANTITIES

CHAPTER 5

FIGURE 5.1 STRUCTURE OF THE GENERATION 3, IRON-SULFUR

REPRESENT ADDITONAL ARMS IDENTICAL TO THE ONE SHOWN CLUSTER CORE DENDRIMER (G3 FLEX). THE CIRCLED – D’S

FIGURE 5.2 CYCLIC VOLTAMMOGRAMS OF DENDRIMER FILMS AS (A) THE COUNTER CATION WAS VARIED FROM TMA Æ TOA PF6 AND (B) THE COUNTER CAION WAS VARIED FROM TOA Æ TMA PF . SCAN RATE = 20 mV/S, PROPYLENE CARBONATE/100 mM SUPPORTING ELECTROLYTE, 10 mM AgNO3/100 mM TETRABUTYLAMMONIUM HEXAFLUOROPHOSPHATE IN MeCN REFERENCE ELECTRODE

6

FIGURE 5.3 VARIATION IN MEASURED REDOX POTENTIAL VERSUS RELATIVE DEBYE LENGTH FOR THREE OF THE FOUR

ELECTROLYTE SALTS STUDIED. THE SOLUBILITY OF TMAPF6 WAS INSUFFICIENT FOR THIS VARIATION

FIGURE 5.4 A TIME AVERAGED ILLUSTRATION OF THE IONIC

ATMOSPHERE AROUND A POSITIVELY (LEFT) AND NEGATIVELY (RIGHT) CHARGED ION

FIGURE 5.5 ILLUSTRATION OF THE RELATIONSHIP BETWEEN SIZE OF THE IONIC ATMOSPHERES OF A M+X- ELECTROLYTE AND LOW (LEFT) AND HIGH (RIGHT) IONIC STRENGTH

List of Tables

CHAPTER 3

TABLE 3-1. HETEROGENEOUS ELECTRON-TRANSFER RATE (kO), REDUCTION POTENTIAL (E1/2), AND TRANSFER COEFFICIENT (α) FOR THE ONE-ELECTRON REDOX COUPLE [Fe4S4(S-DEND)4]

2-/3-TABLE 3-2. DIFFUSION COEFFICIENTS, DO, OBTAINED FROM PULSED FIELD GRADIENT SPIN-ECHO NMR SPECTROSCOPY (PFGSE) AND CHRONOAMPEROMETRY (CA), AND THE CORRESPONDING STOKES-EINSTEIN RADIUS, RH, OF THREE IRON-SULFUR CORE

CONSTITUTIONAL ISOMER PAIRS

CHAPTER 4

TABLE 4-1. REDOX POTENTIAL FOR THE ONE-ELECTRON REDOX

COUPLE [Fe4S4(S-DEND)4]2-/3- IN SOLUTION AND DROP COATED AS A THIN FILM AND THE CORRESPONDING MOLECULAR WEIGHTS FOR IRON-SULFUR CORE G2 – G4 FLEX AND THREE PAIRS OF

CONSTITUTIONAL ISOMER DENDRIMERS

CHAPTER 5

TABLE 5-1. KINETIC PARAMETERS AND REDOX POTENTIAL IN VARIOUS HEXAFLUOROPHOPHATE SUPPORTING ELECTROLYTES OF G3 FLEX DENDRIMER THIN – FILMS

