Three Dimensional Molecular Architectures for the Synthesis
and Improved Properties of High Performance Polymers
by
MASSACHUSMpS INSTITTE
OF TEcHNOLOGY
Brett VanVeller
JUN 0 7 2011
B.Sc. (First Class Honors) Chemistry,
McMaster University, 2006
LIBRARIES
Submitted to the Department of Chemistry
in Partial Fulfillment of the Requirements for the Degree of
ARCHIVES
Doctor of Philosophy
at the
Massachusetts Institute of Technology
June 2011
© Massachusetts Institute of Technology, 2011. All rights reserved.
Signature of Author:
Department of Chemistry
May 18, 2010
Certified by:
Accepted by:
Timothy M. Swager
Thesis Supervisor
Robert W. Field
Studies
Graduate
on
Committee
Departmental
Chairman,
2
This doctoral thesis has been examined by a Committee of the
Department of Chemistrv as folinw-
Professor Stephen L. Buchwald:
Thesis Committee Chair
Professor Timothy M. Swager:
T#is Supervisor
Professor Barbara Imperiali:
Department of Chemistry
4
Three Dimensional Molecular Architectures for the Synthesis
and Improved Properties of High Performance Polymers
by
Brett VanVeller
Submitted to the Department of Chemistry on May 18, 2011
in Partial Fulfillment of the Requirements for the Degree of
Doctor of Philosophy in Chemistry.
ABSTRACT
Conjugated polymers have found various uses in optoelectronic applications,
including chemical sensors, light-emitting diodes, and photovoltaic materials. In
this thesis, we investigate the effect of having a molecular architecture that is
both rigid and three-dimensional might play in the synthesis and performance of
conjugated polymers.
We discuss the efficient synthesis of a hydrophilic monomer bearing a threedimensional noncompliant array of hydroxyl groups that prevents water-driven
excimer features of hydrophobic poly(p-phenylene ethynylene) backbones. We
also use the detection of 3-nitrotyrosine as a probe to learn more about its
physical state in solution.
We further utilize the monomer above in a biocompatible post-polymerization
functionalization reaction, taking advantage of the polymer's structural motif for
the controllable attachment of biotin. The utility of this method is demonstrated
for a model biosensor that responds to streptavidin.
Finally, we discuss how rigid molecular architectures can be harnessed to bring
two reacting groups together for the annulation of various rr-systems. The optical
effects of the transformation are both notable and predictable, and the molecules
have potential as monomers for conjugated polymer application in high
performance organic light emitting diodes and photovoltaic devices.
Thesis Supervisor: Timothy M. Swager, Title: John D. MacArthur Professor of
Chemistry
Dedicatedto Courtney,
my love, whose support
made this possible
Table of Contents
Title Page
Signature Page
Abstract
Dedication
Table of Contents
List of Abbreviations
List of Figures
List of Schemes
List of Tables
1
3
5
6
7
9
10
17
19
Chapter 1. Fluorescent Conjugated Polymer Sensors: A Primer
20
1.1 Introduction
1.2 Electronic Structure
1.3 Exciton Migration and Fluorescence Quenching Amplification
1.3.1 Energy Transfer to an Emissive Quencher
1.4 Higher Order Exciton Migration and Amplification
1.5 Conclusion
1.6 References
21
21
23
25
26
27
28
Chapter 2. Rigid Hydrophilic Structures for Improved Properties
of Conjugated Polymers in Water
29
2.1 Introduction and Design Considerations
2.2 Monomer Synthesis
2.3 Polymer Synthesis
2.4 Monomer Effects on Spectral Purity
2.5 Polymer Solution Properties
2.6 Conclusion
2.7 Experimental Section
30
32
35
37
39
41
42
2.7.1 Optimization of 4 -+ 6-anti/syn:
2.7.2 Optimization of 6-anti/syn -- 8-anti and 8-syn:
2.8 References
Chapter 2 Appendix. 1H-NMR,
47
48
50
C-NMR, UV-vis and
13
53
Fluorescence data, and X-ray Structures
Chapter 3. Biocompatible Post-Polymerization Functionalization
69
3.1
3.2
3.3
3.4
70
72
73
75
Introduction
Post Polymerization Functionalization and Linkage Structure
Effect of Functionalization on Polymer Properties
Response to Streptavidin as a Model Biosensor
3.5 Alternative Sensore Designs for Detection of Native Analytes
3.5.1 Results and Discussion
3.6 Conclusion
3.7 Experimental Section
3.8 References
78
78
82
82
85
Chapter 3 Appendix. 'H-NMR, "C-NMR, UV-vis and
Fluorescence data
87
Chapter 4. Trypticene Diol Scaffolds for rr-System Elaboration
91
4.1 Introduction
4.2 Dihalogen Substituted Trypticene Diols
4.3 Cyclization with Alkynes
4.3.1 Synthesis of Model Compounds for Cyclization
4.3.2 Polymer Synthesis and Cyclization
4.3.3 Photophysical Properties
4.3.4 Electronic Properties
4.3.5 Conclusions: Alkyne Cyclization
4.4 Cyclization with Phenyl Groups
4.4.1 Future Applications of Phenyl Cyclized Trypticene Diols
4.5 Cyclization with Thiophenes
4.5.1 Future Applications of Thiophene Cyclized Trypticene Diols
4.6 Conclusions
4.7 Experimental Section
4.8 References
Chapter 4 Appendix. 'H-NMR,
Curriculum Vitae
Acknowledgements
13C-NMR,
IR Data, and X-ray Structures
92
94
95
96
99
100
103
105
106
107
108
111
113
113
123
126
146
148
List of Abbreviations
ATR-IR attenuated total reflection-infrared spectroscopy
CPE
conjugated polyelectrolyte
DCE
1,2-dichloroethane
DMF
NN-dimethyl formamide
DMSO
dimethyl sulfoxide
ESI
electrospray ionization
EtOH
ethanol
GPC
gel permeation chromatography
HOMO
highest occupied molecular orbital
HRMS
high-resolution mass spectrometry
h
photon
LED
light-emitting diode
lowest unoccupied molecular orbital
LUMO
MeCN
acetonitrile
MeOH
methanol
Mn
number-average molecular weight
MS
mass spectrometry
NMR
nuclear magnetic resonance
OD
optical density
PDI
polydispersity index
PhMe
toluene
PLED
polymer light-emitting diode
PPE
poly(para-phenylene ethynylene)
PPV
poly(para-phenylene vinylene)
PPP
poly(para-phenylene)
PT
polythiophene
fluorescence quencher
Q
rt
room temperature
Sn
singlet electronic state
TBAF
tetrabutylammonium fluoride
THF
tetrahydrofuran
UV-vis ultraviolet-visible
List of Figures
Figure 1.1: Examples of conjugated polymers
21
Figure 1.2: Schematic of the energy gap (Eg) between the HOMO and LUMO
levels and the interaction of light with (a) small molecule MOs and (b) a
conjugated polymer energy band system.
23
Figure 1.3: Schematic of the band structure of a generic conjugated polymer
showing (a) exciton generation, migration, and relaxation (b) exciton
generation, migration, and deacitivation by electron transfer with quencher (Q).
24
Figure 1.4: Unconjugated system of single molecule fluorophores. Binding of a
quenching analyte (Q) affects the florescence of only one molecule.
25
Figure 1.5: Schematic of the band structure of a generic conjugated polymer
showing exciton generation, migration, and energy tranfer to an emissive dye
quencher.
26
Figure 1.6: Representation of exciton migration in conjugated polymers in a)
dilute solution (isolated chains), b) supramolecular aggregate in solution, c)
solid film. Purple star represents the site of exciton generation.
27
Figure 2.1: Effect of interpolymer p-p interactions on spectral purity and signal
intensity
30
Figure 2.2: Supramolecular mitigation of excimer formation. Physical
separation prevents interchain exciton migration
31
Figure 2.3: Penticene (2). Its rigid structure prevents excimer formation yet is
compact, allowing for productive interchain exciton migration
31
32
Figure 2.4: Three dimensional, rigid monomer scaffolds. Goal - apply the
design principles of pentiptycene to aqueous media
Figure 2.5: UV-vis and fluorescence spectra of P1-anti and P-peg in both
water and 1 X PBS solution
38
Figure 2.6: Solubility enhancement of quantum yield of P1-anti . UV-vis
absorption trace (left) of P1-anti in water (black), 1:1 water/glycerol (red), 1:1
water/methanol (green) (units of e = L ' mol-1 cm'). Fluorescence trace (right)
of P1-anti in water (black, <F = 19%), 1:1 water/glycerol (red, (DF 49%), 1:1
water/methanol(red, <DF= 50%).
40
Figure 2.7: Fluroescence spectra for the addition of micromolar quantities of 3nitrotyrosine to P1-anti in IX PBS (plot) and associated Stern-Volmer plot
(inset). Schematic representation of soluble polymer aggregates for each
measured Ksv.
Figure 2.A.1: 1H NMR spectrum of 4 in CDCl 3 (400 MHz)
Figure 2.A.2:
13C
NMR spectrum of 4 in CDCl 3 (125 MHz)
Figure 2.A.3: 1H NMR spectrum of 6-anti/syn in CDCl 3 (400 MHz)
Figure 2.A.4:
13 C
NMR spectrum of 6-anti/syn in CDCl 3 (125 MHz)
Figure 2.A.5: 'H NMR spectrum of 6-anti/syn enriched in 6-anti in CDCl 3
(400 MHz)
Figure 2.A.6:
(125 MHz)
13C
NMR spectrum of 6-anti/syn enriched in 6-anti in CDCl 3
Figure 2.A.7: 'H NMR spectrum of 7 in CDCl 3 (400 MHz)
Figure 2.A.8: 'H NMR spectrum of 8-anti in CDCl 3 (400 MHz)
Figure 2.A.9:
13 C
NMR spectrum of 8-anti in CDCl 3 (125 MHz)
Figure 2.A.10 : 1H NMR spectrum of 8-syn in CDCl 3 (400 MHz)
Figure 2.A.11 : 13C NMR spectrum of 8-syn in CDCl 3 (125 MHz)
Figure 2.A.12 'H NMR spectrum of 9-anti in DMF-d 7 (400 MHz)
Figure 2.A.13 13C NMR spectrum of 9-anti in DMF-d 7 (125 MHz)
Figure 2.A.14 'H NMR spectrum of 9-syn in DMF-d7 (400 MHz)
Figure 2.A.15
13C
NMR spectrum of 9-syn in DMF-d 7 (125 MHz)
Figure 2.A.16 'H NMR spectrum of 1-anti in DMF-d 7 (400 MHz)
Figure 2.A17:
13C
NMR spectrum of 1-anti in DMF-d 7 (125 MHz)
Figure 2.A.18 'H NMR spectrum of 1-syn in DMF-d 7 (400 MHz)
Figure 2.A.19
13C
NMR spectrum of 1-syn in DMF-d 7 (125 MHz)
Figure 2.A.20: 1H NMR spectrum of P1-anti in D20 (600 MHz)
Figure 2.A.21: Stem-Volmer quenching plots of P1-anti with micromolar
quantities of 3-nitrotyrosine under different solvent conditions. (a) water, (b) IX
PBS, (c) 1:1 water/methanol. (d) shows the minimal fluorescence quenching
response of P-peg to 3-nitrotyrosine (Chapter 2.# for explanation).
64
Figure 2.A.22: Crystal Structure of 6-anti.
65
Figure 2.A.23: Crystal Structure of 7.
66
Figure 2.A.24: Crystal Structure of 8-anti.
67
Figure 2.A.25: Crystal Structure of 8-syn.
68
Figure 3.1: (a) Absorbance spectra of P1 and 3a in water and PBS solution. (b)
Fluorescence spectra of P1 and 3a in water and PBS solution.
74
Figure 3.2: Effect of quantum yield of 3a at different pH. Measurements
performed in PBS where pH was adjusted with HCl or NaOH.
74
Figure 3.3: (a) Energy transfer schematic showing how intra- and interchain
exciton migration and enery transfer to TRXS can lead to amplification. (b)
Addition of 9.15 pmol aliquots of TRXS to 3.46 nmol (based on repeat unit
of 3a). (c) Emission of P1 in the presence of 100 pmol of TRXS (black) and
direct excitation of 100 pmol of TRXS (red). (d) Stern-Volmer quenching
analysis of data in (b).
76
Figure 3.4: Comparison of quenching response (Ksv) to TRXS between two
polymers (a) one containing a rigid structural monomer and (b) one bearing
only linear PEG side groups.
77
Figure 3.5: Proposed sensing scheme for native, non-dye
streptavidin
labelled
80
Figure 3.6: (a) Absorbance spectra of P1 and 13 in water and PBS solution.
(b) Fluorescence spectra of P1 and 13 in water and PBS solution. (c) and (d)
Addition of 9.15 pmol aliquots of streptavidin to 3.46 nmol 13 and 14
respectively (based on repeat unit). (e) Emission of 13 (black) and 14 (cyan)
at 390 nm excitation and emission of their respective appended Texas Red
X T (13, red and 14, green) at 580 nm excitation. (f) Stern-Volmer
quenching analysis of data in (e). (f) Addition of 9.15 pmol aliquots of
streptavidin to 3.46 nmol (based on repeat unit of 13). Inset: Stern-Volmer
quenching analysis of data in (f).
81
Figure 3.A.1: 1H NMR spectrum of compound 5 in CDCl 3 (400 MHz)
88
Figure 3.A.2:
3
C NMR spectrum of compound 5 in CDC
3 (125
MHz)
88
Figure 3.A.3: 'H NMR spectrum of compound 6 in CDC13 (400 MHz)
89
Figure 3.A.4: 13C NMR spectrum of compound 6 in CDC 3 (125 MHz)
89
Figure 3.A.5: 'H NMR spectrum of compound 3b in D2 0 (600 MHz)
90
Figure 3.A.6: 'H NMR spectrum of compound 3a in D20 (600 MHz)
90
Figure 4.1: Rational for the potential of trypticene diols for cyclization and
extended planar -systems.
93
Figure 4.2: Absorbance traces for 28 (black) and 29 (green) and fluorescence
traces for 28 (blue) and 29 (red) in CHCl 3.
101
Figure 4.3: Absorbance traces for 30 (black) and 31 (green) and fluorescence
traces for 30 (blue) and 31 (red) in CHC13.
101
Figure 4.4: Absorbance traces for 30 (black) and 31 (green) and fluorescence
traces for 30 (blue) and 31 (red) in thin film.
102
Figure 4.5: Distyrylbenzene 32 and potential nucleophilic site in 31
103
Figure 4.6: Cyclic voltammograms for 29 (a) and 31 (b) in solution, and thin
films of 31 (c), and 30 (d).
Measurements performed under nitrogen in degassed solvents
104
Figure 4.7: General transformation for a PPE to a chain rigidified PPV via
gold(I) catalysis
105
Figure 4.8: Absorbance and fluorescence data for compound 33
107
Figure 4.9: Absorbance and fluorescence data for 39 (a) and 41 (b).
109
Figure 4.10: Comparison of the 'H NMR spectra of 3 (top) and 3 (bottom).
111
Figure 4.11: (a) Planarized monomer for improved charge mobility. (b)
Favorable interactions between fullerene and trypticenes to prevent phase
segregation.
112
Figure 4.A.1: 'H NMR spectrum of 10 in CDCl 3 (400 MHz)
127
Figure 4.A.2:
127
13C
NMR spectrum of 10 in CDCl 3 (125 MHz)
Figure 4.A.3: 'H NMR spectrum of 11 in CDC13 (400 MHz)
Figure 4.A.4:
NMR spectrum of 11 in CDC13 (125 MHz)
13C
127
128
Figure 4.A.5: H NMR spectrum of 12 in CDC13 (400 MHz)
128
NMR spectrum of 12 in CDC13 (125 MHz)
129
Figure 4.A.7: 'H NMR spectrum of 13 in CDC13 (400 MHz)
129
Figure 4.A.6:
13C
Figure 4.A.8:
13C
NMR spectrum of 13 in CDC13 (125 MHz)
Figure 4.A.9: 'H NMR spectrum of 14 in CDC13 (400 MHz)
Figure 4.A.10:
13C
NMR spectrum of 14 in CDC13 (125 MHz)
129
130
130
Figure 4.A.11: 'H NMR spectrum of 15 in CDC13 (400 MHz)
130
NMR spectrum of 15 in CDC13 (125 MHz)
131
Figure 4.A.13: 'H NMR spectrum of 16 in CDCl 3 (400 MHz)
131
Figure 4.A.14: "C NMR spectrum of 16 in CDC13 (125 MHz)
131
Figure 4.A.15: 'H NMR spectrum of 22 in CDC13 (400 MHz)
132
NMR spectrum of 22 in CDC13 (125 MHz)
132
Figure 4.A.17: 1H NMR spectrum of 23 in CDC13 (400 MHz)
132
C NMR spectrum of 23 in CDC13 (125 MHz)
133
Figure 4.A.19: 'H NMR spectrum of 24 in CDCl 3 (400 MHz)
133
C NMR spectrum of 24 in CDC13 (125 MHz)
133
Figure 4.A.21: 'H NMR spectrum of 25 in CDCl 3 (400 MHz)
134
Figure 4.A.22: 13 C NMR spectrum of 25 in CDC13 (125 MHz)
134
Figure 4.A.23: 'H NMR spectrum of 26 in CDC13 (400 MHz and 600 MHz)
134
Figure 4.A.24: gCOSY spectrum of 26 in CDC13 (600 MHz)
135
Figure 4.A.25: 13C NMR spectrum of 26 in CDC13 (125 MHz)
135
Figure 4.A.12:
Figure 4.A.16:
Figure 4.A.18:
Figure 4.A.20:
13C
13C
Figure 4.A.26: 'H NMR spectrum of 27 in C12CD-CDC12 (400 MHz)
Figure 4.A.27:
13 C
NMR spectrum of 27 in C12CD-CDC12 (125 MHz)
135
136
Figure 4.A.28: 1H NMR spectrum of 28 in CDC13 (400 MHz)
136
Figure 4.A.29: 13C NMR spectrum of 28 in CDCl3 (125 MHz)
136
Figure 4.A.30: H NMR spectrum of 29 in CDCl 3 (400 MHz)
136
C NMR spectrum of 29 in CDC13 (125 MHz)
137
Figure 4.A.32: 'H NMR spectrum of 30 in CDC13 (400 MHz)
137
Figure 4.A.33: 'H NMR spectrum of 31 in CDC13 (400 MHz)
137
Figure 4.A.31:
Figure 4.A.34:
C NMR spectrum of 31 in CDCl 3 (125 MHz)
Figure 4.A.35: 1H NMR spectrum of 32 in CDCl 3 (400 MHz)
138
138
C NMR spectrum of 32 in CDC13 (125 MHz)
138
Figure 4.A.37: 'H NMR spectrum of 33 in CDCL3 (400 MHz)
139
NMR spectrum of 33 in CDC13 (125 MHz)
139
Figure 4.A.36:
Figure 4.A.38:
13C
Figure 4.A.39: 1H NMR spectrum of 36 in CDC3 (400 MHz)
139
Figure 4.A.40: 13C NMR spectrum of 36 in CDCl 3 (125 MHz)
140
Figure 4.A.41: 'H NMR spectrum of 37 in CDC13 (400 MHz)
140
NMR spectrum of 37 in CDCl 3 (125 MHz)
140
Figure 4.A.43: 'H NMR spectrum of 40 in CDC13 (400 MHz)
140
Figure 4.A.42:
13C
13 C
NMR spectrum of 40 in CDC13 (125 MHz)
141
Figure 4.A.45: 'H NMR spectrum of 41 in CDC13 (400 MHz)
141
Figure 4.A.46: 13C NMR spectrum of 41 in CDCl 3 (125 MHz)
141
Figure 4.A.47: FT-AT-IR spectrum of 39.
142
Figure 4.A.48: Crystal Structure of 23.
143
Figure 4.A.44:
Figure 4.A.49: Crystal Structure of 27.
144
Figure 4.A.50: Crystal Structure of 33.
144
Figure 4.A.51: Crystal Structure of 38.
145
List of Schemes
Scheme 2.1. Synthesis of the carbon framework
Scheme 2.2: Osmium tetroxide catalyst turnover prevented by dioxo-diosmium
species
34
Scheme 2.3: Rationale for why Upjohn conditions do not result in catalyst
turnover
34
Scheme 2.4: Dihydroxylation
35
Scheme 2.5: Deprotection to reveal 1-anti
35
Scheme 2.6: Oxidative Palladium Acetylene Homocoupling
36
Scheme 2.7: Homopolymerization and Copolymerization
37
Scheme 3.1: Molecules of interest discussed in Chapter 2.
70
Scheme 3.2: Post-polymerization functionalization reaction
72
Scheme 3.3: Model studies and proposed mechanism for azepane formation
73
Scheme 3.4: Synthesis of fractionally dye conjugated polymer sample
80
Scheme 4.1: Synthesis of trypticene diols through [2 + 2 + 2] cylcoaddtion
93
Scheme 4.2: Synthesis of 1,4-dibromo substituted trypticene diols
95
Scheme 4.3: Proposed cyclization of TDs onto alkynes
95
Scheme 4.4: PPE main chain reduction
96
Scheme 4.5: Spontaneous metal-free 5-exo-dig cyclization
97
Scheme 4.6: Electrophilic activation of 6-endo-dig cyclization
98
Scheme 4.7: Electrophilic activation of 6-endo-dig cyclization of more soluble
variants
98
Scheme 4.8: Polymerization and post- cyclization
99
Scheme 4.9: Synthesis of planarized phenylene model compound
106
Scheme 4.10: Future application for ladder phenylene polymers
108
Scheme 4.11: Oxidative cyclization of trypticene diols with thiophenes
109
Scheme 4.12: Cyclization by acid catalyzed trans-etherification
110
List of Tables
Table 2.1: Peak Analysis data for Figure 2.5
38
Table 2.2: Screening of conditions for the di-aryne cycloaddition of 4 and 5.
48
Table 2.3: Screen of reaction conditions for the dihydroxylation of 6-antilsyn
49
Table 2.A.1: Summary of photophysical data of P1-anti
64
Table 1.A.1: X-ray Crystallographic Data
65
Table 3.A.1: Summary of photophysical data of 3a
90
Table 4.1: Summary of photophysical data
103
Chapter 1
Fluorescent Conjugated
Polymer Sensors: A Primer
1.1 Introduction
Conjugated polymers are, most typically, organic polymers whose n-bonding
structure allows for electronic delocalization (orbital conjugation) along the backbone.
This extensive orbital delocalization is responsible for the interesting photophysical and
electronic properties that have allowed these materials to find use in a variety of
applications including light emitting diodes, field-effect transistors, photovoltaics and
chemical sensors. 1 Further, organic conjugated polymers-in addition to the mechanical
and processing advantages inherent to polymers-offer unique opportunities to easily
tailor their structure and properties through organic synthesis (as an alternative to other
inorganic materials used for these purposes). 2 Several examples of different conjugated
polymer structures relavent to the following chapters are shown in Figure 1.1. This
chapter does not seek to encompass the science behind the vast application of conjugated
polymers listed above, but instead seeks some explanation and unpacking of the basic
principles behind fluorescent conjugated polymer sensors. Thus, we will begin with a
brief explanation of the transduction mechanisms.
n
Polyacetylene
PA
Poly(p-phenylene vinylene)
PPV
n
Polythiophene
PT
Poly(p-phenylene ethynylene)
S
Poly(p-phenylene)
PPP
-n
__
-nPP
n
n
n
PPE
Poly(p-phenylene butadiynylene
PPB
Figure 1.1: Examples of conjugated polymers
1.2 Electronic Structure
The fluorescence sensing ability of conjugated polymers follows directly from
their electronic structure. Consider a small molecule containing an isolated double bond
(Figure 2.2a). Upon absorption of a photon with energy greater than the energy gap (Eg),
a y-electron can be promoted from the highest occupied molecular orbital (HOMO) to the
lowest unoccupied molecular orbital (LUMO) to form a singlet excited state. Once in this
excited state the electron may relax down to the ground state by non-radiative vibrational
relaxation (called internal conversion) or emission of a photon (fluorescence from a
singlet excited state or phosphorescence from a triplet excited state). In the case of
conjugated polymers, fluorescence is the dominant form of emission due to negligible
transition rates from singlet to triplet states.
Orbital interactions-double bond conjugation-causes a decrease in the value of
Eg by elevating the HOMO and depressing the LUMO and allowing for lower energy
photon absorption (Figure 1.2b). As the extent of conjugation continues, the density of
molecuar orbital states are more often thought of as a band structure, analogous to
schemes presented in the solid-state physics for inorganic semiconductors like silicon.
The mixing of HOMO levels produces a broadened electron filled band called the
valence band, and the corresponding LUMO levels produce the empty conductance band.
In an analogous manner to small molecule excitation, a suitably energetic photon
can promote an electron from the valence band to the conduction band. The resultant
excited state is typically refered to as an "exciton". An exciton is a quasiparticle
consisting of an electrostatically bound electron-hole pair. 3 Because of the band nature of
the conjugated polymer back bone, the exciton is permited to migrate to another location
within the band until it relaxes back to the ground state (lifetime <1 ns).
Finally, as an aside, the relative HOMO and LUMO levels can be greatly affected
by substituents on the polymer backbone. Electron donating substituents act to raise the
HOMO level relative to the LUMO making the polymer more prone to oxidation, while
electron-withdrawing groups lower the LUMO relative to the HOMO making reduction
more facile. The result in both situations is a decrease in the band gap energy and
generally a red-shift in absorbance and fluorescence.
a)
b)
L-
LUMO
-
-.--
Conduction
Band
LUMO---
AL
--V
Eg
HOMO
E
HOMO
tVLy
:
Valence
.. ... ...........
Band
Isolated
double
bond
Isolated
double
bond
*
Conjugated
polymer
Figure 1.2: Schematic of the energy gap (Eg) between the HOMO and LUMO levels and
the interaction of light with (a) small molecule MOs and (b) a conjugated polymer energy
band system.
1.3 Exciton Migration and Fluorescence Quenching Amplification
Modulation of how excitons return to the ground state is the basis for the
fluorescent conjugated polymer's sensing response. Figure 1.3a shows the band structure
of a generalized conjugated polymer. As discussed above, because all of the repeating
units in the polymer are electrically linked through conjugation, the exciton is permitted
to migrate along the polymer chain until it relaxes back to the ground state by the
competing processes of fluorescence or non-radiative relaxation.
If an analyte with LUMO levels suitably matched to the polymer's Eg comes in
contact with the polymer-the exciton can relax to the ground state through a nonradiative electron transfer mechanism with the LUMO of the analyte-quenching the
excited state (Figure 1.3b). Further, the efficient transport of excitons along the polymer
allows for excitons generated at various locations on the backbone to migrate to the site
of quenching. As a result, one quencher can lead to an amplified decrease in the
fluorescence process through enhanced non-radiative relaxation (greater sensitivity to
quencher). 4
a)
Conduction
Band
-
--- *
Valence
-
Band
n
Figure 1.3: Schematic of the band structure of a generic conjugated polymer showing (a)
exciton generation, migration, and relaxation (b) exciton generation, migration, and
deacitivation by electron transfer with quencher (Q).
24
The above process stands in stark contrast to a sensing scheme involving
unconjugated single molecule fluorescence quenching (Figure 1.4).
Binding of a
quencher results in fluorescence "turn-off' of only one molecule, leaving emission from
unbound fluorophores intact (linear quenching response).
hXx
LO fkET
W
/
Figure 1.4: Unconjugated system of single molecule fluorophores. Binding of a
quenching analyte (Q) affects the florescence of only one molecule.
1.3.1 Energy Transfer to an Emissive Quencher
The energy transferred to the quenching analyte need not be fated to non-radiative
vibrational relaxation. The analyte that quenches the polymer fluorescence may itself be a
fluorescent dye. If the energy levels of the dye are suitably matched to the polymer's Eg
then energy transfer can occur following either the Dexter or the dipole-dipole (Fdrster)
mechanism to yield the emmissive dye excited state (Figure 1.5). In this case emission
from the dye is expected to be greater than direct excitation of itself due to the funneling
of numerous polymer excitons to the dye quencher.
Conduction
-- '
Band
----
*
Energy
Transfer
Eg V
- HOMO
Valence
-©---,-
-----
Band
Figure 1.5: Schematic of the band structure of a generic conjugated polymer showing
exciton generation, migration, and energy tranfer to an emissive dye quencher.
1.4 Higher Order Exciton Migration and Amplification
Critical to the sensitivity of the quenching response is the efficiency with which
the exciton can migrate to the site of quenching before it relaxes to the ground state. The
model of exciton migration discussed in Section 1.3 best approximates a conjugated
polymer in dilute solution (Figure 1.6a). That is, once the exciton is generated, its
movement can be thought as a one-dimensional random walk back and forth along the
isolated chain. However, the nature of this singular pathway for migration is somewhat
inefficient. In the back and forth walk, there is a high probability of sampling the same
"unquenched" polymer segment numerous times and returning to the ground state while
never encountering the bound quencher. Thus, migration efficiency can be enhanced by
decreasing the number of "visits" to unbound polymer segments.
If the polymers are brought within close proximity of eachother-within a
supramolecular aggregate (Figure 1.6b) for instance-then the exciton can hop to an
adjacent chain (through a dipole-dipole coupling energy transfermechanism). This effect
introduces interchain migration in addition to intrachain migration. The result is a higher
dimensional random walk that increases the number of migration pathways, there by
reducing the number of times an exciton revisits an unbound binding site, and providing a
greater realized exciton migration efficiency.5 Further, it allows for excimers on adjacent
chains to contribute to the amplified quenching response.
When spin into a film the polymers are aggregated very closely and the excitons
can migrate even more freely (Figure 1.6c). Revisitation of empty binding sights is at a
minimum and polymer films generally provide the most sensitive chemical sensors. Our
group has reported a highly fluorescent conjugated polymer film that undergoes
amplified fluorescence quenching in response to only trace amounts of trinitrotoluene
(TNT) vapor. 6
hv\
h
a)
b)
c)
Figure 1.6: Representation of exciton migration in conjugated polymers in a) dilute
solution (isolated chains), b) supramolecular aggregate in solution, c) solid film. Purple
star represents the site of exciton generation.
1.5 Conclusion
With this basic understanding of the operation of fluorescent conjugated polymer
sensors in mind, we can now examine other factors affecting their performance. Chapter
2 will discuss low energy emissive defects that are the result of the close association of
polymers within an aggregate (Figure 1.6b). These defects appear as broad ill-defined
bands in the emission spectrum and can behave like energy pot-holes that slow exciton
migration. Chapter 3 will touch on how their removal can lead to a greater sensing
response.
1.6 References
(1) (a) ConjugatedPolymers: The Novel Science and Technology of Highly Conducting
and Nonlinear Optically Active Materials; Bredas, J.-L.; Silbey, R. J., Eds.; Kluwer
Academic Publishers: Boston, 1991. (b) Conjugated Conducting Polymers; Kiess, H. G.;
Baeriswyl, D., Eds.; Springer-Verlag: New York, 1992. (c) Barashkov, N. N.; Gunder, 0.
A. FluorescentPolymers; Ellis Horwood: New York, 1993. (d) Conjugated
Polymers
and Related Materials: The Interconnection of Chemical and Electronic Structure;
Salaneck, W. R.; Lundstr6m, I.; Rainby, B. G., Eds.; Oxford University Press: New York,
1993. (e) Advances in Synthetic Metals: Twenty Years of Progress in Science and
Technology; Bernier, P.; Lefrant, S.; Bidan, G., Eds.; Elsevier: New York, 1999. (f) Roth,
S.; Carroll, D. One-Dimensional Metals: Conjugated Polymers, Organic Crystals,
CarbonNanotubes, 2nd ed.; Wiley-VCH: Weinheim, 2004. (g) Handbook of Conducting
Polymers, 3rd ed.; Skotheim, T. A.; Elsenbaumer, R. L.; Reynolds, J. R., Eds.; CRC
Press: New York, 2007.
(2) Moliton, A.; Hiorns, R. C. Polym. Int. 2004, 53, 1397-1412.
(3) (a) Turro, N. J. Modern Molecular Photochemistry; University Science Books:
Sausalito, CA, 1991. (b) Yan, M.; Rothberg, L.; Hsieh, B. R.; Alfano, R. R.Phys. Rev. B
1994, 49, 9419-9422.
(4) (a) Zhou,
Q.;
Swager, T. M. J Am. Chem. Soc. 1995, 117, 7017-7018. (b) Zhou,
Q.;
Swager, T. M. J. Am. Chem. Soc. 1995, 117, 12593-12602.
(5) (a) Levitsky, I. A.; Kim, J.; Swager, T. M. J. Am. Chem. Soc. 1999, 121, 1466-1472.
(b) Hennebicq, E.; Pourtois, G.; Scholes, G. D.; Herz, L. M.; Russell, D. M.; Silva, C.;
Setayesh, S.; Grimsdale, A. C.; Millen, K.; Bredas, J.-L.; Beljonne, D. J. Am. Chem. Soc.
2005, 127, 4744-4762.
(6) (a) Yang, J. S.; Swager, T. M. J Am. Chem. Soc. 1998, 120, 5321-5322. (b) Yang, J.
S.; Swager, T. M. J. Am. Chem. Soc. 1998, 120, 11864-11873.
Chapter 2
Rigid Hydrophilic Structures for
Improved Properties of Conjugated
Polymers in Water
Adapted and reproduced in part with permission from:
VanVeller, B.; Miki, K.; Swager, T. M. Org. Lett. 2010, 12, 1292-1295
2.1 Introduction and Design Considerations
Fluorescent conjugated polyelectrolytes (CPEs) are conjugated polymers made
water soluble by pendant ionic functionalities along the polymer backbone. CPEs have
seen application in a variety of chemical and biological sensing schemes' because the
intra- and interchain migration of excitons along the polymer backbone results in the
amplification of fluorescence signals relative to small-molecule fluorophores.'a
However, the rigid hydrophobic main chains of CPEs are prone to interpolymer itit interactions leading to broad, ill-defined emission features and reduced luminescence
(Figure 2.1).'
"Film induced"
or
Solvent induced
aggregation
"excimer"
formation
rigid hydrophobic
main chain
E.
broad, ill-defined
emission features
W
Wavelength
Figure 2.1: Effect of interpolymer
x-it
interactions on spectral purity and signal intensity
Supramolecular and macromolecular approaches to mitigate these effects have
been developed that effectively isolate polymer chains from each other.4 However, these
strategies can result in large interpolymer separation that can reduce energy transfer
between chains (Figure 2.2), which is the basis of some transduction schemes need that
aggregation figure to elaborate this point (see Section 1.4 ).
isolated chains,
therefore no excimer
formation
large side chains
reduced
interchain
energy
transfer
efficiency
C
I
reduced amplification
response
Figure 2.2: Supramolecular mitigation of excimer formation. Physical separation
prevents interchain exciton migration
/
* Rigid, three-dimensional structure
* Prevents strong quenching interactions in thin film
* "Minimalist" structure maintains energy transfer
efficiency
H
H
2
high efficiency
interchain energy
transfer maintained
Figure 2.3: Penticene (2). Its rigid structure prevents excimer formation yet is compact,
allowing for productive interchain exciton migration
The three-dimensional, noncompliant structure of iptycene-type monomers (2,
Figure 2.3 and 2.4) has been shown by our laboratory to prevent strong quenching
interactions between polymer chains while still promoting productive interpolymer
energy transfer necessary for amplification. We hypothesized that monomer 1, with its
three dimensional hydrophilic architecture, might impart the same properties to water
soluble polymers as 2 does in non-polar media (Figure 2.4).
Organic
H
H
2
/
Figure 2.4: Three dimensional, rigid monomer scaffolds. Goal
-
apply the design
principles of pentiptycene to aqueous media
2.2 Monomer Synthesis
The synthesis of 1 began with p-bromanil (3); double addition of TIPS acetylide
to 3 followed by SnCl 2 reductive aromatization provided 4 (Scheme 2.1).7 We envisioned
that the three dimensional carbon framework might be established in one step via a
double aryne-cycloaddition protocol.8 In the event, addition of n-BuLi to dienophile
precursor 4 at -45 *C produces a benzyne intermediate after initial lithium-halogen
exchange. This putative dienophile underwent [4+2] cycloaddition with 59 to provide a
mixture of 6-anti and 6-syn cycloadditon products in a ratio of 1.7:1. The reaction was
evaluated under a variety of solvent and temperature conditions (a more detailed
discussion can be found in the Experimental Section 2.7.1), but the ratio of isomers
varied only slightly. The isomers were not easily separated so the mixture was carried on
to the next step; however, sufficient quantities of 6-anti could be isolated to confirm the
stereochemistry by X-ray crystallography (Scheme 2.1). The structure of 6-syn was
determined from a dioxo-diosmium bridged species isolated in a subsequent step (vide
infra Scheme 2.2). Despite a modest yield, this procedure creates considerable structural
complexity in a single step. Further, this transformation can be performed on multigram
scales (>5 g).
Scheme 2.1. Synthesis of the carbon framework
TIPS
OC 0X
0
Br
1TIPS
Br
Br
2. SnC
--
5 (3 eq.)
n-BuLi (2.4 eq.)