TABLE 5-2. KINETIC PARAMETERS OF G3 FLEX DENDRIMER THIN FILMS AFTER A 15 MINUTE PRE-SOAK IN VARIOUS

HEXAFLUOROPHOSPHATE SUPPORTING ELECTROLYTES

TABLE 5-3. DATA CALCULATIONS OF THIN FILM PROPERTEIS OF G3 FLEXIBLE IRON-SULFUR CORE DENDRIMERS DROP-COATED ON PLATINUM

64

75

100

120

122

List of Schemes

CHAPTER 2

SCHEME 2.1 SYNTHETIC SCHEME FOR 2,3 EXTENDED AND BACKFOLDED DENDRITIC ARCHITECTURES

SCHEME 2.2 SYNTHETIC SCHEME FOR 3,2 EXTENDED AND BACKFOLDED DENDRITIC ARCHITECTURES

SCHEME 2.3 SYNTHETIC SCHEME FOR 2,2 BACKFOLDED DENDRITIC ARCHITECTURE

SCHEME 2.4 SYNTHETIC SCHEME FOR THE

PROTECTION/DEPROTECTION OF THE DENDRITIC AROMATIC THIOL FOCAL UNITS

SCHEME 2.5 SYNTHETIC SCHEME FOR DENDRITIC LIGAND EXCHANGE WITH A Fe4S4 CLUSTER

35

36

36

37

Chapter 1

1.1 Origin of Dendrimers

Dendrimer chemistry began nearly two decades ago with the synthesis and characterization

of a family of highly branched macromolecules.1,2 The general dendrimer structure consisted

of an inner core molecule with hyperbranched polymeric structures, known as dendrons,

extending outward from the core. Each dendritic branch was terminated with a chosen

periphery structure (Figure 1.1). The ability to synthesize well-defined monodisperse

macromolecules using repetitive activate/couple growth cycles added a new dimension to

polymer chemistry.

Core (with intrinsic measurable properties)

Dendrons

(hyperbranched

attached to core)

Periphery

groups of the dendrons) (terminal

organic material

1.2 Dendrimer Synthesis: Convergent vs. Divergent

The development of new synthetic schemes enabled manipulation of the structure of

dendrimers. One scheme, the divergent strategy, consisted of an interactive synthesis

originating with the core and adding repeat units in an outward fashion (Figure 1.2).3 A

nearly monodisperse macromolecule with high molecular weights could be synthesized

through repetitive deprotection and coupling reactions.1 The disadvantage of the divergent

synthesis was the large excess of reagents required due to the large number of reactive sites.

To eliminate this problem, a convergent strategy for the synthesis of dendrimers was

developed. This strategy originates with the peripheral units and uses the same iterative

deprotection and coupling scheme to construct the dendritic branches inward (Figure 1.2).

Each coupling cycle designates a new layer of branch points referred to as a generation. The

dendritic arms are ultimately terminated with a linking unit that is used for core attachment.4

Monodispersity becomes a problem at high molecular weights therefore, the convergent

1.3 Dendrimer Encapsulation

It is known that the primary structure of the dendrons can be used to bias the conformation to

achieve general structures and shapes.6-15 These structures are governed by many factors

including solvation, sterics, hydrogen bonding, stereocenters, and benzyl substitution

patterns.16-27 Dendrimer structure is of significant interest due to the ability to encapsulate

core moieties at a sufficient size. The ability to effectively encapsulate the functional core is

interesting due to the possibility of revealing unique and potentially useful properties.3

1.3.1. Detection of Encapsulation: Photophysical Properties

The observation of photophysical changes were the first evidence of encapsulation behavior

of dendrimers.28-33 Hawker et al. coupled Frechet-type dendrons to a

4-(N-methylamino)-1-nitrobenzene core and observed an increase in the solvatochromic shift in the absorption

spectra as the dendrimer generation increased.28 The results indicated the larger generation

dendrimers effectively shielded solvent and created an intrinsic microenvironment around the

core. Additional techniques to further elucidate structure-property relationships of

dendrimers include fluorescence quenching,34-36 luminescence,37 and electrochemistry.36,38-46

1.3.2. Detection of Encapsulation: Electrochemical Properties

Dendrimers are attractive candidate molecules for studying electron transfer based solely on

the intrinsic ability of the dendrons (for a given molecular weight) to effectively shield the

core with organic material. The distance of electron travel and the material surrounding the

increasing the bulk material of the dendrons around the redox-active core, and/or 2) alter the

dendritic architecture to create a dynamic conformational change of the dendrimer. Both

strategies would result in an increase in the effective encapsulation and, subsequently, the

distance of electron transfer to the redox active core.

e - e -

e -

electrode electrode

e -

Redox-active Core Dendron Encapsulated Redox-active Core

Figure 1.3 Illustration of electron transfer between redox active molecules (left) and redox active molecules surrounded (encapsulated) by organic material (right).