Li
2
90% overall
Br
Tol/Hex
-45 0C to rt
0
67%
TIPS
0
0
(1.7:1)
/ /
o
+
/
7/
TIPS
TIPS
inseparable mixture
anti: syn
/
o0
/
00
0
0
6-anti
ntl
TIPS
6-syn
Modeling studies suggested that the double dihydroxylation of 6 would occur on
the less hindered face of the alkene in 6-anti/syn to produce the corresponding isomers 8anti and 8-syn (Scheme 2). Unfortuantely, all attempts with a variety of NMO mediated
osmium tetroxide dihydroxylation conditions (Upjohn process)' 0 ' showed no conversion
of starting material. However, 'H NMR analyses of the crude reaction mixtures revealed
the amount of 6-syn diminished relative to 6-anti with increasing Os04 loadings. To
investigate this observation further, a reaction using a stoichiometric amount of Os04 was
performed and 7 was obtained. While dioxo-diosmium type species are known,' 2 the cisdioxo variant 7 demonstrates remarkable stability in a variety of solvents and can be
purified by silica gel chromatography. The steric bulk surrounding the osmium in this
system likely prevents re-oxidation by NMO, thus trapping the osmium catalyst and
halting the catalytic cycle (Scheme 2.3).
Scheme 2.2: Osmium tetroxide catalyst turnover prevented by dioxo-diosmium species
TIPS
7
o
stoich.
0O
Os0
4
0
6-antiVsyn
TIPS
(1.7:1)
NMO
Os0 4 V
(Upjohn X
process)
TIPS
TIPS
OH
H
HO
O
OH
OH 7
TIPS
+
HO
HO
.
0
0
7
0
TIPS
8-anti
8-syn
Scheme 2.3: Rationale for why Upjohn conditions do not result in catalyst turnover
TIPS
O
0
'
0
H
H
_'O
I
Hydrolysis
Os0
TIPS
These observations led us to examine the Sharpless asymmetric dihydroxylation (SAD),
where conditions allow for hydrolysis of the osmate ester (7) prior to reoxidation in free
solution.' 3 After some modification of the SAD conditions (see Experimental Section
2.7.2 for further details), separable isomers of 8-anti and 8-syn were isolated in excellent
yield and the geometry of dihydroxylation was confirmed by X-ray crystallography
(Scheme 2.4). Finally, global deprotection of 8-anti (see Experimental Section for 8-syn)
with BC13 to remove the acetonide groups followed by TBAF to remove the TIPS groups
provided 1-anti (Scheme 2.5).
4
Scheme 2.4: Dihydroxylation
TIPS
o
0
----
/
/
0
O
0
t-BuOH/H 2 0 (1:1), rt
OH
6-antl/syn
TIPS
90% overall
(1.7:1)
TIPS
TIPS
K2 Os 2(OH) 4 (3 mol%)
DABCO (15 mol%)
K3 Fe(CN) 6 (6 eq)
K2 CO3 (6 eq)
MeSO 2NH 2 (6 eq)
/
-
TIPS
//
S
+
OH
0
HO
OH
HO
HO
HO
.-
0
C
/7
TIPS
8-anti (57%)
0
0
(33%)
8-Syn
X-ray of
8-syn
Scheme 2.5: Deprotection to reveal 1-anti
TIPS
HO
HO
O
8n
OH
//
OH
TIPS
O
BC3
DCM
88%
TBAF
OH
1H
THF
92%
'OH
-OH
8-anti
2.3 Polymer Synthesis
Initial attempts at polymerization of 1-anti focused on homopolymerization using
palladium mediated oxidative homocoupling of acetylenes (Scheme 2.6 and 2.7).'1 The
reaction makes use of the facile way in which butadiynes (K) can be formed through
reductive elimination from Pd" (a common reaction to activate Pd" precatalysts to Pd).
Scheme 2.6 shows the mechanism of how these butadiynes can be applied to polymer
synthesis. As stated, the Pd" (J), serves as the active catalyst begins with a double
transmetallation step to form G followed by reductive elimination to produce A and K. A
stoichiometric oxidant is required to convert A back to the Pd" species J, and the cycle
repeats. In contrast to the Sonogashira reaction where the amine base is required in
stoichiometric quantities, here the amine acts as a proton transfer catalyst.
Scheme 2.6: Oxidative Palladium Acetylene Homocoupling
OH
R3NH+X
CuX
2 R3 N + |
OH
LnPd"
H
O
2 R3NH+ +
+ :NR 3
|
Oxidant L O
CuF
oxidation
LnPd0 A
double transmetallation
reductive
elimination
R2
R2
DE
/R2
R2
LnPd"
G
GR
2
Product K
Unfortunately, the reaction proved unsuccessful in all attempts at direct
homopolymerization of 1-anti and only insoluble material could be isolated. Attempts to
polymerize diol protected versions of 1-anti and then deprotect after polymerization also
failed to yield water soluble homopolymers (Scheme 2.7). These observations suggest
the rigid structure of 1-anti may not provide enough favorable entropic interactions with
water to produce a soluble homopolymer. Copolymerization however, with the sulfonated
diiodide 103a,1s by Sonogashira polymerization produced high molecular weight (M" =
14,500, PDI = 1.7, DP = 18) and highly water-soluble (>8 mg/mL) polymers (P1-anti) in
good yield.
Scheme 2.7: Homopolymerization and Copolymerization
n
HO
HO
HO
HO
OH
OH
OH
OH
Short oligomers
and insoluble material
ui H(i-P r)2
benzoquinone
DMF/ H20
Deprotection
R=H
H
RO
OR
OR
OR
//
R = protecting groups:
OR
n
RO
RO
Pd(PPh 3)4, Cul,
benzoquinone
HN(i-Pr)2, solvent
/0RO
//
RO
RO
RO
esters, orthoesters, acetals
-
O
RO
OR
OR
OR
OR
H
Na
3S
O
NaO 3 S,-
O
HO
HO
,O
n
/O
10
A~- SO3 Na
Pd(PPh 3)4, Cui
DMF, H20, HN(i-Pr) 2
88%
R=H
6H
OH
SO 3 Na
HO
HO
//
OH
OH
P1-anti
2.4 Monomer Effects on Spectral Purity
The immediate effects of incorporating a monomer such as 1-anti with its noncompliant three dimensional architecture can be seen in Figure 2.5. The emission
characteristics of P1-anti in comparison to an analogous control polymer (P-peg)5 a
lacking a deaggregating structure' 6 is evident by the sharper, well-defined emission
features. Further, sensing of biological analytes will likely not take place in pure water
but in higher ionic strength solutions, such as phosphate buffered saline (PBS). Indeed,
P1-anti shows the same sharp emission features in 1X PBS with a quantum yield within
the error of measurement (Table 2.1). The control polymer however, shows lower energy
emission features, consistent with the formation of low-energy emissive traps arising
from interpolymer n-n interactions.
0.08
-
0.070.060.050.040.030.02
0.01
0.00300
350
NaO 3 S,-
400 450 500
Wavelength (nm)
O
n
/
HO
NaO
O
450
500 550 600 650 700
Wavelength (nm)
3 S-,O
n
/O
SO
3 Na
"
SO3Na
HO
HO
O)H
O
400
550 600
HO3
HO
...
/
OH*
OH
P1-anti
MeO
water OF19%
o
F
O
Z
0
Ooe
P-peg
N PBSF=7%
M water, 4)F
GF
s PBS,
19
F=12%
Figure 2.5: UV-vis and fluorescence spectra of P1-anti and P-peg in both water and I X
PBS solution
Table 2.1: Peak Analysis data for Figure 2.5
Entry
1
2
3
4
5
6
<DF
P1-anti, water
P1-anti, X PBS
P-peg, water
P-peg, 1X PBS
P1-anti, water:glycerol (1:1)
P1-anti, water:methanol (1:1)
a Arbitrary
1
17%
1
9%
1
4
5
peak heighta
41.81
36.99
22.10
10.86
143.7
149.9
fwhma,
ratioc
32.50
24.82
92.47
100.29
28.48
29.51
1.30
1.50
0.24
0.11
5.04
5.08
units. b fwhm = full width at half maximum. ' Ratio = (peak height):(fwhm).
Peak analysis data in Table 2.1 shows numerically what is visually represented in
Figure 2.5. By examining the ratio between the peak height and the peak's full width at
half maximum, it is clear that the presence of 1-anti (P1-anti) produces distinctly sharper
fluorescence signals with visible vibrational features (Table 2.1, entries 1-4). The blue
shifted absorbance and emission of P1-anti relative to the control is due to a lower
HOMO level resulting from the absence conjugated oxygen lone pairs in 1-anti (See
Section 1.2 for further explanation).
2.5 Polymer Solution Properties
Interestingly, despite the sharper emission peaks of P1-anti, there is not an
observed increase in quantum yield often seen when bulky side chains are used. This is
possibly due to close proximity of the the hydroxyl groups of 1-anti to the polymer chain.
The hydrogen bonding of the aqueous media with the hydroxyl group array might
encourage non-radiative vibration relaxation of the excited state. This theory is supported
by the increase in quantum yield for entries 5 and 6 in Table 2.1 (also see Figure 2.6); the
presence of alcohol solvent does decreases the overall hydrogen bonding of the media.
However, we believe that this increase in quantum yield may be due to water:alcohol
solvent mixtures being more solubilizing for P1-anti. This would imply that the P1-anti,
while soluble in water and PBS, is infact in an aggregated form and undergoing selfquenching while not experiencing excimer formation.
50
,
4
-
03
Ii
0
0-
Cu
300
I
350
400
450
Wavelength (nm)
500
400
I
i
I
450
500
550
Wavelength (nm)
600
Figure 2.6: Solubility enhancement of quantum yield of P1-anti . UV-vis absorption
trace (left) of P1-anti in water (black), 1:1 water/glycerol (red), 1:1 water/methanol
(green) (units of E= L 'mol-* cm'1). Fluorescence trace (right) of P1-anti in water (black,
DF = 19%), 1:1 water/glycerol (red,
F=
49%), 1:1 water/methanol(red, <DF = 50%).
To further understand the nature of P1-anti in solution, Stern-Volmer quenching
experiments were performed with 3-nitrotyrosine, a modified tyrosine residue associated
with over 50 disease states (Figure 2.7).17 A greater quenching constant can be expected
for more aggregated polymers because of increased interchain exciton migration and
transfer to the electron-deficient nitroaromatic quencher (see Section 1.4 for details).
Indeed, a Ksv of 27,737 was found in PBS and the Ksv decreased for better solvents
(4,774 in water and 1,232 in water:methanol), indicating a decrease in aggreagation with
better solvents. Quenching experiments performed with P-peg as control showed no
response, presumably because the aggregated emissive states of the polymer provide
lower energy states than the LUMO of 3-nitrotyrosine.
4x10
1.17 -
3x10
-
-
U 1.14
1.11
"
O2N
.
3-nitrotyrosine
/CO
2
1.511
21
NH 3+
1.02
096 0
NaO
2X4(6
/O
11HHO
HO
SONa
3
"
7/HO
HO
0
[
SA,-O
3
6
0
-
450
Ksv
500
550
Wavelength (nm)
OH
OOH
600
PBS
27,737
Water
Water/MeOH
4,774
1,232
Figure 2.7: Fluroescence spectra for the addition of micromolar quantities of 3nitrotyrosine to P1-anti in 1X PBS (plot) and associated Stern-Volmer plot (inset).
Schematic representation of soluble polymer aggregates for each measured Ksv.
2.6 Conclusion
In summary, we have developed an expedient synthesis of monomer 1-anti (and 1-syn,
see Experimental Section). The hydrophilic three-dimensional structure of 1-anti was
shown to promote spectral purity with decreased lower energy excimer emission in both
water and PBS despite an aggreagted state. Further interchain energy migration was
shown through Stem-Volmer analysis and work towards applying interpolymer energy
transfer for further sensing applications is underway.
2.7 Experimental Section
Materials: Silica gel (40 prm) was purchased from SiliCycle. All solvents used for
photophysical experiments were spectral grade. Pd(PPh 3)4 was purchased from Strem
Chemicals, Inc. All other reagent grade materials were purchased from Aldrich, TCI
America, and Alfa Aesar, and used without further purification.
Experimental:
NMR Spectroscopy: 'H and 13C NMR spectra for all compounds were acquired in CDCl 3,
D2 0 and DMF-d 7 on a Bruker Avance Spectrometer operating at 400 and 100 MHz,
respectively. The chemical shift data are reported in units of 6 (ppm) relative to residual
solvent.
Gel Permeation Chromatography (GPC): Polymer molecular weights were determined
using a triple detection method for calibration with poly(acrylic acid) standards on a
Viscotek TDA 305-040 instrument equipped with two Viscotek A-MBHMW-3078
columns. and analyzed with light scattering and refractive index detectors. Samples were
dissolved in 5% NH4 0H.
Absorption and Emission Spectroscopy: Fluorescence spectra were measured on a SPEX
Fluorolog-T3 fluorometer (model FL-321, 450 W Xenon lamp) using right-angle
detection. Ultraviolet-visible absorption spectra were measured with an Agilent 8453
diode array spectrophotometer and corrected for background signal with a solvent filled
cuvette. Fluorescence quantum yields of P1-anti in both water and 1X PBS were
determined relative to perylene and are corrected for solvent refractive index and
absorption differences at the excitation wavelength. The quantum yield of P-peg in IX
PBS was determined relative to P-peg in pure water.
Lifetime measurements: Time resolved fluorescence measurements were performed by
exciting the samples with 160 femtosecond pulses at 390 nm from the double output of a
Coherent RegA Ti:Sapphire amplifier. The resulting fluorescence was spectrally and
temporally resolved with a Hamamatsu C4780 Streak Camera system.
Stern-Volmer Quenching Experiments: A 4 mL solution of P1-anti, at an appropriate
concentration for UV-vis and fluorescence measurements, was prepared and 1 mL this
solution was used to dissolve 3-nitrotyrosine (0.045-0.055 mg). 20 [tL additions of the 1
mL were made to the original P1-anti solution and measurements taken after addition
and mixing (5 additions). The 3-nitrotyrosine absorbance overlaps with P1-anti so a
corrected Stern-Volmer protocol was applied to the data following reference 8.
Synthetic Procedures
Diaryne precursor 4. The procedure of Bowles et. al.' was used with little modification.
TIPS acetylene (6.93 g, 54.3 mmol) was dissolved in 190 mL of dry THF under argon.
Following, n-BuLi (52 mmol, 1.6 M in Hexane) was added dropwise at room temperature
and the mixture was stirred for 30 min. Compound 3 (10g, 23.6 mmol) was added in one
portion and the reaction immediately turned dark. The solution was stirred at 60 C for 30
min and cooled to room temperature. The reaction was quenched with 200 mL of sat.
NH 4C1 and extracted with one portion Hexanes, then DCM. The combined organic layers
were concentrated in vacuo and the residue was dissolved in 500 mL of MeCN. SnCl 2 (18
g, 95 mmol) and 2 mL of water was added and the reaction refluxed for 12 hrs. After
cooling to room temperature, the suspension was filtered through a thick pad of alumina,
eluting with hexanes until UV-active material no longer eluted from the bottom of the
column (checked with TLC at 254nm). The solvent was removed under reduced pressure
and the residue recrystallized from EtOAc to give 4 (95%). 1H NMR (400 MHz, CDCl 3 ):
d 1.16 (m, 42H).
13
C NMR (125 MHz, CDC13) d 129.2, 128.36, 105.8, 104.8, 18.9, 11.5.
HRMS (EI) calcd. for C2 8H42 Br 4 Si2 [M] 753.9556, found 753.9524.
Dicycloaddition products 6-anti/6-syn. To a suspension of 4 (5 g, 6.63mmol) and 59
(3.03 g, 11.94 mmol) in dry toluene at -45 0C under argon was added dropwise 10 mL nBuLi (1.6 M in hexane) that had been further diluted to 40 mL of hexanes by syringe
pump over 1.5 h. Once addition was complete the reaction was allowed to warm to rt and
stirred for 2 hr. The reaction was quenched with methanol and water and the volatiles
were removed in vacuo. The residue was taken up and partitioned between water and
DCM (50 mL each). The aqueous phase was washed with DCM (2 x 50 mL) and the
combined organic layers were dried over Na2 SO 4 and the solvent removed in vacuo. The
residue was purified by flash chromatography (silica gel, 6:4 Hexanes:DCM, Rf= 0.4) to
yield 4 as an inseparable mixture of 6-anti/6-syn mixture (67%, 1.7:1 by NMR).
6-anti: 'H NMR (400 MHz, CDCl 3): d 6.49 (m, 4H), 4.65 (m, 4H), 4.20 (m, 4H), 1.40 (s,
6H), 1.25 (s, 6H), 1.17 (m, 42H).
13
C NMR (125 MHz, CDCl 3): d 140.6, 132.8, 116.8,
112.3, 101.8, 99.6, 78.6, 44.0, 26.0, 25.5, 19.0, 11.5. HRMS (ESI) caled. for C4 6H6 6 0 4 Si2
[M+Na*] 761.4392, found 761.4415.
6-syn: 1H NMR (400 MHz, CDC13): d 6.44 (m, 4H), 4.65 (m, 4H), 4.27 (m, 4H), 1.41 (s,
6H), 1.28 (s, 6H), 1.17 (m, 42H).
13
C NMR (125 MHz, CDCl 3): d 140.7, 132.8, 116.7,
112.3, 101.9, 99.5, 78.6, 44.0, 26.0, 25.6, 19.0, 11.5. HRMS (ESI) calcd. for C4 6 H6 60 4 Si2
[M+Na*] 761.4392, found 761.4415.
Diosmium bridged species 7: To a solution of 6-anti/6-syn (10 mg, 0.013 mmol) in 2
mL of acetone was added solid Os04 (0.158 mmol). The solution turned dark and was
stirred for 15 h. The reaction was partitioned betweened water and DCM and the organic
layer was collected, dried with Na 2 SO 4 and evaporated to dryness. Silica gel
chromatography (8:2) Hexanes:EtOAc provided 7 as a purple solid. (80%). 1H NMR (400
MHz, CDCl 3): d 5.83 (m, 4H), 4.53 (in, 4H), 4.36 (in, 4H), 1.56 (s, 6H), 1.36 (s, 6H),
1.17 (in, 42H). HRMS (ESI) calcd. for C4 6H 66 0 12 0s 2 Si 2 Na [M+Na*] 1273.3220, found
1095.4094, 1363.3888, 1430.5004, parent ion not found. X-ray crystal structure, see
Figure S2.
Dihydroxylation to give 8-anti and 8-syn. A round bottom flask was charged with
K3Fe(CN)6 (5.34 g, 16.23 mmol), K2 C0 3 (2.24 g, 16.23 mmol), MeSO 2NH 2 (1.54 g,
16.23 mmol), K2 0sO2 (OH)4 (60 mg, 0.163 mmol) and DABCO (46 mg, 0.407 mmol),
27 mL of t-BuOH and 27 mL H20. After 10 min of stirring, 6-anti/syn was added and the
reaction suspension stirred at room temperature for 24 h. The reaction was quenched with
8 g of sodium sulfite, stirred for 10 min, and finally diluted with 2M KOH and stirred for
2 h. The mixture was extracted with EtOAc (2 x 80 mL) and the combined organic layers
were combined, washed with 2M KOH (2 x 80 mL), dried over Na 2 SO 4 and the solvent
removed in vacuo. The combine organic layers were further washed with 2M KOH,
dried over NaSO 4 and concentrated in vacuo. The residue was purified by flash
chromatography (silica gel, DCM) to remove unreacted starting material, then elution
with (8:4 hexanes:EtOAc, Rf = 0.3) to yield 8-anti (57%), finally elution with (1:1
hexanes:EtOAc, Rf= 0.4) to yield 8-syn (33%) as separable isomers (90% overall).
8-anti: 'H NMR (400 MHz, CDCl 3): d 4.60 (m, 4H), 4.20 (m, 4H), 4.13 (m, 4H), 1.91
(br s, 40H), 1.53 (s, 6H), 1.31 (s, 6H), 1.16 (m, 42H).
13
C NMR (125 MHz, CDCl 3): d
137.7, 122.2, 111.6, 101.3, 100.9, 74.9, 65.2, 45.1, 26.0, 24.0, 19.0, 11.5. HRMS (ESI)
calcd. for C4 6H7 00sSi 2 [M+Na*] 829.4507, found 829.4434.
8-syn: 'H NMR (400 MHz, CDCl 3): d 4.41 (m, 4H), 4.05 (m, 4H), 4.02 (m, 4H), 2.54 (br
s, 40H), 1.50 (s, 6H), 1.26 (s, 6H), 1.15 (m, 42H).
13C
NMR (125 MHz, CDCl 3): d 137.7,
122.0, 111.8, 101.3, 101.1, 75.2, 65.4, 45.1, 26.1, 24.0, 19.0, 11.5. HRMS (ESI) calcd.
for C4 6H7 00sSi 2 [M+Na*] 829.4507, found 829.4448.
Acetonide deprotection to give 9-anti. Under argon, 8-anti (1 g, 1.24 mmol) was
dissolved in 20 mL of dry DCM and cooled to -78 C. Boron trichloride (6.19 mmol, 1M
in DCM) was added dropwise and the reaction was allowed to warm to room temperature
and stirred for 2 h. The reaction was quenched with ice (100 g) and the mixture was
stirred at 80'C where upon the DCM was distilled off. After 1 h the reaction was cooled
in an ice bath, filtered and washed with cold water to give 9-anti as a white powder
(88%). 1H NMR (400 MHz, DMF-d 7 ): d 5.18 (m, 4H), 4.52 (m, 4H), 3.41 (m, 4H), 3.96
(in, 4H), 3.62 (in, 4H), 1.18 (in, 42H).
13 C
NMR (125 MHz, DMF-d 7): d 138.7, 120.4,
104.1, 97.42, 65.5, 64.4, 48.6, 18.7, 11.6. HRMS (DART FT-MS) calcd. for C4 0H62 0 8Si 2
[M+H+] 727.4056, found 727.4049.
Acetonide deprotection to give 9-syn. Under argon, 8-syn (1 g, 1.24 mmol) was
dissolved in 20 mL of dry DCM and cooled to -78 C. Boron trichloride (6.19 mmol, 1M
in DCM) was added dropwise and the reaction was allowed to warm to room temperature
and stirred for 2 h. The reaction was quenched with ice (100 g) and the mixture was
stirred at 800C where upon the DCM was distilled off. After 1 h the reaction was cooled
in an ice bath and filtered and dried to give crude 9-syn as a powder. The syn isomer
required a further reflux in IM HCl for 2 h after which the suspension was cooled in an
ice bath, filtered and dried to give pure 9-syn as a white powder (75%). 1H NMR (400
MHz, DMF-d7 ): d 5.19 (m, 4H), 4.52 (in, 4H), 4.27 (m, 4H), 3.97 (m, 4H), 3.58 (m, 4H),
1.18 (m, 42H). '3 C NMR (125 MHz, DMF-d 7): d 138.8, 120.4, 104.0, 97.5, 65.6, 64.4,
48.7, 18.7, 11.6. HRMS (DART FT-MS) caled. for C40 H62 0 8 Si 2 [M+NH 4+] 744.4321,
found 744.4330.
TIPS removal to give 1-anti. Tetrabutylammonium fluoride (2.41 mmol, IM in THF)
was added to 9-anti in 5 mL DMF and 15 mL THF and stirred for 3 h. The THF was
removed in vacuo, and acetic acid (2 mL) and chloroform (50 mL) were added. The
product precipitated with cooling in an ice bath. Filtration yielded 1 as a white solid
(92%). 'H NMR (400 MHz, DMF-d7 ): d 5.10 (in, 4H), 4.53 (m, 4H), 4.49 (s, 2H), 4.35
(m, 4H), 3.87 (m, 4H), 3.61 (in, 4H).
13C
NMR (125 MHz, DMF-d): d 138.7, 119.7,
86.5, 80.2, 65.4, 64.3, 48.4. HRMS (DART FT-MS) calcd. for C2 2 H22 0 8 [M+H*]
415.1387, found 415.1377.
TIPS removal to give 1-syn. The same procedure was used as for 1-anti. (95%). 'H
NMR (400 MHz, DMF-d 7 ): d 5.10 (in, 4H), 4.53 (m, 4H), 4.50 (s, 2H), 4.31 (m, 4H),
3.87 (in, 4H), 3.58 (m, 4H). "3 C NMR (125 MHz, DMF-d 7): d 138.7, 119.7, 86.5, 80.1,
65.5, 64.2, 48.4. HRMS (DART FT-MS) calcd. for C22 H22 0 8 [M+NH 4 *] 432.1653, found
432.1654. Calcd. for C22 H22 0 8 [M+H t ] 415.1393, found 415.1393.
Polymer Synthesis: A suspension of 1-anti (38.2 mg, mmol) and 10 (60 mg, mmol) in
2.4 mL of DMF:H 2 0 (1:1) was degassed with three cycles of freeze-pump-thaw. A
mixture of Pd(PPh 3)4 (4 mg, 3.5 tmol) and CuL (8 mg, 42 tmol) in 1.2 mL DMF:HN(iPr)2 was added by cannula and the reaction stirred at 55 C.After 12 h the mixture was
diluted to 50 mL with water and stirred for several hours to completely dissolve the
polymer. The solution was centrifuged and particulate removed by decanting the yellow
supernatant. The volume of the solution was reduced in vacuo (~15 mL) and added
dropwise to 60 mL of acetone with stirring. The mixture was strongly basified with
aqueous NaOH
and the polymer precipitated as an orange gel. The supernatant was
decanted off and discarded; 60 mL of fresh acetone was added to the gel residue and
stirred, then left to stand. The supematant was discarded and this process was repeated
twice more with EtOAc, then THF. The gel residue was then suspended in 50 mL of
water and dialyzed against de-ionized water with 6 changes of water. Lyophilization
yielded P1-anti as a yellow solid (88%). GPC gave M, = 14,500 Mw = 24,700 PDI = 1.7
DP
=
18. 'H NMR (400 MHz, D2 0): d7.42 (s, 2H), 4.61 (broad, 4H), 4.35 (broad t, 4H),
4.03 (broad, 4H), 3.88 (braod, 4H), 3.16 (broad t, 4H), 2.33 (broad t, 4H).
Synthetic Optimizations - Extended Discussions
2.7.1 Optimization of 4 -> 6-anti/syn:
Upon addition of n-BuLi, 4 undergoes lithium halogen exchange to give an anion, which
then eliminates the adjacent bromide to produce a benzyne-like intermediate. This
putative dienophile undergoes [4+2] cycloaddtion with 5. The reaction was evaluated
with slow addition of n-BuLi in hexanes to a chilled suspension of 4 and 5 in toluene.
Initial temperature screens revealed that -45 C gave the highest yields (Table S2, entries
1-4). Additional equivalents of diene did not greatly improve the yield and complicated
product purification (entry 6). A smaller silyl group resulted in an improved yield (entry
7), but product solubility was greatly reduced with this variant. Tetrahydrofuran was also
tested as the reaction solvent but appears to be inferior to toluene (entry 8). Interestingly,
the ratio of product isomers varied only slightly (6-anti : 6-syn, 1.7:1) across all
conditions. A slower rate of addition (2 hr.) of n-BuLi gave cleaner reaction products but
did not greatly affect the yield.
Table 2.2: Screening of conditions for the di-aryne cycloaddition of 4 and 5.
R
R
n-BuLi (2.5 eq)
Toluene
Hexane
Br
Br
+ n
0
Br
Br
4
5
Syringe pump
addition
2h
Entry
T [0C]
n
3
1
-78
2
3
-45
3
3
-15
4
rt
3
2
5
-45
6
6
-45
3
7
-45
3
-45
8
a THF used in place of tolu ene
2.7.2 Optimization of 6-anti/syn
->
R
0
0
/7
6-anti
R
isomers not separable
R
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
TMS
TIPS
0//0
/7
0
(1.7:1
6-syn
Yield [%]
51
67
55
44
60
65
75
28a
8-anti and 8-syn:
Modeling studies suggested dihydroxylation would occur on the less hindered face of the
alkene and the modified NMO conditions of Sharpless et. al. were initially tried.
Unfortunately, all attempts with a variety of NMO conditions proved unsuccessful (Table
S3, entries 1-5). Increased osmium loading results in a reduction of the amount of 6-syn
observed in the crude product mixture. (entries 2-5). To investigate this observation
further, a stoichiometric reaction was performed (entry 6) and the product 7 was
obtained. While dioxo-diosmium type species are known, this particular example
demonstrates remarkable stability to a variety of solvents and even silica gel. The steric
bulk surrounding the osmium in this system likely prevents re-oxidation by NMO, thus
trapping the osmium catalyst and halting the catalytic cycle (Figure refer to above figure).
These observations lead us to examine the Sharpless Asymmetric Dihydroxylation
(SAD), where conditions allow for hydrolysis of the osmate ester before reoxidation. It
was hoped that attack of a smaller hydroxide anion would be faster than a bulky NMO
molecule, resulting in more efficient catalytic turnover. Indeed, initial attempts using ADmix-c and the hydrolysis accelerant methane-sulfonamide looked promising (entry 7).
Switching to a smaller tertiary amine, 1,4-diazobicyclo[2.2.2]octane (DABCO), and
increasing the catalyst loading resulted in higher conversions (entries 9-10). Upon
purification, 6-anti still contained small amounts of osmium that were observed to
precipitate as osmium(0) in the subsequent step (acetonide deprotection). Thus, after
reductively quenching the reaction with Na 2 SO 3 , the reaction was stirred with 2M KOH
for several hours to completely hydrolyze the residual osmate ester (entry 11). The result
was a near quantitative conversion.
Table 2.3: Screen of reaction conditions for the dihydroxylation of 6-antilsyn
TIPS
TIPS
OH
//
O
0
Conditions
/
N. /
HOH
0nHO
/
T
6-anti/syn mix
TIPS
(1.7:1)
C
8-anti
Entry
1
2
3
4
5
6
7
8a
Os catalyst
0.1% K20sO 2(OH) 4
0.5% K20sO 2(OH) 4
2% OS04
5% Os0 4
10% OsO4
Stoich. OS04
AD-mix-a (2 eq)
0.2% K20sO2(OH) 4
6 K3Fe(CN)6
Solvent
H20/t-BuOH (1:1)
Pyridine
Acetone/H 20(9:1)
Acetone/H20(9:1)
Acetone/H 2 0(9:1)
Acetone
H20/t-BuOH (1:1)
H20/t-BuOH (1:1)
9
3% K2 0sO2(OH) 4
6 K3Fe(CN)6
H20/t-BuOH (1:1)
10
6% K2 0sO2(OH) 4
6 K3Fe(CN)6
H20/t-BuOH (1:1)
6% K2 0sO 2(OH) 4
6 K3Fe(CN) 6
H20/t-BuOH (1:1)
11
b
Additives
4 Citric acid
8-syn
Conv.
Yield
[%]
1%]
1%]
[%]
rt
rt
rt
rt
rt
rt
[h]
15
15
15
15
15
15
48
48
-anti
0
0
0
0
0
0
44
53
-syn
0
0
2
5
8
86
90
85
-anti
0
0
0
0
0
0
14
20
-syn
0
0
0
0
0
0
80
75
50
48
85
>95
80
90
rt
24
95
>95
84
93
rt
24
95
>95
95
93
[0C]
120
AD-mix-a: (DHQ) 2PHAL (1 mol%), K20sO2(OH) 4 (0.4 mol%), K 3Fe(CN)6 (3 eq.), K CO (3 eq.)
2
3
b After reductive quenching with Na 2 SO3 , 2M KOH was added and the mixture stirred for several hours
a
Yield
Conv.
rt
3 MeSO 2NH 2
0.1 DABCO
3 MeSO 2NH 2
6 K2C03
0.1 DABCO
6 MeSO 2NH 2
6 K2 CO3
0.15 DABCO
6 MeSO 2NH 2
6 K2 CO3
0.15 DABCO
6 MeSO2NH 2
6 K2 C0 3
TI PS
Time
Temp
Reoxidant
2.2 NMO
2.2 NMO
2.2 NMO
2.2 NMO
2.2 NMO
HO
OH
0
TIPS
TIPS
separable isomers
2.8 References
(1) (a) Thomas, S. W.; Joly, G. D.; Swager, T. M. Chem. Rev. 2007, 107, 1339. (b)
Satrijo, A.; Swager, T. M. J. Am. Chem. Soc. 2007, 129, 16020. (c) Wosnick, J. H.;
Mello, C. M.; Swager, T. M. J. Am. Chem. Soc. 2005, 127, 3400. (d) Gaylord, B. S.;
Heeger, A. J.; Bazan, G. C. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 10954. (e) Wang, D.;
Gong, X.; Heeger, P. S.; Rininsland, F.; Bazan, G. C.; Heeger, A. J. Proc. Natl. Acad
Sci. U.S.A. 2002, 99, 49. (f) Wang, S.; Gaylord, B. S.; Bazan, G. C. J Am. Chem. Soc.
2004, 126, 5446. (g) Kumaraswamy, S.; Bergstedt, T.; Shi, X.; Rininsland, F.; Kushon,
S.; Xia, W.; Ley, K.; Achyuthan, K.; McBranch, D.; Whitten, D. Proc. Natl. Acad Sci.
U.S.A. 2004, 101, 7511. (h) Phillips, R. L.; Miranda, 0. R.; You, C. C.; Rotello, V. M.;
Bunz, U. H. F. Angew. Chem. Int. Ed. 2008, 47, 2590. (i) You, C. C.; Miranda, 0. R.;
Gider, B.; Ghosh, P. S.; Kim, I. B.; Erdogan, B.; Krovi, S. A.; Bunz, U. H. F.; Rotello, V.
M. Nat. Nanotechnol. 2007, 2, 318. (j) Yang, C. Y.; Pinto, M.; Schanze, K.; Tan, W.
Angew. Chem. Int. Ed. 2005, 44, 2572. (k) Pinto, M. R.; Schanze, K. S. Proc.Natl. Acad.
Sci. USA 2004, 101, 7505. (1)Xu, H.; Wu, H.; Huang, F.; Song, S.; Li, W.; Cao, Y.; Fan,
C. Nucleic Acids Res. 2005, 33, e83. (m) Ho, H. A.; Najari, A.; Leclerc, M. Acc. Chem.
Res. 2008, 41, 168. (n) Ho, H. A.; Boissinot, M.; Bergeron, M. G.; Corbeil, G.; Dore, K.;
Boudreau, D.; Leclerc, M. Angew. Chem. Int. Ed. 2002, 41, 1548. (o) Nilsson, K. P. R.;
Inganas, 0. Nat. Mater. 2003, 2, 419. (p) Sigurdson, C. J.; Nilsson, K. P. R.; Homemdnn,
S.; Manco, G.; Polymenidou, M.; Schwarz, P.; Leclerc, M.; Hammarstrom, P.; Wiithrich,
K.; Aguzzi, A. Nat. Methods 2007, 4, 1023. (q) Li, C.; Numata, M.; Takeuchi, M.;
Shinkai, S. Angew. Chem. Int. Ed. 2005, 44, 6371. (r) Feng, F.; Wang, H.; Han, L.;
Wang, S. J. Am. Chem. Soc. 2008, 130, 11338. (s) Feng, F.; Tang, Y.; Wang, S.; Li, Y.;
Zhu, D. Angew. Chem. Int. Ed. 2007, 46, 7882. (t) Tang, Y.; Feng, F.; He, F.; Wang, S.;
Li, Y.; Zhu, D. J. Am. Chem. Soc. 2006, 128, 14972. (u) An, L.; Liu, L.; Wang, S.;
Bazan, G. C. Angew. Chem. Int. Ed. 2009, 48, 4372.
(2) Swager, T. M. Acc. Chem. Res. 1998, 31, 201.
(3) (a) Tan, C.; Pinto, M. R.; Schanze, K. S. Chem. Commun. 2002, 446. (b) Tan, C.;
Alas, E.; MUller, J. G.; Pinto, M. R.; Kleiman, V. D.; Schanze, K. S. J. Am. Chem. Soc.
2004, 126, 13685. (c) Chen, L.; McBranch, D. W.; Wang, H. L.; Helgeson, R.; Wudl, F.;
Whitten, D. G. Proc. Natl. Acad Sci. U.S.A. 1999, 96, 12287.
(4) For a review see: Frampton, M. J.; Anderson, H. L. Angew. Chem. Int. Ed. 2007, 46,
1028.
(5) (a) Lee, K.; Cho, J. C.; DeHeck, J.; Kim, J. Chem. Commun. 2006, 1983. (b) Khan,
A.; Miller, S.; Hecht, S. Chem. Commun. 2005, 584. (c) Jiang, D. L.; Choi, C. K.;
Honda, K.; Li, W. S.; Yuzawa, T.; Aida, T. J Am. Chem. Soc. 2004, 126, 12084. (d)
Kuroda, K.; Swager, T. M. Chem. Commun. 2003, 26. (e) Terao, J.; Tsuda, S.; Tanaka,
Y.; Okoshi, K.; Fujihara, T.; Tsuji, Y.; Kambe, N. J. Am. Chem. Soc. 2009, 131, 16004.
(f) Terao, J.; Tanaka, Y.; Tsuda, S.; Kambe, N.; Taniguchi, M.; Kawai, T.; Saeki, A.;
Seki, ShuJ Am. Chem. Soc. 2009, 131, 18046.
(6) Swager, T. M. Acc. Chem. Res. 2008, 41, 1181.
(7) Bowles, D. M.; Palmer, G. J.; Landis, C. A.; Scott, J. L.; Anthony, J. E. Tetrahedron
2001,57,3753.
(8) (a) Hart, H.; Lai, C.; Nwokogu, G. C.; Shamouilian, S. Tetrahedron 1987, 43, 5203.
(b) Chen, C. L.; Sparks, S. M.; Martin, S. F. J. Am. Chem. Soc. 2006, 128, 13696.
(9) (a) Baran, A.; Segen, H.; Balci, M. Synthesis 2003, 1500. (b) Yang, N. C. C.; Chen,
M. J.; Chen, P. J. Am. Chem. Soc. 1984, 106, 7310.
(10) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. TetrahedronLett. 1976, 1973.
(11) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K. B. Adv. Synth.
Catal. 2002, 344, 421.