Dendritic encapsulation has also been studied via changes in the kinetic and thermodynamic

properties of redox-active core dendrimers.6-8,16-19,36,37,39,41,46-64 Kinetic effects are manifested

as changes in the heterogeneous electron transfer rate, while thermodynamic changes become

apparent through shifts in redox potential. The attenuation of heterogeneous electron transfer

rates has been studied thoroughly, resulting in the further understanding of effective

encapsulation of redox active core moieties.6-8,16-19,36,39,41,46-61 In contrast, thermodynamics

potential shifts relate to structure-property relationships of redox-active dendrimers.

8,37,46,51,61-64

Research on electroactive dendrimers was introduced by Diederich and coworkers, who

studied the electron transfer kinetics of Zn-porphyrin core dendrimers encapsulated with

ethylene glycol terminated dendrons as a function of generation.46 As expected, the higher

generation molecules attenuated electron transfer more efficiently, displaying effective

encapsulation of the electroactive core. A decrease in electrochemical reversibility was also

seen by Frechet et al. with Zn-porphyrin cores surrounded by benzyl ether functionalities.36

In addition to porphyrin dendrimers, other types of dendrimers have displayed similar

electrochemical behavior during encapsulation studies.41

Kaifer, and matching work by Balzani, recently showed inconsistency with the general trend

of electron transfer attenuation with increasing generation.58,59 The molecules studied were

4,4’-bipyridinium core dendrimers containing Frechet-type benzyl-ether dendrons. Cyclic

voltammetry was used to measure the electron transfer kinetics using the Nicholson

analysis.65 It was shown that as dendrimer generation increased, the electron transfer kinetics

remained unchanged. This observation was contrary to all previous electronic studies of

redox-active dendrimer studies. However, a possible explanation is that due to the low

number of dendritic arms and therefore, low dendritic mass, effective encapsulation of the

bipyridine core dendrimers, including larger generation dendrons must be completed to fully

understand the observed results.

In addition to increasing mass, attempts have been made to elucidate structure-property

relationships by controlling the primary structure of the dendrons and studying the effects on

the overall conformation (shape) of the macromolecule.6-8,16-19,36,47,48,54-56 The introduction of

functional groups to achieve hydrogen bonding effects have been used previously to bias

dendron architecture.18,19 Synthetic attempts at restricting the intrinsic flexibility of these

macromolecules using chiral structures and acetylene units have been successful.17,47,48,54,55

Control of the primary architecture containing redox-active core moieties has been

studied.39,47,49-51,60,61 This research has shown the ability to change and control the primary

structure of the dendrimer. Biasing the dendritic architecture allows for the manipulation of

the molecule to further understand the factors governing the electronic property changes of

the redox-active core. Newkome and coworkers first synthesized asymmetrical Ruthenium

bis-terpyridine complexes39 _{and used cyclic voltammetry to probe the reversibility of the}

redox reaction demonstrating an attenuation of the electron transfer rate. Chow et al. further

supported these finding on symmetric and asymmetric Ru-bis-terpy complexed dendrimers

from generations 1-3.49

The overall size of the dendrimer, the orientation of the branches, and the organic material of

coworkers explored the electrochemical behavior of asymmetric ferrocene core dendrimers.61

They found that encapsulation increased as generation increased, illustrated by a decrease in

the heterogeneous electron transfer rate to/from the electrode. They hypothesized that the

dendritic arm was flexible enough to backfold and effectively shield the ferrocene core.

Other encapsulation studies were completed with the asymmetric molecules including β

-cyclodextrin capping of the ferrocene units,51 and the use of charged peripheral groups to

orient the molecules at the electrode surface.60 Both experiments probed the manipulation of

dendritic material to effectively shield the core.

1.4 Dendrimer Applications

1.4.1. Electronic Materials

The ultimate goal of creating a molecule that could be synthesized to electronically trap and

accomplish electron trapping and potential unimolecular memory storage device applications.