(12) (a) Phillips, F. L.; Skapski, A. C. J. Chem. Soc., Dalton Trans. 1975, 2586. (b)
Casey, C. P. J. Chem. Soc., Chem. Commun. 1983, 126. (c) Cartwright, B. A.; Griffith,
W. P.; Schr6der, M.; Skapski, A. C. J. Chem. Soc., Chem. Commun. 1978, 853. (d)
Cleare, M. J.; Hydes, P. C.; Griffith, W. P.; Wright, M. J. J. Chem. Soc,. Dalton Trans.
1977, 941. (e) Marzilli, L. G.; Hanson, B. E.; Kistenmacher, T. J.; Epps, L. A.; Stewart,
R. C. Inorg. Chem. 1976, 15, 1661.
(13) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
(14) Williams, V. E.; Swager, T. M. J. Polym. Sci., Part A: Polym. Chem. 2000, 38,
4669.
(15) Chen, W.; Joly, A. G.; Malm, J. 0.; Bovin, J. 0.; Wang, S. J. Phys. Chem. B. 2003,
107, 6544.
(16) CPE copolymers with 2 are not readily soluble in water, see Zheng, J.; Swager, T.
M. Chem. Commun. 2004, 2798.
(17) Neumann, H.; Hazen, J. L.; Weinstein, J.; Mehl, R. A.; Chin, J. W. J. Am. Chem.
Soc. 2008, 130, 4028 and references there in.
Chapter 2 Appendix
1H-NMR, "C-NMR,
UV-vis and Fluorescence data,
and X-ray Structures
TIPS
B B
Br
Br
4
TIPS
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
ppm
Figure 2.A.1: 'H NMR spectrum of 4 in CDCl 3 (400 MHz)
TIPS
||
Br
Br
Br
Br
4
TIPS
210 200
Figure 2.A.2:
190
13
180 170 160 150 140 130 120 110
100
90
80
70
C NMR spectrum of 4 in CDC13 (125 MHz)
60
50
40
30 20
ppm
TIPS
//
o
/
/
TIPS
TIPS
inseparable mixture
anti : syn
(I. 7 1)
TIPS
/
/
/i
6-anti
/
N/
TIPS
/P
o6
6-syn
~i1
7.0
6.5
6.0
5.5
5.0
4.5
i~i
4.0
3.5
3.0
2.5
2.0
1.5
L1.0
0.5
ppm
0
ppm
Figure 2.A.3: H NMR spectrum of 6-anti/syn in CDC13 (400 MHz)
TIPS
inseparable mixture
anti :syn
(1.7 :1)
TIPS
0
/
TIP G-1/ i
TIPS
200
Figure 2.A.4:
6-anti
180
13
TIPS
160
140
o
6-syn
120
100
80
60
40
C NMR spectrum of 6-anti/syn in CDC13 (125 MHz)
20
TIPS
0
T
-
TIPS
I
A
7.0
6.5
Figure 2.A.5:
6.0
5.5
5.0
6-anti
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
ppm
NMR spectrum of 6-anti/syn enriched in 6-anti in CDC13 (400 MHz)
TIPS
T
,
O
TIPS
200
Figure 2.A.6:
6-anti
180
13
160
140
120
100
80
60
40
20
0
ppm
C NMR spectrum of 6-anti/syn enriched in 6-anti in CDC13 (125 MHz)
56
0
0
TI PS
N
7
fIPS
I
7.5
7.0
I
I
I
I
6.5
6.0
5.5
I~
5.0
I
I
I
4.5
4.0
3.5
TIPS
3.0
2.5
2.0
1.5
1.0
0.5 ppm
Figure 2.A.7: H NMR spectrum of 7 in CDC13 (400 MHz)
TIPS
A-O
O
OH
OH
TIPS
7.0
6.5
HO
-HO
6.0
/
0
8-anti
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
Figure 2.A.8: H NMR spectrum of 8-anti in CDC13 (400 MHz)
1.5
1.0
0.5
ppm
TIPS
O
O-
/
HO
HO
OH
OH
O
TIPS
200
Figure 2.A.9:
$-anti
180
13 C
160
140
120
100
80
60
40
20
0
ppm
NMR spectrum of 8-and in CDC13 (125 MHz)
TIPS
OH
OH '
0
HO
HO
-
AO
n
TIPS
8-syn
JL__
t
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
Figure 2.A.10: 'H NMR spectrum of 8-syn in CDC13 (400 MHz)
1.5
1.0
0.5
ppm
TIPS
OH
HO
0
//
O
8-syn
TIPS
I
..
200
Figure 2.A.11:
180
13 C
160
140
120
I.
--.
100
-
L
80
-
.
60
- -
--
40
NMR spectrum of 8-syn in CDC13 (125 MHz)
ll
20
0
ppm
TIPS/
8.0
7.5
7.0
6.5
9-anti
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
1.5
2.0
1.0
0.5 ppm
Figure 2.A.12: 'H NMR spectrum of 9-anti in DMF-d 7 (400 MHz)
TIPS
HO
HO
/HO
HO
OH
OH
TIPS
200
Figure 2.A.13:
180
13C
160
140
120
OH
/
OH
9-anti
100
80
60
40
NMR spectrum of 9-anti in DMF-d 7 (125 MHz)
20
0
ppm
TIPS
OH
HO
OH
HO
HO
HO
OH
OH
9-syn
TIPS
k--LJA-j,
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
ki
3.0
2.5
2.0
1.5
1.0
0.5 ppm
Figure 2.A.14: 'H NMR spectrum of 9-syn in DMF-d 7 (400 MHz)
TIPS
OH
OH
OH
//
TIPS
200
Figure 2.A.15:
180
13
160
140
120
HO
HO
HO
HO
OH
9-syn
100
80
60
40
C NMR spectrum of 9-syn in DMF-d 7 (125 MHz)
20
0
ppm
H
HO
HO
"
HO
HO
OH
O
OH
OOH
1-anti
H
LJL"
8.0
7.0
7.5
6.5
6.0
5.5
5.0
4.0
4.5
3.5
2.5
3.0
2.0
1.5
I
1.0
0.5 ppm
Figure 2.A.16: H NMR spectrum of 1-anti in DMF-d 7 (400 MHz)
L
---.
A&
200
160
180
Figure 2.A17:
13C
140
-
120
I--
lj"_&L6AL
80
100
40
60
0
20
ppm
NMR spectrum of 1-anti in DMF-d 7 (125 MHz)
H
/ HO
HO
HO
OH
HO
HO
OH
OH
H
1-syn
Lii
------------
8.0
7.5
Figure 2.A.18:
7.0
1H
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
NMR spectrum of 1-syn in DMF-d 7 (400 MHz)
1.5
1.0
0.5 ppm
H
OH
OH
/
HO
HO
HO
HO*
OH
//
H
200
180
Figure 2.A.19:
13
160
140
120
OH
1-syn
100
80
60
40
0
20
ppm
C NMR spectrum of 1-syn in DMF-d 7 (125 MHz)
NaO 3 S S
0O
n
10-O
HO
HO
--
SO Na
3
HO
HO
-
OH
OH
OH
OH
P1-anti
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
Figure 2.A.20: 1H NMR spectrum of P1-anti in D20 (600 MHz)
1.5
1.0
ppm
Table 2.A.1: Summary of photophysical data of P1-anti
Em Xmax (nm)
Abs max (nm)
451
435
P1-anti,water
462
451
P1-anti, 1X PBS
1.07
(ns)
0.61
Tsoln
1.17 (b)
1.06 (a)
1.051
1.04
1.1
U
u- 1.03
.02
1.08
1.01
1.00 -
1.05
1.02 -
U
U
U
0.990.98
<DF
19%
17%
1.20
,
,
,
log E
4.68
4.74
0.99
,
,
,
,
2
0
,
4
,
,
6
8
0.96
-
0
-
2
4
6
[Q] 1 mol/L
[Q] 1 mol/L
0.990
-
0.985 (c)
(d)
0.980
0.975
U
U
0.970-
0.9601
2
6
4
jmol/L
[Q]
8
450
500
550 600 650
Wavelength (nm)
700
Figure 2.A.21: Stern-Volmer quenching plots of P1-anti with micromolar quantities of
3-nitrotyrosine under different solvent conditions. (a) water, (b) 1X PBS, (c) 1:1
water/methanol. (d) shows the minimal fluorescence quenching response of P-peg to 3nitrotyrosine (Chapter 2.# for explanation).
Table 1.A.1: X-ray Crystallographic Data
Empirical formula
FW
Space group
a (A)
b (A)
c (A)
a (deg)
#6(deg)
y (de )
V(A)
z
dcic (g cm-3)
p (mm-')
Omax
(deg)
Reflections
collected
Unique data
GOF
RI [I>2o(1)],
wR2 (all data)
Apmaxmin
(e-A -3)
6-anti
C46H66O4Si 2
739.17
P2(1)/c
13.6286
10.5494
16.1848
90.00
104.6470
90.00
2251.32
2
1.090
0.117
29.13
36249
C46H660 Os
12 2Si2
1290.65
P2(1)/c
16.6965
11.8460
26.3463
90.00
98.013
90.00
5160.1
4
1.661
8-anti
C46H70O8Si 2
806.4609
P-1
9.0065
12.0657
12.5677
93.4460
94.1180
105.0570
1311.03
1
1.205
8-syn
C 46H700 8Si2
806.4609
P-1
12.7591
13.1605
14.7690
70.182
76.378
74.595
2220.1
2
1.207
1.131
68.89
7754
5.025
29.57
0.124
29.57
143487
35043
5364
1.021
0.0443, 0.1222
14476
1.089
0.0207, 0.0468
7347
1.029
0.0377, 0.1053
1.050
0.0457, 0.1201
0.852, -0.459
1.318, -0.455
0.521, -0.211
0.722, -0.568
7754
Figure 2.A.22: Crystal Structure of 6-anti.
Suitable crystals were grown using t-BuOH-DCM solution followed by slow solvent
evaporation. Anisotropic thermal ellipsoids set at 50% probability.
Figure 2.A.23: Crystal Structure of 7.
Suitable crystals were grown using DCM-Hexane solution followed by slow solvent
evaporation. One of the TIPS groups showed disorder in the structure (top). These
features are omitted for clarity (bottom). Anisotropic thermal ellipsoids set at 50%
probability.
66
Figure 2.A.24: Crystal Structure of 8-anti.
Suitable crystals were grown using (9:1:90) DCM-THF-Hexane solution followed by
slow solvent evaporation. Anisotropic thermal ellipsoids set at 50% probability. THF
found with structure not shown.
Figure 2.A.25: Crystal Structure of 8-syn.
Suitable crystals were grown (9:1:90) DCM-THF-Hexane solution followed by slow
solvent evaporation. The TIPS groups and other parts of the structure showed disorder
(top, anisotropic thermal ellipsoids set at 50% probability). These features are omitted for
clarity (bottom, anisotropic thermal ellipsoids set at 30% probability).
Chapter 3
Biocompatible Post-Polymerization
Functionalization
Adapted and reproduced in part with permission from:
VanVeller, B.; Swager, T. M. Chem. Commun. 2010,46,5761-5763
3.1 Introduction
(PPF)
Strategies for the post-polymerization functionalization
of polymers are
advantageous in that they allow for tuning of a polymer's properties without synthetically
retreating to the monomer stage. In effect, a variety of different polymer properties and/or
architectures can be realized late in the synthetic process from a common precursor.
Further, PPF permits the incorporation of functional groups that may be incompatible
with polymerization conditions. This chapter will focus specifically on side chain
modification of PPE polymers, while Chapter 4 will discuss PPF strategies targeted at
alterations in the conjugated polymer backbone.
Several strategies for the PPF of conjugated polymers have been reported. A
number of designs involve substitution reactions with pendant halogen,I alcohol, 2 or
carboxylic acid moieties, 3 and application of high yielding click chemistries 4 like the 1,3dipolar cycloaddtion of alkynes and azides 5 or thiol-conjugate addition 6 have also been
reported. Two potential drawbacks are characteristic of the above strategies: (i) an
appropriately functionalized monomer specific for the intended PPF must be incorporated
into the polymer synthesis-often in protected form and (ii) it can be difficult to control
the extent of functionalization.
Scheme 3.1: Molecules of interest discussed in Chapter 2.
NaO 3 S,
H
.O
n
/HO
HO
HO
O
HO
O0
OH
OH//
H
HO
OH
OH
OH
H
1OH//
SONa
-
HO
HO
HO
OH
OH
OH
p1
Chapter 2 discussed the synthesis of a rigid hydrophilic monomer (1) that-when
incorporated into poly(p-phenylene ethynylenes) (PPEs) 7 (P1)-lead to increased spectral
purity by preventing hydrophobically induced aggregate emission (Scheme 3.1).8 We
envisioned that the three dimensional array of vicinal hydroxyl groups might be further
elaborated through periodate oxidation and reductive amination (P1-+2->3, Scheme
3.2).9 Similar processes have been widely applied for bioconjugation through periodate
oxidation of carbohydrate residues, making this process compatible with existing
bioconjugation schemes.
Herein we report a biocompatible
post-polymerization
biotinylation of P1, where (i) the need for a PPF specific monomer is negated by
activation of an existing structural motif (already present in the polymer for purposes
outlined above, also see Chapter 2) and (ii) the extent of functionalization can be
controlled by the equivalents of the NaIO 4 reagent. Further, the improved spectral purity
imparted by the presence of 1 in 3a is not lost. In turn, this results in a more sensitive
signal amplified biosensorlo response to fluorophore-labeled streptavidin, a tetrameric
protein with high biotin affinity (4 x 10-14 M)1 1 that has been applied to a variety of
conjugated polymer affinitychromic3, 12 and agglutination 2b biosensor designs.
3.2 Post Polymerization Functionalization and Linkage Structure
Treatment of P1 with 0.2 equivalents of NaIO 4 in water generated 1,6dialdehyde moieties at random positions along the backbone (2, Scheme 3.2).13
Subsequent incubation with an excess of amine-containing compound (a or b) in
aqueous alkaline solution generated the putative Schiff base, which was reduced in
situ to the tertiary amine azepane 3 with NaCNBH 3 (vide infra, Scheme 3
Scheme 3.2: Post-polymerization functionalization reaction
NaO 3 S-O
n-0.2n
-
O-'
HO
HO
NaIO 4
P1
(0.2 eq.)
P1
0
H2
/HO
HO
OH
OH //
0
NaO 3
O
/ O''SONa
SONa
HO
HO
1. a orb
2. NaCNBH 3
H20
O
OH
OH
OH
OH
(40 mM)
SO3 Na
O'
HO
HO
OH
Na2HP04
-0.2n
n-O.2n
NaO 3 S,-,O
OH
/,
.2n
0'O
HO
OH
SONa
HO
HO
HO
OH
OH
OH
OH
OH
2
OH
OH
OH 3a R = Biotin-PEG -N
OH
3b R = Piv-Lys-N
0
HN
0
NH
H
S
,)N
0
H
'^
NH2
B
a, Bioin-PEG3-NH2
O
HN
t-Bu
0
NH2
b, Piv-Lys-NH 2
The proposed azepane linkage in 3 is based on two model studies. Firstly, the
broad nature of the 'H NMR signals of 3a overlapped with the weaker biotin signals
making determination of the extent of functionalization difficult. Thus, 3bexhibiting a strong, unobstructed pivalamide signal-was prepared under identical
conditions for 3a. Integration analysis revealed a 18-20% incorporation of b (Chapter
3 Appendix, Figure 3.A.5). Therefore, while 0.2 equivalents of NaIO 4 oxidant should
generate 0.4 aldehyde equivalents, there appears to only be 0.2 equivalents of the
incorporated amine. Secondly, acetonide protected 4-a synthetic intermediate in the
synthesis of 18-was treated with periodate anion and produced the tetraaldehyde 5
(Scheme 3.3a). Addition of an excess of butyl amine and NaCNBH 3 to 4 in methanol
gave 5 as the major product. Such products have been observed for bridging 1,6dialdehydes1 5 and likely form via a 7-exo-trig reductive cyclization to install one
amine for every dialdehyde present (Scheme 3.3b). Thus, we propose the PPF in
Scheme 3.2 proceeds in an analogous manner, allowing for the extent of
functionalization to be controlled by the molar equivalents of NaIO 4.
Scheme 3.3: Model studies and proposed mechanism for azepane formation
(a)
TIPS
// HO
O
HO
OH
OH
~
0
0//
NaIO 4
Os
cat. TBAIO
THF/H 20
reflux
TIPS
(b)
.
..
00
//
0
TIPS
BuNH 2
NaCNBH 3
5
'
7/
7-exo-tri
,NBu
0
MeOH, reflux
N
/
Bu'
7-exo-trig
TIPS
H
.NHBu
N
0
1. BuNH 2
2. NaCNBH 3
O
.- NBu
O
ONBu
TIPS
TIPS
7/
0
0
6
Bu
ig
I Bu
NaCNBH 3
10
10
Bu
--
.
1
11
3.3 Effect of Functionalization on Polymer Properties
The effect of the described PPF method on the photophysical properties of the
polymer can be seen in Figure 3. la and 3.1b. The absorbance and fluorescence maxima
of 3a show excellent overlap with the parent polymer P1 in both water and PBS solution,
indicating that the oxidation and reductive amination reactions leave the conjugated
polymer backbone intact. The origin of the reduced quantum yield of 3a is unclear. It is
possible that the newly installed amine lone pairs-held closely to the polymer
backbone-might quench the polymer excited state through excited state photo-electron
transfer (PET) from the electron rich amine to the polymer. To test this hypothesis the pH
of the solution was varied (pH = 1-12, Figure 3.2). In theory, at low pH, protonated
quaternary ammonium groups would be unable to participate in PET and the quantum
yield should increase sharply relative to higher pH. As seen in Figure 3.2, no dramatic
changes were observed over the pH range; the minor deviations in quantum yield are
likely due to solvent effects. The reduced quantum yield may be attributed to replacing
diol moieties with the relatively insoluble biotin, leading to a more aggregated state of the
polymer and diminished quantum yield. In any event, the effect of incorporating 1 in 3a
is still present as no lower energy excimer emission is observed and spectral purity is
maintained.
(a) 1.0j.8
0.6
0.40.2
0.0300
350
500
450
400
Wavelength (nm)
400
550
450
500
550 600
Wavelength (nm)
650
Figure 3.1: (a) Absorbance spectra of P1 and 3a in water and PBS solution. (b)
Fluorescence spectra of P1 and 3a in water and PBS solution.
1
3
9
7.4
12
pH
Figure 3.2: Effect of quantum yield of 3a at different pH. Measurements performed in
PBS where pH was adjusted with HCl or NaOH.
3.4 Response to Streptavidin as a Model Biosensor
The response to streptavidin in the presence of 3a is represented schematically
in Fig. 3.3a, where Texas Red XTM-labeled streptavidin (TRXS) is able to gather the
biotinylated polymers (3a) into a supramolecular aggregate. Amplification is achieved
through the funneling of polymer excitons to the lower energy Texas Red XTM dyes
through intra- and interchain energy migration within the aggregate. The results of
serial additions of TRXS to 3a at room temperature in PBS solution are shown in
Figure 3.3b. As anticipated, a decrease in the 3a emission and a corresponding
increase in dye emission was observed (see Section 1.3.1 for details). The amplifying
effect of the polymer sensor can be seen through direct excitation of the dye (Figure
3.3c, red). Finally, incubation of TRXS with P1 showed no response (Figure 3.3c,
black).
To better understand the nature of the interaction between TRXS and 3a and to
determine the overall quenching response, we determined the Stern-Volmer
quenching constant for the polymer emission (460 nm) in Figure 3.3b. The SternVolmer plot showed positive curvature (Figure 3.3d), which is likely due to additional
energy migration pathways within the polymer assembly' 6 produced by the strong
biotin-streptavidin association. Further, no detectable excited state lifetime change
was observed with increasing TRXS concentration, indicating that static quenching is
the dominant mechanism of energy transfer.
A comparison of the response of 3a to a previous system (12),1o which lacks
the rigid hydrophilic monomer 1, showed
a 100 fold greater quenching response
based on a Ksv values (2x10 7 mol-I vs 1
x
105 mol- 1, Figure 3.4). This higher
sensitivity is likely due to enhanced energy transfer-more excitons reaching the
dye-through avoidance of lower energy excimers (broad featureless emission in
Figure 3.4b). These states-negated by the presence of 1 in P1-are localized and
perhaps too low in energy to undergo transfer to the dye.
(a) Energy Transfer (ET) Schematic
dye-labeled
streptavidin
3a
(b)
(c)
CO
C
I
450
500
550 600 650
Wavelength (nm)
(d)
3.5
700
*1
450
500
550 600 650
Wavelength (nm)
700
U
-U
3.0
Ksv =2 x10 7
u.. 2.5
-
U-
=
U
2.0
U
1.5
U
U
1.0
0
20
80
40
60
[Q] nmol/L
100
Figure 3.3: (a) Energy transfer schematic showing how intra- and interchain exciton
migration and enery transfer to TRXS can lead to amplification. (b) Addition of 9.15
pmol aliquots of TRXS to 3.46 nmol (based on repeat unit of 3a). (c) Emission of P1
in the presence of 100 pmol of TRXS (black) and direct excitation of 100 pmol of
TRXS (red). (d) Stern-Volmer quenching analysis of data in (b).
(b)
(a)
C
C
C
450
500
550 600 650
Wavelength (nm)
700
500
450
600
650
550
Wavelength (nm)
(Ksv=2x107
700
Ksv= 1 X 105
MeO
'OX
ln-0.2n
HI
NaO 3S,
MeOk
MeO
O
Figure 3.4: Comparison of quenching response (Ksv) to TRXS between two polymers
(a) one containing a rigid structural monomer and (b) one bearing only linear PEG
side groups.
3.5 Alternative Sensore Designs for Detection of Native Analytes
In principle, the sensing scheme described above (Section 3.4 and Figure 3.3a)
can be extended to any analyte that exhibits multivalent binding of a specific ligand
bound to P1. Indeed, we hypothesize that the higher the binding valency of the
analyte, the greater the response because the larger the aggregate the greater
opportunity for absorption, exciton formation, and amplification. However, the
scheme outlined in Figure 3.3a is contingent on the streptavidin protein (or general
multivalent analyte of interest) bearing a dye suitable for energy transfer. It would be
advantages to sense native analytes that do not require modification with a specific
dye, and we hoped to extend the PPF procedure even further to allow sensing of
native streptavidin (i.e. no dye labelling).
To this end we synthesized polymers 13 (Scheme3.4) using the same PPF
strategy as above (reductive amination following periodate oxidation). Biotin along
with a small amount of Texas Red
XTM
(an amount of dye calculated to match the dye
content in Figure 3.3b) were attached in a one-step procedure. We hoped the result
would be a polymer sample rich in biotinylated polymer (3a) with a fraction of the
polymers bearing both dye and biotin (Figure 3.5). A schematic of the proposed
sensor's operation can be seen in Figure 3.5. In an analogous manner to Figure 3.3a,
the biotinylated polymers form the supramolecular aggregate induced by the presence
of streptavidin. Once polymers bearing the dye are incorporated into the aggregate,
enhanced migration pathways allow for the funneling of excitons from the polymer
aggregate into the dye for a turn on response.
3.5.1 Results and Discussion
The absorbance and fluorescence speactra of 13 in comparison to P1 are
shown in Figure 3.6a and b. Initial results were encouraging as the small signal at
-620 nm of 13 (Figure 3.6b) was attributed to emission from Texas Red
XTM
following energy transfer from the polymer (polymer excitation at 400 nm). Further,
enhanced dye fluorescence upon excitation of the polymer (Figure 3.6e, black)
compared to direct excitation of the dye (Figure 3.6e, red) confirmed amplified
energy transfer. The result of serial additions of streptavidin are shown in Figure 3.6c.
Unfortunately, the sensing scheme discussed above was not realized in practice as
there was no observed increase in dye emission with added streptavidin (as with the
analogous TRXS expeiment in Figure 3.3b). To confirm the presence of biotin
attached to the polymer, 13 was subjected to the same experiment with TRXS as in
Figure 3.3b and turn-on energy transfer to the dye was observed in an analogous way
(Figure 3.6f), albeit with reduced Ksv likely the result of a lower biotin content
relative to P1.
The failure of the proposed sensing scheme is somewhat unclear. It seems
apparent that energy transfer to the dye is occuring (Figure 3.6c and e). However, it
appears that aggregate formation with streptavidin is not generating additional,
fruitful exciton migration pathways to allow for greater amplification of the dye (see
Chapter 1.4).
Polymer 14 was then synthesized with a calculated dye content approaching
one dye per polymer. Polymer 14 can be considered to be approaching the theoretical
limit of amplification, as every polymer in the sample is capable of energy transfer to
a pendant dye even without the occurrence of aggreagation. From Figure 3.6e it is
clear that there is energy transfer to the dye occuring (signal at 620 nm with polymer
excitation at 400 nm) and amplification of the dye's fluorescence is occuring
following the same arguments for 13 as above for Figure 3.6e. Despite the fact that
every polymer theoretically possess a pendant dye, the effective energy transfer to the
dye is quite small (see the relative peak heights in Figure 3.6d). The failure of the
sensor design may lie in the fact that initial energy transfer to the dye is quite poor
and outweighs any exciton migration enhancement.
Scheme 3.4: Synthesis of fractionally dye conjugated polymer sample
NaO 38
,O
n
'O
HO
HO
-
SO
3 Na
HHO
HO
1. NalO 4 (0.2 eq.)
2. Binary Mixture
3. NaCNBH 3
H
OH
H
OH
Binary Mixture
N
0
H2 N
-
HN
o
NH
SONH(CH2)5 NH2
0 3S T
0
NH
0
13 =1:24
a
Texas Red X~~ 14 =1:4
q_
streptavidin
excess
Figure 3.5: Proposed sensing scheme for native, non-dye labelled streptavidin
( b) 1
(a)
1-0
0.8
08
- - 13 in H20
- PI in PBS
- 13 in PBS
1
-P1
-13
-P1
13
,
1.0- - P1 in H 0
2
0-
0.6-
S0.6-
0.4-
.04
10.2z
0.0-
. inH20, DF =19%
inH20, <DF = 6%
inPBS, <F =17%
in PBS, <DF = 5%
0.2
0.0
300
350
400
450
500
Wavelength (nm)
550
400
450
500 550 600 650 700
Wavelength (nm)
(d)
(c)
400
450
500 550 600
Wavelength (nm)
650
400
450
500 550 600
Wavelength (nm)
650
(f)
1.6
15
1.4
Mu
Ksv=6x10
6
*
10
0
400
450
500 550 600 650 700
Wavelength (nm)
400 450
20
40
60
80
[Q]nmo/L
10(
-
500 550 600 650 700
Wavelength (nm)
Figure 3.6: (a) Absorbance spectra of P1 and 13 in water and PBS solution. (b)
Fluorescence spectra of P1 and 13 in water and PBS solution. (c) and (d) Addition of
9.15 pmol aliquots of streptavidin to 3.46 nmol 13 and 14 respectively (based on
repeat unit). (e) Emission of 13 (black) and 14 (cyan) at 390 nm excitation and
emission of their respective appended Texas Red XTM (13, red and 14, green) at 580
nm excitation. (f) Stern-Volmer quenching analysis of data in (e). (f) Addition of
9.15 pmol aliquots of streptavidin to 3.46 nmol (based on repeat unit of 13). Inset:
Stern-Volmer quenching analysis of data in (f).
3.6 Conclusion
In summary, a biocompatible PPF strategy has been developed, which takes
advantage of existing monomer functionality and design. Further, the extent of
functionalization can be controlled through the equivalents of NaIO 4 . Finally, a highly
sensitive (Ksv = 2x10 7 mol-1) turn-on model biosensor based on ET between 3a and
TRXS was demonstrated where the presence of 1 lead to dramatically increased
sensitivity.
3.7 Experimental Section
Materials: Silica gel (40 pim) was purchased from SiliCycle. All solvents used for
photophysical experiments were spectral grade. Pd(PPh 3)4 was purchased from Strem
Chemicals, Inc. All other reagent grade materials were purchased from Aldrich, TCI
America, and Alfa Aesar, and used without further purification.
Experimental:
NMR Spectroscopy: 1H and
13C
NMR spectra for all compounds were acquired in CDCl 3,
D2 0 and DMF-d 7 on a Bruker Avance Spectrometer operating at 400 and 100 MHz,
respectively. The chemical shift data are reported in units of 6 (ppm) relative to residual
solvent.
Gel Permeation Chromatography (GPC): Polymer molecular weights were determined
using a triple detection method for calibration with poly(acrylic acid) standards on a
Viscotek TDA 305-040 instrument equipped with two Viscotek A-MBHMW-3078
columns and analyzed with light scattering and refractive index detectors. Samples were
dissolved in 5% NH4 0H.
Absorption and Emission Spectroscopy: Fluorescence spectra were measured on a SPEX
Fluorolog-t3 fluorometer (model FL-321, 450 W Xenon lamp) using right-angle
detection. Ultraviolet-visible absorption spectra were measured with an Agilent 8453
diode array spectrophotometer and corrected for background signal with a solvent filled
cuvette. Fluorescence quantum yields of 3a in both water and 1X PBS were determined
relative to perylene and are corrected for solvent refractive index and absorption
differences at the excitation wavelength.
General protocol for energy transfer assays in PBS:
50 p.L of a stock polymer solution (0.056 mg/mL in PBS) was diluted with PBS to a total
volume of 3 mL in a fluorescence cuvette. To this was added aliquots of Texas Red-XTM
labeled streptavidin (0.5 piL of a 1 mg/mL solution) and fluorescence emission was taken
at each addition. Excitation wavelength was 426 nm.
Synthetic Procedures
Biotin functionalization, synthesis of 3a: Polymer 1 (11.8 mg, 14.6 iimol based on
repeat unit) was dissolved in 4 mL of H20 and NaIO 4 (2.92 tmol in 0.2 mL) was added
dropwise under vigorous stirring. After 30 min, a (Biotin-PEG 3-NH 2, 3 mg, 7 Rmol in 1
mL of 0.2M Na2HPO 4) was added and the reaction was stirred for 20 min. A solution of
NaCNBH 3 (15 mg, 239 [mol in 1 mL of 40 mM Na 2HPO 4) was added and the reaction
stirred for 3 hours. The reaction was dialyzed against water with 5 changes of water and
lyophilized to yield 3a. GPC gave Mn = 38,474, PDI = 3.4. 'H NMR (600 MHz, D20):
67.44 (s, 2H), 4.64 (broad, 4H), 4.37 (broad, 4H), 4.05 (broad, 4H), 3.89 (broad, 4H),
3.80-3.30 (biotin, PEG), 3.18 (broad, 4H) 2.35 (broad, 4H), 1.30-0.90 (biotin).
Piv-Lysine functionalization, synthesis of 3b: Prepared using identical conditions as
above for 3a except that b (Piv-Lys-NH 2) was used in place of a. GPC gave Mn =
49,073, PDI = 4.9. 1H NMR (600 MHz, D20): 67.42 (s, 2H), 4.61 (broad, 4H), 4.35
(broad, 4H), 4.03 (broad, 4H), 3.88 (broad, 4H), 3.16 (broad, 4H), 2.33 (broad, 4H), 1.05
(broad, tBu, 1.6-1.8*).
*Based on three experiments and corresponds to 18-20%.
Synthesis of tetraaldehyde 5: A solution NaIO 4 (0.200 g, 0.935 mmol) in 10 mL of
water was added to a solution of 4 (0.200 g, 0.248 mmol) in 10 mL of THF. Solid
TBAIO 4 (54 mg, 0.124 mmol) was added directly and the solution was refluxed for 30
min. After cooling, the reaction was partitioned between EtOAc and brine and the
organic phase collected. The aqueous layer was washed with fresh EtOAc and the
combined organic layers were dried over Na 2 S0 4 and concentrated in vacuo. The residue
was eluted through a silica gel plug using EtOAc to give 5 (95%). 1H NMR (400 MHz,
CDCl 3): d 9.65 (d, J=2, 4H), 4.98 (nfo, actual ddd, J=6.6, 2.8, 2, 4H), 4.89 (dd, J=6.6,
2.8, 4H), 1.48 (s, 6H), 1.46 (s, 6H), 1.12 (s, 42H). 13C NMR (125 MHz, CDCl 3) 8 197.6,
134.1, 125.9, 110.7, 105.7, 101.2, 73.9, 54.5, 25.9, 24.2, 18.8, 11.4. HRMS (EI) calcd. for
C4 6H66 O8 Si 2 [M+H] 803.4369, found 803.4344.
Synthesis of amine 6: To a solution of 5 (0.150 g, 0.186 mmol) in 10 mL of MeOH was
added butyl amine (82 mg, 1.12 mmol). After stirring for 10 min at room temperature,
NaCNBH 3 (0.250 g, 3.98 mmol) was added and the mixture was refluxed for 3 hours.
Once cool, 1 mL of Sat. NaHCO 3 was added and the solvent was removed in vacuo. The
residue was partitioned between DCM and sat. NaHCO 3 . The organic layer was dried
over Na 2 SO 4 and evaporated to dryness. Silica gel chromatography (EtOAc:Hex, 8:2)
provided 6 (65%) as a white solid. 1H NMR (400 MHz, CDCl 3): d 4.33 (dd, J=4.0, 2.4,
4H), 4.00 (m, 4H), 2.84 (d, J=12, 4H), 2.58 (dd, J=1 1.8, 7.5, 4H), 2.29 (br t, 4H), 1.64 (s,
6H), 1.40 (s, 6H), 1.28 (in, 4H), 1.12 (br s, 42H), 1.06 (m, 4H), 0.74 (t, J=7.4, 6H).
13
C
NMR (125 MHz, CDCl 3) 6 139.5, 119.8, 110.8, 103.2, 98.3, 76.5, 57.4, 48.7, 41.5, 28.7,
25.9, 24.7, 20.7, 19.0, 14.1, 11.6. HRMS (El) calcd. for C54H 88N 2O 4 Si2 [M+H] 885.6355,
found 885.6357.
3.8 References
1 (a) C. Xue, F. T. Luo, H. Y. Liu, Macromolecules, 2007, 40, 6863; (b) C. Xue, V. R.
R. Donuru, H. Y. Liu, Macromolecules, 2006, 39, 5747; (c) Y. Li, G. Vamvounis, J.
Yu, S. Holdcroft, Macromolecules, 2001, 34, 3130; (d) J. Tolosa, C. Kub, U. H. F.
Bunz, Angew. Chem. Int. Ed., 2009, 48, 4610.
2 (a) C. A. Breen, T. Deng, T. Breiner, E. L. Thomas, T. M. Swager, J. Am. Chem. Soc.,
2003, 125, 9942; (b) J. N. Wilson, Y. Wang, J. J. Lavigne, U. H. F. Bunz, Chem.
Commun., 2003, 1626.
3 S. Bernier, S. Garreau, M. Bera-Aberem, C. Gravel, M. Leclerc, J. Am. Chem. Soc.,
2002, 124, 12463.
4 H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed., 2001, 40, 2004.
5 (a) B. C. Englert, S. Bakbak, U. H. F. Bunz, Macromolecules, 2005, 38, 5868; (b) T.
L. Benanti, A. Kalaydjian, D. Venkataraman, Macromolecules, 2008, 41, 8312; (c) H.
B. Bu, G. Gbtz, E. Reinold, A. Vogt, S. Schmid, R. Blanco, J. L. Segura, P. Bauerle,
Chem. Commun., 2008, 1320; (d)
Q. Chen,
B. H. Han, J. Polym. Sci., PartA: Polym.
Chem., 2009, 47, 2948.
6 G. C. Bailey, T. M. Swager, Macromolecules, 2006, 39, 2815.
7 B. VanVeller, T. M. Swager, Poly(aryleneethynylene)s. In Design and Synthesis of
ConjugatedPolymers, M. Leclerc, J. Morin, Eds. Wiley-VCH: Weinheim, 2010; pp
175-200.
8 B. VanVeller, K. Miki, T. M. Swager, Org. Lett., 2010, 12, 1292.
9 G. T. Hermanson, Bioconjugation Techniques. Elsevier Science: San Diego, 1996.
10 J. Zheng, T. M. Swager, Chem. Commun., 2004, 2798.
11 N. M. Green, Methods Enzymol., 1990, 184, 51.
12 E. Geiger, P. Hug, B. A. Keller, Macromol. Chem. Phys., 2002, 203, 2422.
13 IH NMR analysis of 2 showed little bias regarding which diol moiety (endo or exo)
was oxidized.
14 Based on three experiments.
15 (a) G. F. Painter, A. Falshaw, H. Wong, Org. Biomol. Chem., 2004, 2, 1007; (b) V.
Bonnet, R. Duval, V. Tran, C. Rabiller, Eur. J. Org. Chem., 2003, 4810; (c) A.
Robinson, G. L. Thomas, R. J. Spandl, M. Welch, D. R. Spring, Org. Biomol. Chem.,
2008, 6, 2978; (d) P. R. Brooks, S. Caron, J. W. Coe, K. K. Ng, R. A. Singer, E.
Vazquez, M. G. Vetelino, H. H. Watson, D. C. Whritenour, M. C. Wirtz, Synthesis,
2004, 1755; (e) A. H. Fray, D. J. Augeri, E. F. Kleinman, J. Org. Chem., 1988, 53,
896; (/) P. Stoy, J. Rush, W. H. Pearson, Synth. Commun., 2004, 34, 3481.
16 (a) I. A. Levitsky, J. S. Kim, T. M. Swager, J. Am. Chem. Soc., 1999, 121, 1466; (b)
Satrijo, A.; Swager, T. M., J. Am. Chem. Soc., 2007, 129, 16020.