Ideally, dendrimers tethered to a surface would encapsulate charge preventing “leaking” of

release this charge from molecule to molecule (Figure 1.4). This system could translate into

a binary representation where the charged molecules would represent ‘1s’ and a neutral

molecules, charge is intriguing. The encapsulating ability of dendrimers is desirable to ‘0s’.

Unimolecular storage would eliminate problems with mechanical scale down approaches,

which are approaching the lower limits of fabrication. Molecular devices would increase

memory storage capacities (per given area) well into the tera-byte realm versus the giga-byte

“0” “1”

Encapsulating Dendrimer Redox-active Molecule

“0” “1”

0 -1

0 -1

X

Figure 1.4 Illustration of the ideological use of dendrimers as charge trapping units to create a unimolecular binary memory system. Unencapsulated redox molecules (left) allow charge transfer between sites, scrambling information, while encapsulating dendrimers trap charge creating a binary system of 0’s (uncharged) and 1’s (charged).

1.4.2. Biological Models

Dendrimer interest spans not only within the area of molecular electronics, but also in the

biological model complexes where their function is governed by electron transfer.3,51,63 The

intrinsic ability of dendrimers to encapsulate and provide unique synthetic control creates an

ideal molecular model for determining the structure property relationships responsible for

tuning the electronic properties of biological molecules. Structural elements can be included

specifically to create structural facility that is unlike other attempts at creating protein mimics

and models.66-81 These attempts include mutant proteins68-73 and small molecule models.74-81

In all cases, problems surfaced when attempts were made to determine their

structure-property relationships. For mutants, determination of true structure and behavior can be

challenging,73 while small molecule models do not contain the steric protection required to

encapsulate and, ultimately, alter solvation of the functional moiety.76

1.5 Iron-Sulfur (Fe

S

) Core Dendrimers

Iron-sulfur clusters are particularly interesting redox centers due to their sensitivity to

changes of their surrounding environment. These changes can be detected by multiple

techniques including electrochemistry and nuclear magnetic resonance. Understanding how

dendritic structure and structural elements of the dendrimer affects the intrinsic, measurable

properties of the core, allows us to probe structure-property relationships of these molecules.

Elucidating structure-property relationships allows for the determination of the structural

Our interest in iron-sulfur clusters stem from their ubiquitous appearance in many biological

proteins. Iron-sulfur proteins are necessary for the execution of many life processes

including electron transfer across membranes82,83 and metabolic and enzymatic processes.84-86

Understanding the role of iron-sulfur clusters within biological proteins, may assist in

identifying the role of electron transfer as it relates to these life processes. More specifically,

understanding the structure-property relationships which govern/tune redox potential in

iron-sulfur proteins may provide insight of protein function and its’ relation to aging,87 disease,

87-89 _{and disorders.}90_.

Factors governing redox potential in iron-sulfur proteins have been discussed previously.

91-102 _{More specifically, considerable effort probing the effects of steric shielding,}93,95-100

adjacent hydrogen bonding functionalities94,101,102 and solvation91,92 on redox behavior has

been attempted. However, these efforts via biological models/mimics, have encountered

many challenges.66,67,73,76,101,103

Holm et al. initiated the first studies of synthetic iron-sulfur cluster models to probe structural

effects governing redox potential.104-109 Their focus began with the successful synthesis of

iron-sulfur clusters (Fe4S4) outside of a protein environment. They discovered iron-sulfur

clusters were susceptible to facile ligand exchange with aromatic thiol terminated

ligands.74,110-112 Synthesis via ligand exchange created a rapid and selective synthetic route

for the construction of Fe4S4 molecular motifs. This facile synthesis was the impetus leading

have hypothesized that iron-sulfur core dendrimers contain the structural capability to control

the sulfur cluster microenvironment. To this end, our work focuses on the use of

iron-sulfur core dendrimers as a model to determine the factors governing the redox properties of

iron-sulfur clusters.