Chapter 3 Appendix
'H-NMR, 3 C-NMR,
UV-vis and Fluorescence data
0
0~0
TIPS
J
-L
10
9
8
7
6
5
4
3
2
1
ppm
20
ppm
Figure 3.A.1: H NMR spectrum of compound 5 in CDC13 (400 MHz)
TIPS
0~
o
0<
TIPS
210
200
Figure 3.A.2:
190
13
180 170
160 150 140
130 120
110 100
90
80
70
60
50
40
C NMR spectrum of compound 5 in CDCl 3 (125 MHz)
30
TIPS
XO
0
//
N
O
N
O'?
N'//
ii AA
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
LI~
.
2.0
1.5
1.0
0.5
ppm
Figure 3.A.3: H NMR spectrum of compound 6 in CDC13 (400 MHz)
TIPS
O
N
N
O
TIPS
ii
I
4114 No
190
180
Figure 3.A.4:
170
13
160
150
140
130
11- IN
I'mah
ill,
120
110
100
I
Ld-W-1. .. ..
I
I
90
80
70
60
50
40
C NMR spectrum of compound 6 in CDCl 3 (125 MHz)
30
20
ppm
NaO 3 S-..
O
n-O 2n
.
O
HO
HO
O
OH
NaO3 S
O
O
/O
HO
OH
OH
/
OH
0.2n
..-
HO
'SO
3
Na
N
0
-
/
6H
OH
f-8U
NH
OH
OH
-'SONa
"HO
HO
.
OH
0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5 ppm
Figure 3.A.5: 'H NMR spectrum of compound 3b in D20 (600 MHz)
NaO3
...
..
...
n-02n
S0
HO
HO
OH
OH
OH
OH
H
OH
H
0OH
SONa
HO
HO
HN NHf
NH
S
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
Figure 3.A.6: 1H NMR spectrum of compound 3a in D20 (600 MHz)
Table 3.A.1: Summary of photophysical data of 3a
Abs Xmax (nm)
Em Xmax
log E
(nm)
4.52
451
436
3a, water
461
4.58
3a, 1X PBS
450
O)F
8%
7%
1.0
0.5 ppm
Chapter 4
Trypticene Diol Scaffolds
for n-System Elaboration
4.1 Introduction
Critical to the performance of many polymer electronics is the presence of chain
planarity along the polymer backbone. Coplanarity of the adjacent monomers (often
aromatic moieties of some structural type, see Chapter 1, Figure 1.1) allows for more
effective overlap of adjacent it-orbitals, resulting in less energetic disorder along the
backbone. The result is more efficient exciton delocalization and charge transport (along
the a-way). Strategies for the synthesis and introduction of highly planarized, a-extended,
monomers have been reported for a variety of different classes of conjugated polymers.
However, the synthetic strategy is often only applicable within one structural class.
Iptycenes are molecules built upon [2,2,2]-ring systems in which the bridges are
aromatic rings 1, and their three dimensional shape creates interstitial free volume around
the molecule. A growing number of research efforts have been reported using the rigid
three-dimensional structure of iptycenes to introduce new supramolecular interactions
and achieve new material properties.1' 2
Free
Volume\\
OH
2
3
1
The simplest member of the iptycene family is the trypticene 2. Recently, Taylor
and Swager reported an efficient synthesis of a trypticene diol (TD, 3), bearing alcohols
at the bridgehead carbons (Scheme 4. 1).3 Starting from anthraquinone (4), a moderately
selective syn-addition of lithium acetylide provided 5. Once deprotected (5-+>6) the newly
installed syn-alkynes were shown to be geometrically disposed to Rh catalyzed [2 + 2 +
2] cycloaddition with either terminal alkynes or norbornadiene (an acetylene equivalent,
vide infra) to give the TDs (7 and 8).
Scheme 4.1: Synthesis of trypticene diols through [2+ 2 +2] cylcoaddtion
Li =
KOH
R'
Toluene
2.1:1 selectivity
MeOH, THF
R1 = TMS
R1 = Ph, TMS
R1
~~~
5or6
H'
5
6
R2
Rh(PPh 3)3CI
5
-
Toluene, 100
OC
[Rh(cod)C] 2
Toluene, 100 OC
()
R1= Ph, H
R' =Ph
We hoped to extend this method into 1,4-dihalogen variants suitable for Pdcatalyzed cross-coupling with a variety of a-systems (Figure 4.1). We theorized the rigid
scaffold enforced by the trypticene would hold the alcohol and newly coupled it-system
in close proximity to promote cyclization under appropriate conditions. The result would
be a higher order planarized trypticene it-system. When incorporated into conjugated
polymers, this should allow for an increase in conjugation length. Additionally, this
strategy would allow us to evaluate cyclization with x-systems of different structural
classes.
Rigid scaffold enforces
close proximity of alcohol
and reacting partner
X
Pd-catalyzed
cross-coupling
Cyclization
HO
X
1,4-dihalogen subsituted
trypticene diol
Extended planar
n-system
Figure 4.1: Rational for the potential of trypticene diols for cyclization and extended
planar i-systems.
4.2 Dihalogen Substituted Trypticene Diols
Synthesis of TDs-bearing the 1,4-halogen substitution pattern proposedfollowed the same strategy of the initial TDO synthesis outlined in Scheme 4.1. However,
for reasons unclear, the presence of bromine substituents did not permit direct transfer of
previous synthetic conditions. Thus, a modified synthesis is presented herein (Scheme
4.2). Starting from commercially
available
9, a Sandmeyer reaction afforded
dibromoanthroquinone 10 in excellent yield. Double addition of TIPS acetylide to 10 in
toluene provided the syn-addition product (11) with modest selectivity (2.3:1, the
analogous TMS acetylide reagent gave a 1:1 mixture of syn and anti addition products).
Finally, fluoride deprotection revealed the cyclization substrate 12.
procedure showed Wilkinson's catalyst [Rh(PPh 3)Cl]
The previous
to be superior for [2 + 2 + 2]
cycloaddtion, but this protocol was completely ineffective for 12-again, the failure of
these conditions for the dibromo substrate is unclear. The ruthenium catalyst
[CpRu(PPh 3)2C] in dioxane was found to be superior for the [2 + 2 + 2] cycloaddtion
with terminal alkynes to yield enantiomeric products (13-15).
Finally, the formal
cycloaddtion with acetylene was obtained (16) by reaction of norbornadiene in the
presence of [Rh(cod)C12], a reaction postulated to proceed by [2 + 2 + 2] cycloaddtion
followed by retro-Diels-Alder reaction and expulsion of cyclopentadiene.4
With the 1,4-dibromo trypticene diol scaffold in hand, we sought to investigate
the proposed cyclization pathway outlined in Figure 4.1 with three different 7-systems:
alkynes (Section 4.3), phenyls (Section 4.4), and thiophenes (Section 4.5).
94
Scheme 4.2: Synthesis of 1,4-dibromo substituted trypticene diols
TIPS
o
CuBr 2
t-BuONO
O
MeCN
65 OC
94%
NH2
9
o
Br
Br
Li-=---TIPS
TBAF
Toluene
65 OC, 70%
THF, rt
91%
10
H/
12
R
OH
HO
Br
/\
(*)
Br
CpRu(PPh 3)2C
12
Dioxane
105 OC
[Rh(cod)CI] 2
/
W.
OH
Br
--
Toluene
105 OC, 87%
HO
Br
16
13 R = n-Bu, 89%
14 R = n-Oct, 85%
15 R = n-Dec, 86%
4.3 Cyclization with Alkynes
Our initial investigation of substituent-cyclized TDs focused on alkynes due to the
large literature surrounding alcohol cyclization onto alkynes using Lewis acids (Scheme
4.3).5 Further, in the context of polymer chemistry, we envisioned such a transformation
might also provide an uncommon form of post-polymerization modification.
Scheme 4.3: Proposed cyclization of TDs onto alkynes
H
~-
R
Sonogashira
cross-coupling
/
Lewis acid
catalyzed
cyclization
R
/O
6-endo-dig
0-
R
18
Chapter 3 discussed post-polymerization functionalization as an efficient strategy
for late stage polymer diversification in the context of side chain modification or
elaboration. A far more rare type of post-polymerization modification is alteration of the
polymer's main chain or backbone. This type of transformation is inherently different as
the polymer's identity as a conjugated polymer is fundamentally changed to a different
class of conjugated polymer. Scheme 4.4 outlines some examples that have been applied
to main chain alteration of poly(p-phenylene ethynylene)s (PPEs) through reduction of
the triple bonds. The full reduction of PPEs to the unconjugated poly(p-xylene)s can be
achieved under a variety of hydrogenation conditions (19-+->20),6-8 and the partial
reduction to cis-poly(p-phenylene vinylene)s (PPVs) was recently reported by Moslin and
Swager (19--21).9
Scheme 4.4: PPE main chain reduction
R
2. i-PrMgCI
or
R
R
20
TosNHNH 2
NPr 3, 110 0 C
-n
n
1
1. Ti(Oi-Pr)4
R
RhCI(PPh 3)3/H
500 bar, 350 0C2
-
R
3. H20
19
-n
-
21
R
In the context of the transformation outlined in Scheme 4.3, such a reaction of a
PPE possessing the TD moiety would result in a trans-PPV.Further, it would provide for
a rarely seen substitution of the vinyl segment of a PPV with an electron donating oxygen
group,10 11 all while creating greater planarity in the PPV backbone.
4.3.1 Synthesis of Model Compounds for Cyclization
Compound 16 was used to investigate the cyclization reaction with alkyne
substituents. Compound 22 was initially synthesized by Sonogashira cross coupling for
investigation
as
a polymerizable
monomer
(Scheme
4.5). Interestingly,
upon
deprotection, spontaneous metal-free cyclization occurred on one side of the molecule to
give 23. NMR analysis indicated the product to be the 5-exo-dig cyclization (based on
vinyl coupling constants), and X-ray crystallography revealed how closure of the fivemembered ring prevents cyclization on the other side by pulling the alkyne and alcohol
apart. Investigation of molecular models suggested that cyclization of the alcohol oxygen
onto the terminal carbon of the alkyne (6-endo-dig) would lead to a less strained 6-
membered ring with less structural distortion, and might allow for double cyclization to
take place.
Scheme 4.5: Spontaneous metal-free 5-exo-dig cyclization
\
HO
OH
PdCl2 (PPh 3) 2
Cul
_
Toluene, NEt 3
Br
/''''/HO
85
16 Br
/
SiMe 3
/
SiMe 3
OH
.~~~
//
0C,
22
Me3 Si
TBAF, THF
or
KOH, MeOH, THF
87%
.d
5-exo-dig
0
X-ray of 23
-- /
HO
//23
H
Phenyl acetylene analogue 24 was found to not undergo spontaneous cyclization,
which allowed for exploration of the 6-endo-dig cyclization through electrophilic
activation of the alkyne (Scheme 4.6). Gratifyingly, treatment with electrophilic iodine
sources5h provided the double cyclization product (25)-consistent with the 6-endo-dig
hypothesis above. Further, electrophilic gold(III) proved moderately effective in
promoting the 6-endo-dig isomerization of 24 to the mono- and doubly cyclized
compounds 26 and 27.
Compound 27 displayed poor solubility making analysis and further method
development difficult. To this end, compound 14, bearing a solubilizing alkyl side chain
was elaborated to the diphenyl acetylene 28 (Scheme 4.7). Subsequent 6-endo-dig
isomerization of the alkyne to the oxygen substituted alkene (28--+29) using a more
active gold(I) catalyst system provided 29 in good yield (spot to spot conversion by
TLC). We now felt confident that we could extend these methods to reactions on
polymers for the post polymerization alteration of PPEs into PPVs. Finally, as an aside,
the 1H NMR chemical shift for the bridgehead alcohol in the alkyne precursors 22, 24,
and 28 was found further downfield (6 5.6-5.9) relative to more typical benzyl alcohols (6
4.5) indicating some through space deshielding effects from the phenylene ethynylene Rsystem.
Scheme 4.6: Electrophilic activation of 6-endo-dig cyclization
ICI, DCM
-
/
OH
HO
16 Br
~780C to rt
Ph
86%
PdCl 2(PPh 3)2
Br
Cul
OR
12,NaHCO 3
MeCN, rt
24%
Toluene, NEt 3
85 OC, 93%
AuCl3
6-endo-dig THF:MeCN
(4:1), rt
X-ray
of 27
H
0
-
27
Yo
-
40%
Scheme 4.7: Electrophilic activation of 6-endo-dig cyclization of more soluble variants
n-Oct
/I'
/
110
10
14 Br
/
-Ph
OH
/Io__
Ph3PAuCI (6 mol%)
AgSbF6 (6 mol%)
B
PdCl 2(PPh 3)2
Br
Cul
_
-
/O
_
THF:DCE (1:1)
rt, 4 h, 85%
Toluene, NEt 3
85 OC, 93%
98
0
-
29
4.3.2 Polymer Synthesis and Cyclization
To examine the effectiveness of the electrophilic gold(l) conditions in the context
of a polymer, compound 14 was polymerized with 1,4-diethynylbenzene under
Sonogashira conditions (Scheme 4.8). Compound 14, in addition to the n-octyl side
chain, is also racemic. This leads to a region-random orientation of the n-octyl side chain
along the polymer that assists in solubility (i.e. interpolymer crystallization is impeded by
the random orientation of side chains). Unfortunately, while reasonably high molecular
weight polymer was isolated 30 (M, = 12,500, PDI = 1.44, DP = 24), the yield was low
due to large quantities of insoluble polymer presumably too long in length to be soluble.
In any case, 30 was subjected to a two stage addition of gold(I) catalyst to produce
cyclized polymer 31 (Mn = 14,700, PDI = 1.16 DP = 28) as expected. The increase in
molecular weight of 31 relative to 30 is likely due to the increased rigidity along the
chain. The rigidity increases the persistence length of the polymer making it appear larger
under size exclusion measurements.
Scheme 4.8: Polymerization and post- cyclization
n-Oct
n-Oct
PdCl 2(PPh 3 )2
OH
/
HO
14
Br
+
uiOH
\
-85
Toluene, NEt3
OC
H
Br
30
n-Oct
n
//
Ph3PAuCI (20 mol%)
AgSbF6 (20 mol%)
THF:DCE (1:1)
rt, 24 h
/
0
O
0
/
-
99
4.3.3 Photophysical Properties
The effect of the transformation on the x-system of 29 can be seen in Figure 4.2.
Both 28 and 29 show very small stokes shifts when considering the band edges of
absorption (ignoring the (0,0) absorption transition is not the
Xmax).
However both the
absorbance and fluorescence maximums of 29 red-shift by almost 100 nm (Figure 4.2b
and d)(Table 1). This closing of the band gap energy is ascribed to both the increased
planarity of 29 and the presence of electron rich oxygen donor atoms on the alkene,
which raise the HOMO level. Indeed, the band gap of 29 appears to be among the
smallest for any phenylene vinylene trimer bearing either electron withdrawing or
donating substituents. 12-18 The increased planarity was also evidenced by the distinctly
sharper emission features of 29 which reveal the vibrational transitions. Further, an
associated increase in fluorescence quantum yield was observed for 29 compared to 28
(Table 1), likely due to removal of vibrational relaxation through planarization and
rigidification. Interestingly, the (0,0) transition of both 28 and 29 are not the most intense
bands in the absorption spectrum (Figure 4.2a and c), but they are the most intense in the
emission spectrum. This indicates the terminal phenyl rings for both 28 and 29 may not
be coplanar in the ground state but are so in the excited state.
Similar effects observed between the model small molecule compounds 28 and 29
were also seen for polymers 30 and 31. Both polymer band gaps are diminished relative
to their small molecule analogues due to greater delocalization along the conjugated
polymer backbone (Figure 4.3). Again, small Stokes shifts were observed for both
polymers and polymer 31 showed approximately a 100 nm red shift in absorbance and
emission upon cyclization (Figure 4.3b and d) (Table 1). Further, the planarity imparted
to 31 preserves the vibrational fine structure even in a less structurally defined
polydisperse polymer. In contrast to 29, polymer 31 did not have an associated increase
in fluorescence quantum yield relative to precursor polymer 30. This is likely due to the
fluorescence lifetime (TF) of 31 being more than double that of 30 (Table 1) allowing
more time for non-radiative deactivation of the excited state. It is indeed ironic that the
cyclization, originally designed to impart better spectral features and properties through
planarization, prolongs the lifetime of the excited state such that polymer 31, hoisted by
its own petard, has a lower observable quantum yield.
100
0)
0
-
C
300
400
500
600
Wavelength (nm)
Figure 4.2: Absorbance traces for 28 (black) and 29 (green) and fluorescence traces for
28 (blue) and 29 (red) in CHCl 3.
C
0)
%%00
CD
300
400
500
600
Wavelength (nm)
700
Figure 4.3: Absorbance traces for 30 (black) and 31 (green) and fluorescence traces for
30 (blue) and 31 (red) in CHCl3 .
101
The thin film spectra of both polymers are shown in Figure 4.4. Both polymers
remain visibly fluorescent in thin film, and 31 still maintains a significant red shift
relative to 30 (Figure 4.4b and d). It would appear that the trypticene is not sufficient to
prevent n-t interactions between polymer chains as both polymers display significant
broadening of their absorbance and fluorescence spectra; however, polymer 31 appears to
retain some vibrational structure in its fluorescence spectrum (Figure 4.4c).
C:
(0
C
300
400
500
600
700
Wavelength (nm)
Figure 4.4: Absorbance traces for 30 (black) and 31 (green) and fluorescence traces for
30 (blue) and 31 (red) in thin film.
102
Table 4.1: Summary of photophysical data
Compound abs Amax
em
2Amaxa
log ,
DF
TF
Eg,opticaib
[ns]
[eV]
[nm]
[nm]
28
322
349
4.74
0.65
1.11
3.5
29
395
427
4.63
0.89
1.77
2.8
30
372
408
4.62
0.74
0.53
2.8
31
460
507
5.23
0.46
1.28
2.4
30, film
384
495
0.15
1.20c
2.8
31, film
435
523
0.03
1.10d 2.3
a Measured in CHCl 3, b Band gap, estimated by onset of absorption
spectrum
c Bi-exponential lifetime 82.9%. Second exponential 3.5 ns, 17.1%
d Bi-exponential lifetime 91.7%. Second exponential
3.0 ns, 8.3%
4.3.4 Electronic Properties
Cyclic voltammetry was used to investigate the redox behavior of the cyclized
model 29 and the two polymers discussed above (Figure 4.6). In the case of the
molecules discussed, the newly introduced electron donating oxygen atoms should result
in a more electron rich system that is more readily oxidized as opposed to reduced
(however, the rigid structure may limit the extent of donation relative to an alkoxy side
chain because the oxygen must an energy penalty to assume sp2 hybridization for
donation). This was indeed the case as 29 showed reversible single electron oxidation at
+1.05 and +1.39 V in solution (Figure 4.6a). It is interesting to note that the completely
unsubstituted distyrylbenzene 32 (Figure 4.5) is more readily reduced (single electron
reductions at -2.48 V and -2.74 V) further demonstrating the power of substitution to
tune the HOMO-LUMO levels of conjugated polymers.
n-Oct
n
-
0
enol ether,
potential nucleophile
t__
1'0
32
31
Figure 4.5: Distyrylbenzene 32 and potential nucleophilic site in 31
103
8.0
(a)-Scan
1
-Scan 2
- Scan 3
-
Figure
4.6:
Cyclic
voltammograms for 29 (a)
and 31 (b) in solution, and
thin films of 31 (c), and 30
(d).