Our group has recently probed the effects of generation and dendritic architecture on the

kinetics of heterogeneous electron transfer.47 Iron-sulfur core dendrimers containing

“flexible” 4,4-bis(hydroxyphenyl)pentanol dendritic architectures, introduced by Frechet,

were directly compared to a “rigid” architecture containing phenylacetylene units (Figure

1.5, 1.6).52,53 Chronoamperometry, cyclic voltammetry, and Osteryoung square wave

voltammetry were used to find the diffusion coefficient, redox potential, and electron transfer

Figure 1.5 Generations 0-4 of “flexible” 4,4’-bis(hydroxyphenyl)pentanol repeat unit dendrimers (G0 - G4

Figure 1.6 Generations 0-4 of “rigid” 3,5-disubstituted phenylacetylene repeat unit dendrimers (G0 – G4

Rigid). Graphic from Gorman et al.47

Results showed, as expected, that electron transfer rate attenuation occurred as the generation

increased for both types of dendrimers. Figure 1.7 displays electron transfer versus

molecular weight clearly indicating a greater attenuation for the phenylacetylene structure

the “rigid” architecture effectively encapsulated the core more efficiently than the “flexible”

architecture. This observation was intuitive since the phenylacetylene architecture allowed

for very little flexibility and was conformationally biased in which all branches were

extended, increasing the distance between the electrode surface and the iron-sulfur core.

Conversely, the comparison of electron transfer versus the apparent radius of the dendrimer

revealed an interesting anomaly (Figure 1.8). The transfer of electrons through the “rigid”

architecture versus the “flexible” was, in fact, more facile as a function of size. It was

hypothesized that even though the cross-conjugated phenylacetylene branches were effective

in shielding the core from the electrode surface, the large number of π-bonds actually acted

as a pathway for through bond electron tunneling resulting in a nanowire effect. This

observation indicates that electron transfer is not only a distance phenomenon, but can be

Figure 1.7 Heterogeneous electron transfer rates for the “flexible” and “rigid” dendrimers plotted as a function

Figure 1.8 Heterogeneous electron transfer rates for the “flexible” and “rigid” dendrimers plotted as a function

of the molecular radius of gyration. Graphic from Gorman et al.47

In addition, to heterogeneous electron transfer kinetics, the thermodynamic redox potentials

have also been noted in the literature.8,37,46,51,61-64 Gorman and Smith hypothesized that redox

potential shifts were controlled by the microenvironment around the redox active core.63 The

microenvironment was defined by the ability of the dendritic material to stabilize/destabilize

the charge associated with the particular redox core. Electronically, changes in the

microenvironment are denoted as relative shifts in the HOMO/LUMO gap resulting in a

change in the energy required to add/remove an electron into/out of the energy levels. In

this hypothesis, however, further research must be done to truly understand how the

HOMO/LUMO gap of the redox-active core can be controlled directly by dendritic structure.

1.6 Perspectives of Dissertation Research

A synthetic scheme has recently been reported using substitution patterns around phenyl

rings to manipulate the dendron structure resulting in a backfolded architecture.16 In this

work, an attempt was made to bias dendrimer conformation into a more backfolded

architecture by way of benzyl ring substitution patterns resulting in a more shape persistent

structure. Chapter 2 reports the synthesis of three constitutional isomer pair dendrimers to

compare extended and backfolded architectures that are independent of molecular weight.

This bias of dendritic architecture was expected to increase encapsulation around an

environmentally sensitive iron-sulfur core, resulting in heterogeneous electron transfer rate

attenuation (Chapter 3). The use of electrochemical techniques on dendrimers containing

redox-active cores have shown to be useful in the attempt to elucidate structure-property

relationships.8,42,47 _{In addition, a change in the dynamic conformation of the dendrimers was}

probed using nuclear magnetic techniques (Chapter 3). The use of NMR to probe dendrimer

structure has been employed previously.47,113

To further understand structure-property relationships governing the electronic behavior of

iron-sulfur clusters, studies were carried out on iron-sulfur core dendrimer thin films.

role in governing the electronic properties of redox-active molecules.114-117 In many cases,

the protein creates an environment where structural material governs the electronic properties

of iron-sulfur core dendrimers due to the exclusion of solvent.118 Therefore, thin films of

iron-sulfur core dendrimers were utilized to create a solvent excluded environment where the

electronic properties and structure-property relationships of iron-sulfur clusters could be

probed (Chapter 4 & 5). In these experiments, dendritic material and counterion migration

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Chapter 2

Synthesis and Characterization of Constitutional Isomers of

Benzyl-Ether Iron-Sulfur Core Dendrimers

The synthetic efforts of Rakesh Sachdeva, Qun Li, and Zemin Li, as well as Randall J. Petrie and his Matrix Assisted Laser Desorption Ionization expertise should not go unmentioned and is gratefully acknowledged here.

2.1 Introduction

A decisive way to probe the influence of structure on encapsulation via conformation is

through the study of constitutional isomers. The synthesis1,2 and study of dendrimer isomers

has had some precedent including the study of linear versus hyperbranched structures,3,4

supramolecular organization of different dendrimer isomers,5 stereoisomers in dendrimers

(e.g. cis vs. trans azobenzene or stilbene linkages in dendrimers)6-13 and isomeric

metallodendrimers.14 Recently, the relative rates of photoinduced, intramolecular electron

transfer of constitutional isomers of a triphenylamine core dendrimer substituted with a

peryleneimide acceptor at the periphery were probed.15

Ideal dendrimer isomers differ only in their primary structure. Changes in the primary

structure of the dendrimer can result in a change in its’ conformation (e.g. the disposition of

the arms around the core and the relative degree to which the core is buried within the

dendrimer). This change in conformation could be reflected in a change in the measured

degree of encapsulation of the core. For example, in the case of an electroactive core (such

as is discussed here), a change in the kinetics and/or thermodynamics of electron transfer

to/from that core is expected.

Several notable efforts have elucidated structure-property relationships by changing the

primary structure of the dendrons to bias dendrimer conformation.1,16-22 _{Conformation can}

internal hydrogen bonding sites,24-27 and steric factors including chiral moieties within the

primary structure.6,28-36

S O O O O O O O O O O O O O O S O O O O O O O O O S

O O _O

O O O O O O O S O O O O O O O O O S O O O O O O O O O S O Fe S S S Fe Fe Fe S

O

O

O

O

3,2 Extended (3,2)

2,2 Extended (2,2)

3,2 Backfolded (3,2B)

2,2 Backfolded (2B,2B)

2,3 Extended (2,3)

Figure 2.1. Structures of the constitutional isomeric dendrimer pairs. Each dendrimer has the form

(nBu4N)2{Fe4S4D4}, where D indicates a dendron substituted initially with a focal aromatic thiol. For each

molecule, four identical ligands are attached to the iron-sulfur core (denoted by a circled D).

We and others29,30,37-43 have hypothesized that primary structural elements that create

around the core moiety of the dendrimer. This behavior should lead to more effective

encapsulation. To probe this hypothesis experimentally, three pairs of constitutional

isomeric dendrimers containing benzyl-ether repeat units (Figure 2.1) were synthesized and

studied. These molecules allow the direct comparison of extended and backfolded

architecture independent of the molecular weight.

2.2. Results and Discussion

2.2.1. General Synthetic Methods

Each dendrimer structure synthesized consisted of benzyl ether-based repeat units previously

Scheme 2.1 Synthetic scheme for 2,3 extended and backfolded dendritic architectures. O O O Cl O O O

O O _{O O}

O X O O O O O O O O X

X=CO₂CH₃

X=CH2Cl

X=CH2OH

X=CH₂OH

X=CH2Br

CH2OH

HO OH

K₂CO₃

Acetone reflux/72hrs

DCM

0o/2hrs

70% 70%

CO₂CH₃

OH HO

LiAlH₄, THF

0o/2hrs

82%

DCM 0o/2hrs

76%

CBr₄, PPh_3,

89%

CCl₄, PPh₃

Scheme 2.2 Synthetic scheme for 3,2 extended and backfolded dendritic architectures.

X=CO2CH3 X=CH2OH

X=CH₂Cl

X=CH₂Br

X O O O O O O O O O X O O O O O O O O O O O O O Cl Br 93% 86%

K₂CO₃

Acetone reflux/72hrs

CO2CH3

HO

OHOH

LiAlH4, THF

0o/2hrs

90%

87%

SOCl2, DCM

Proton Sponge

DCM 0o/2hrs

63%

CBr4, PPh3

70%

0o/2hrs

7 8 9,13 10 14 11 12

Scheme 2.3 Synthetic scheme for 2,2 backfolded dendritic architecture.

X=CO₂CH₃

X=CH2OH X=CH2Br

O O

Br

K₂CO₃ Acetone reflux/72 hrs

LiAlH₄, THF 0o/2 hrs

Et₂O/DCM 0o/30 min

PBr₃ 11 O O O O O O X HO OH

O OCH3

Scheme 2.4 Synthetic scheme for the protection/deprotection of the dendritic aromatic thiol focal units.

3,2-Cl

3,2B-Br

2,3-Cl

2B,3-Br

O

OH S

K₂CO₃ Acetone 72 hrs, reflux

X =

O

O S X =

AgNO₃/aq. THF NaSH/DCM

90 min, rt O S 3

10 14

19 2,3-X 60%

20 2B,3-X 90%

21 3,2-X 75%

22 3,2_B-X 84%

23 2,2-X 67%

24 2B,2B 49%

37

2,2-Br

18

2_B,2_B-Br

17

25 2,3-X 93%

26 2B,3-X 94%

27 3,2-X 88%

28 3,2B-X 91%

29 2,2-X 93%

30 2_B,2_B 87%

6

H

Scheme 2.5 Synthetic scheme for dendritic ligand exchange with a Fe4S4 cluster.

O SH

X = + DMF, 1hr

N2 Fe S S S Fe

FeS Fe

_O

O

O

X =

O

2_B,3-X 25 27 28 2,2-X

30 2_B,2_B-X

29 26 3,2-X 3,2_B-X 2,3-X

{Fe4S4[SC(CH3)3]4}[N((CH2)3CH3)4]2

31 2,3-X 80% 32 2_B,3-X 80% 33 3,2-X 90% 34 3,2_B-X 86% 35 2,2-X 74% 36 2_B,2_B 62%

Each dendrimer was synthesized using a convergent activate/couple approach (Schemes 2.1 –

2.5). The extended and backfolded designations refer to the aromatic substitution patterns of

the benzyl ether groups. Isomers containing 3,5-di-substituted linkages are designated as

It is important to note that significant care had to be taken with all benzyl ether dendrons due

to their susceptibility to acid cleavage of the benzyl ether groups as detailed previously.21,39

Reaction and purification steps had to be carried out in neutral or slightly basic conditions for

these particular compounds.

2.2.1.1. General Method for Halogenation

The halogenation synthetic steps were substitution reactions converting a benzyl alcohol to a

benzyl halide. This reaction was required to activate the dendritic branch for further

coupling with phenol functionalities resulting in subsequent generation increases. Further,

the halogenation of G2 dendrons acts as an activation step prior to coupling with the

dendritic focal unit.

Multiple halogenation schemes were attempted for each dendron. In many cases, however,

only one of the selected halogenation schemes resulted in the desired product. This result

was primarily due to particular dendrons increased susceptibility to hydrolysis from acidic

side products. Solutions included introducing a weak base to neutralize acidic side products

and using different halides (Cl, Br) to exploit differences in reactivity.

Further, the halogenated compounds were carried on immediately without purification. In

multiple instances, halogenated compounds that were allowed to sit for extended periods of

time, degraded rapidly. The degradation was apparent by 1H-NMR and immediately

visualized by a significant color and texture change from a white powder to a dark, red/black

colorless to a deep red. During purification, this band remained stationary and the overall

yield was significantly reduced. All halogenated intermediates were thus carried on without

purification.

General Method for Chlorination (SOCl2)

To a solution of the alcohol (1 equiv) and proton sponge (1.5 equiv) dissolved in methylene

chloride and cooled in an ice bath, was added thionyl chloride (1.1 equiv) dropwise while

stirring. The mixture was allowed to warm to room temperature under continuous stirring.

After 2h, a color change was observed and the mixture was quenched with water. The

organics were extracted with methylene chloride three times. The combined organic extracts

were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.

General Method for Chlorination (CCl4/PPh3)

To a solution of the alcohol (1.0 equiv) at 0oC, tri-phenyl phosphine (1.3 equiv) and carbon

tetra-chloride (3.5 equiv) at 0oC was cannulated dropwise while stirring. The temperature

was allowed to rise to ambient over 2h. The reaction was quenched with water, the organics

were extracted with DCM, washed with saturated NaCl and dried using MgSO4. The mixture

was filtered and concentrated.

General Method for Bromination (CBr4/PPh3)

To a solution of the alcohol (1.0 equiv) and tri-phenyl phosphine (1.1 equiv) in THF or DCM

equiv) in THF or DCM while stirring. The temperature was allowed to rise to ambient over

2h. The reaction was quenched with water and stirred for 2 hours. The organics were

extracted with DCM, washed with saturated NaCl and dried using Na2SO4 or MgSO4. The

mixture was filtered and concentrated.

General Method for Bromination (PBr3)

To a solution of the alcohol (2.7 equiv) in Et2O or THF cooled in an ice bath, was added a

solution of PBr3 (1.0 equiv) in Et2O or THF, dropwise via cannulation while stirring. The

temperature was kept at 0oC for 1 hour. The reaction was warmed to room temperature and

quenched with water. The organics were extracted with ethyl acetate and washed with

saturated sodium bicarbonate and dried using Na2SO4. The mixture was filtered and

concentrated.

2.2.1.2 General Method for Coupling Reaction

To a solution of the phenol derivative (1.0 equiv), dry acetone (50-60 equiv), potassium

carbonate (1.1 equiv per OH in phenol), and 18-crown-6 (0.01-0.02 equiv) was added a

benzyl halide derivative (1.1-1.2 equiv per OH in phenol). The mixture was then refluxed for

2-3 days under nitrogen with vigorous stirring. The mixture was cooled and concentrated to

half the volume. Water was added to dissolve the salts and the organics extracted into ethyl

acetate, methylene chloride, or ether. The organic extract was washed with brine or NaHCO3

under reduced pressure gave the crude product. The individual purification techniques are

shown for each compound in Section 2.3. Experimental/Compound Data.

2.2.1.3. General Method for Reduction

The ester (1.0 equiv) was cannulated into a solution of LiAlH4 (1.3 equiv) in dry THF (21

equiv) cooled in an ice-water bath stirring continuously for 2 hours. The reaction was

quenched with H2O, 15% NaOH, or aqueous NH4Cl. This was followed by addition of 6M

HCl to dissolve the salts. After the reaction was complete (few hours for extended and

overnight for backfolded), the reaction was carefully worked up with water and the solids

filtered by passing through a bed of Celite. The organics were extracted into ethyl acetate or

DCM. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and

placed under vacuum overnight. The crude alcohol was purified as shown in Section 2.3.

Experimental/Compound Data.

2.2.1.4. General Method for Deprotection

Tetrahydropyran (THP) protected thiol 37 (Experimental/Compound Data Section 2.3)(1.0

equiv) was dissolved in tetrahydrofuran. Excess of silver nitrate was added. Water was then

added to the mixture until bright yellow precipitate forms and the solution was stirred for 20

min. The mixture was diluted ten-fold with DCM. NaSH (solid, 10 equiv) was added and

stirred vigorously for thirty minutes. The result was a black precipitate, which was removed

by filtration. The precipitate was washed twice with DCM. The aqueous and organic phases