Measurements performed
under nitrogen in degassed
solvents, DCM for (a) and
(b) and MeCN for (c) and
4.0-
0.0
-4.0
2.0
-
(b) -Scan
(d).
1
Scan 2
-Scan
3
n-Oct
1.0 k
-Oc"
0
-
0.0 L
-1.0
10
(c) -Scan
8.0
-
1
-Scan2
-
Scan 3
n-Oct
6.0
ZNn
4.0
\
0
2.0
0.0
-2.0
4.0
-
3.0
(d) -
Scan 1
-
Scan 2
Scan 3
2.01.0 0.0
-1.0 L.
0.0
1.5
1.0
0.5
Potential (Vvs. SCE)
2.0
104
Electrolyte
=
0.1
AgNO 3/0.1 TBAPF 6. 1.6
mm diameter Pt button
electrode. Scan rate = 50
mV/sec
/
ZN
-
In contrast to 29, polymer 31 undergoes irreversible oxidation at a similar
potential in solution (Figure 4.6b). This irreversibility is even more evident in the thin
film (Figure 4.6c) where solid-state effects such as counter ion penetration into the film
may prevent reversibility. The difference in behavior of 29 and 31 is unclear. Another
possibility regarding the thin film of 31 is the nucleophilic nature of the enol ether
present (Figure 4.5). Perhaps, cations generated on adjacent chains are attacked by the
enol ether and irreversibility crosslinked.
PPEs typically display poor electrochemical behavior so it is not surprising that
30 also displays irreversible oxidation. The polymer shows a first wave oxidation. The
propensity to oxidize might stem from through space donation of the nonbonding
electrons of the alcohol to the 7-system.19
4.3.5 Conclusions: Alkyne Cyclization
In summary, we have developed a highly efficient strategy to introduce planarity
along a conjugated polymer backbone using a catalytic main chain alteration of a PPE
into a different class of conjugated polymer, a PPV (Figure 4.7). As predicted, the PPV
demonstrates red shifted photophysics, and the established planarity provides it with well
defined vibrational features. The effect of the trypticene, the simplest member of the
iptycene family, does not appear sufficient to suppress unfavorable a-7U interactions
between polymer chains in thin film. Finally, while the small molecule model compounds
displayed reversible redox behavior, the polymer versions suffered from irreversible
oxidation.
n-Oct
n-Oct
\n
Au(I)
OH
HO
MO
--
Figure 4.7: General transformation for a PPE to a chain rigidified PPV via gold(l)
catalysis
105
4.4 Cyclization with Phenyl Groups
We next turned out attention to cylcization of TDs onto other ir-systems. Phenyl
groups were a promising target as the cyclization would result in a highly planarized
penylene moiety. Phenylenes have received wide attention as blue emitting materials for
organic light emitting diodes (OLEDs). 20 Thus, the highly planarized structure might lead
to a higher performing phenylene through greater charge delocalization and mobility.
Scheme 4.9: Synthesis of planarized phenylene model compound
(3 eq.)
&B(OH)2
,Br
PdCI 2 (PPh 3 ) 2
)
THF
K3 PO4 (0.5M)
60 0C, 98%
I-
/
-
OH
y /
/
HO
K2 S 2 0 8 (4 eq.)
Cu(OAc) 2 (8 eq.)
KOAc (12 eq.)
AcOH, 113 0C
-
77%
\
/
32
/0
0
-
\
/
33
X-ray of 33
To investigate the feasibility of TD cyclization with benzene, 32 was synthesized
in a straight forward manner from 16 under Suzuki conditions (Scheme 4.9). The
cyclization was achieved under oxidative conditions using Cu(II) and persulfate.
Presumably, the reaction occurs by oxidation of the phenyl rings followed by attack by
the proximal alcohol and subsequent rearomatization. Oxygen radical attack by the
alcohol may also be playing a role as oxygen radical generation has been associated with
these conditions.n-2 4
106
= 81%8
4abs = 3 5 nm
(IDF
Xem = 359 nm
0
-0 3-
0300
400
350
Wavelength (nm)
450
Figure 4.8: Absorbance and fluorescence data for compound 33
The effect of the cyclization and planarization of the terphenylene moiety in 33 is
evident from sharp absorbance and emission spectrum (Figure 4.8) similar to 29 above.
The rigidity of the system preserves the vibronic structure of the electronic transitions
and endows it with a fairly high quantum yield.
4.4.1 Future Applications of Phenyl Cyclized Trypticene Diols
Current synthetic efforts are focused on the synthesis of polymers based on 33
(Scheme 4.10). Suzuki poly-condensation polymerization of 14 with benzene-1,4bis(pinacol boronic ester) should lead to the alternating copolymer 34. Following,
oxidative cyclization would lead to a polymer with monomers held in what is called a
ladder polymer structure (the polymer is composed of fused ring systems). Further, the
alternating trypticene motif would result in a polymer possessing a repeating structure
that more closely resembles a pentypticene architecture, a molecular shape more effective
at decreasing interpolymer x-7i interactions (Chapter 2, Figure 2.3). The racemic nature of
14 would also be helpful for solubility as discussed above for 31. Unfortunately, the
presence of benzylic positions in 35 might require a more mild oxidation protocol.
107
Scheme 4.10: Future application for ladder phenylene polymers
n-Oct
(3 eq.)
O
/B
/ OH
Br
Br
n-Oct
O0
&
B
/O
Pd cat.
HO
34
14 Br
n-Oct
Oxidation
---------------
n-uct
/
/--
/
0/
~-35
4.5 Cyclization with Thiophenes
Finally, thiophenes were investigated in the cyclization with TDs (Scheme 4.11
and 4.12). The Suzuki cross-coupling between TD and thiophene boronic acid was found
to be most efficient using a newly developed palladium precatalyst (16-+36 and 37).
Unfortunately, the oxidative conditions applied to the phenylene series failed to yield any
cyclized product (36--38). This unsurprising result is likely due to the electron rich
nature of thiophene and its propensity for oxidative polymerization. To investigate this
result further, a methyl-capped analogue was prepared (36) and subjected to the oxidative
conditions. A highly polar molecule was isolated from the reaction mixture which, based
on preliminary characterization (IR, 1H NMR), was found to possess sulfonic and
carboxylic residues (39). Further, based on its absorbance and fluorescence spectrum
(Figure 4.9a) appears to be a cyclized product. From these results is appears the
thiophene moiety is too sensitive to undergo cyclization under such strongly oxidizing
conditions.
108
Scheme 4.11: Oxidative cyclization of trypticene diols with thiophenes
(3 eq.)
R
s
B(OH) 2
-R
Pd cat.
K2S208 (4 eq.)
Cu(OAc) 2 (8 eq.)
KOAc (12 eq.)
0
Ac H
R =H
THF
K3PO4 (0.5M)
-/O
38
Ss
40 0C, 98%
K2 S20 8 (4 eq.)
Cu(OAc) 2 (8 eq.)
KOAc (12 eq.)
AcOH, 113 OC
R = Me
Pd cat.
C02H
XPhos-Pd-NH 2
CI
0
-
\
-:0
HO2C
39
(tentative structural assignment)
O
350 400 450 500 550 600650
Wavelength (nm)
300
350
400
450
Wavelength (nm)
Figure 4.9: Absorbance and fluorescence data for 39 (a) and 41 (b).
109
500
Scheme 4.12: Cyclization by acid catalyzed trans-etherification
OMe (3 eq.)
\\MeO
OH
C/s
Br
-
HO
16
Br
/
B(pinacol)
OH 3
Pd cat.
/-
THF
K3PO4 (0.5M)
rt, 82%
H
HOH
TsOH
eH 2 0
Toluene
-
85 0C
S
\13
S
0
S
40
75%
0
-
38
OMe
X-ray of 38
In general, 3-methoxythiophene derivatives are known to undergo substitution of
the methyl ether group under acid catalyzed conditions.
In the context of 40 the alcohol
of the TD is held in close proximity to the carbon in the 3-position of the thiophene
(Scheme 4.12). Thus, upon protonation of the methoxy group, a 6-membered transition
state attack of the TD alcohol on at the thiophene 3-position resulted in the desired
cyclized product 41. As expected, the photophysical characteristics of 41 are in alignment
with all of the cyclized TD molecules presented thus far, sharp vibrational transitions and
minimal stokes shift (Figure 4.9b). An interesting result is also observed in the 1H NMR
spectra of the 40 and 41. The methoxy signal along with the TD alcohol and even the
protons on the "wings" of the TD are broadened, perhaps due to rotamers and
intermolecular hydrogen bonding (Figure 4.10 top). Upon cyclization, removal of the
rotational degrees of freedom produces a sharply defined spectrum (Figure 4.10 bottom).
110
OMe
H
OH
-
H
H
0
H
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
Figure 4.10: Comparison of the 'H NMR spectra of 40 (top) and 38 (bottom).
4.5.1 Future Applications of Thiophene Cyclized Trypticene Diols
Compound 41 might show promise as a monomer for polymer solar cells based
on the bulk heterojunction (BHJ) design. The BHJ structure is usually formed by
blending a p-type conjugated polymer with an n-type fullerene to form a bicontinuous,
interpenetrating network. Power conversion is achieved through absorption of a photon
by the conjugated polymer and charge separation of the excited electron onto the n-type
fullerene, leaving the hole on the p-type polymer. Critical to the success of this process is
the interaction between polymer and fullerene. Crystallization and phase separation
between the two materials can often lead to inefficient charge transfer and lower current
output. Finally, also critical to device efficiency is the charge mobility within the
polymer; as once charge separation occurs, the hole must rapidly diffuse to the electrode
or charge recombination might result (i.e. a waste of a photon).
111
It is our hope that the structural characteristics of 38 might lend some
improvement to both the phase separation and charge mobility issues mentioned above.
Monomers similar to 38, possessing the same planarized thiophene-phenylene-thiophene
structural motif, have already been shown to improve hole mobility in solar cells with
efficiencies greater than 6% (Figure 4.11 a).26 Further, pendant alkyl phenyl groups in 41
are stereochemically perpendicular to the planar a-system. The phenyl "wings" of the
trypticene in 38 are similarly disposed, indicating the three-dimensional effect might not
be detrimental to charge mobility within the polymer. Regarding the charge separation
interface (heterojunction), trypticenes have long been known to form intercalating
networks with fullerenes (Figure 4.11b). 27 -30 It is conceivable that the polymers
incorporating 38 would be less prone to phase segregation and reduced charge separation
efficiency.
(a)
(b)
C6H13C6H13
41
C6H13C6H13
Figure 4.11: (a) Planarized monomer for improved charge mobility. (b) Visualization of
favorable interactions between fullerene and trypticenes to prevent phase segregation
(based upon X-ray crystal structures 27 30)
112
4.6 Conclusions
Critical to the design of conjugated polymers is the effective conjugation length.
We have shown that the rigid structure of TDs promotes cyclization of the TD alcohol
onto alkynes, phenyls and thiophenes to form relatively unstrained 6-membered rings.
Several applications of these newly formed planar a-systems have been discussed from
OLEDs to photo-voltaic materials.
4.7 Experimental Section
Materials: Silica gel (40 pIm) was purchased from SiliCycle. All solvents used for
photophysical experiments were spectral grade. All reagent grade materials were
purchased from Aldrich, TCI America, Strem Chemicals Inc., and Alfa Aesar, and used
without further purification.
Experimental:
NMR Spectroscopy: 1H and 13C NMR spectra for all compounds were acquired in CDCl 3,
CDCl 2- CDCl 2 and THF-d8 on a Bruker Avance Spectrometer operating at 400 and 125
MHz, respectively. The chemical shift data are reported in units of 6 (ppm) relative to
residual solvent.
Gel Permeation Chromatography (GPC): Polymer molecular weights were determined
using a triple detection method for calibration with poly(acrylic acid) standards on a
Viscotek TDA 305-040 instrument equipped with two Viscotek A-MBHMW-3078
columns. and analyzed with light scattering and refractive index detectors. Samples were
dissolved in 5%NH 40H.
Absorption andEmission Spectroscopy: Fluorescence spectra were measured on a SPEX
Fluorolog-t3 fluorometer (model FL-321, 450 W Xenon lamp) using right-angle
detection. Ultraviolet-visible absorption spectra were measured with an Agilent 8453
diode array spectrophotometer and corrected for background signal with a solvent filled
113
cuvette. Fluorescence quantum yields of P1-anti in both water and IX PBS were
determined relative to perylene and are corrected for solvent refractive index and
absorption differences at the excitation wavelength. The quantum yield of P-peg in IX
PBS was determined relative to P-peg in pure water.
Lifetime measurements: Time resolved fluorescence measurements were performed by
exciting the samples with 160 femtosecond pulses at 390 nm from the double output of a
Coherent RegA Ti:Sapphire amplifier. The resulting fluorescence was spectrally and
temporally resolved with a Hamamatsu C4780 Streak Camera system.
Electrochemistry: Electrochemical measurements were carried out using an Autolab
PGSTAT 10 or PGSTAT 20 potentiostat (Eco Chemie) in a three-electrode cell
configuration consisting of a quasi- internal Ag wire reference electrode (BioAnalytical
Systems) submerged in 0.01 AgNO3 / 0.1 M tetrabutylammonium hexafluorophosphate
(TBAPF6) in anhydrous CH3CN, a Pt button (1.6 mm in diameter), 5-pm interdigitated
micro-, or ITO-coated glass electrodes as the working electrode, and a Pt coil or Pt gauze
as the counter electrode. The ferrocene/ferrocenium (Fc/Fc+) redox couple was used as
an external reference. Half-wave potentials of Fc/Fc+ were observed between 88-95 mV
in CH3CN and 210-245 mV (all vs. Ag/Ag+) in CH2Cl2.
Synthetic Procedures
Synthesis of 10: 1,4-diaminoanthraquinone (2g, 8.39 mmol) was added to 16 mL of
acetonitrile and CuBr 2 (4.22 g, 18.89 mmol, 2.25 equiv) and t-butylnitrite (t-BuONO)
(1.95 g, 18.89 mmol, 2.25mmol) were subsequently added. The mixture was stirred at 650
C for 5 h. Volatiles were removed in vacuo and the residue was partitioned between
DCM and IM HCl and washed with 1M HCl twice more. The organic layer was dried
with Na 2SO 4 and concentrated in vacuo. The residue was purified via column
chromatography (4:1, DCM:Hexanes) to give 10 (94%). 1H NMR (400 MHz, CDC3): 6
8.21 (dd, J=6, 3.6, 2H), 7.81 (s, 2H), 7.80 (dd, J=6, 3.6, 2H).
13 C
NMR (125 MHz,
CDCl3) 6 181.7, 140.7, 134.3, 133.6, 133.5, 127.0, 122.1. HRMS (ESI) calcd. for
C14 H6 Br 2 O 2 [M+Na] 366.8627, found 386.8614.
114
Synthesis of 11: TIPS acetylene (2.63 g, 3.24 mL 14.44 mmol) was dissolved in 28 mL
of dry toluene under argon. Following, n-BuLi (13.9 mmol, 1.6 M in Hexane) was added
dropwise at room temperature and the mixture was stirred for 10 min. Compound 10 (1 g,
2.78 mmol) was added in one portion. The solution was stirred at 60 C for 2 h and
cooled to room temperature. The reaction was quenched with sat. NH 4 C1 and the volatiles
were removed in vacuo. The residue was partitioned between DCM and water and the
organic layer was dried over Na2 SO4 and concentrated in vacuo. The residue was purified
by silica gel chromatography (4:1, DCM:Hexanes) to give 11 (70%). 1H NMR (400
MHz, CDCl3): 6 7.92 (dd, J=6, 3.2, 2H), 7.57 (s, 2H), 7.43 (dd, J=6, 3.2, 2H), 4.53 (s,
2H), 0.96 (m, 42H).
13
C NMR (125 MHz, CDCl3) 6 136.7, 136.2, 134.5, 128.9, 128.4,
123.2, 108.54, 89.3, 66.7, 18.7, 11.4. HRMS (ESI) calcd. for C36H5 oBr 20 2 Si 2 [M+Na]
751.1608, found 751.1592.
NOTE: The trans-diolisomer elutes faster than the syn-diol isomer.
Synthesis of 12: Compound 11 (1 g, 1.37 mmol) was dissolved in 13 mL of THF and
TBAF (3.0 mmol, IM in THF) was added. After stirring for 15 h at 23 'C, the reaction
was partitioned between EtOAc and Brine. The organic layer was washed with Brine
twice more and then dried with Na2 SO 4 and concentrated in vacuo. The residue was
purified by silica gel chromatography (DCM to 1:1 DCM:EtOAc) to give 12 (91%). 1H
NMR (400 MHz, CDCl3): 6 7.95 (dd, J=6, 3.6, 2H), 7.62 (s, 2H), 7.51 (dd, J=6, 3.6, 2H),
4.60 (s, 2H), 2.69 (s, 2H).
13
C NMR (125 MHz, CDCl3) 6 136.7, 136.4, 134.1, 129.6,
128.1, 123.2, 84.9, 75.6, 66.1. HRMS (ESI) calcd. for Ci 8H10Br 20 2 [M+H] 438.8940,
found 438.8924.
Synthesis of 13: Compound 12 (50 mg, 0.12 mmol) and CpRu(PPh 3)2Cl (8.71 mg, 0.012
mmol) were suspended in 1.2 mL dry dioxane under argon. 1-Hexyne (0.1mL, 5.98
mmol) was added and the flask was sealed and heated at 105
0C
for 12 h. The reaction
was cooled to 23" C and the volatiles removed in vacuo. The residue was purified by
silica gel chromatography (9:1, hexanes:EtOAc) to give 13 (89%). 1H NMR (400 MHz,
CDCl3): 6 7.68 (m, 2H), 7.57 (d, J=7.6, 1H), 7.51 (d, J=1.3, lH), 7.19 (dd, J=5.6, 3.2,
2H), 7.00 (s, 2H), 6.99 (dd, J=7.6, 1.6, lH), 4.55 (s, 1H), 4.51 (s, 1H), 2.60 (pseudo t,
115
J=8, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.91 (t, J=7.4, 3H).
13C
NMR (125 MHz, CDC13) 6
144.8, 144.7, 143.7, 143.6, 143.4, 141.4, 140.9, 133.6, 133.5, 126.3, 126.2, 126.1, 120.3,
120.03, 120.01, 119.9, 114.4, 114.3, 80.8, 80.7, 35.9, 33.9, 22.7, 14.2. HRMS (ESI)
calcd. for C24H20Br 2O2 [M+H] 498.9903, found 498.9911.
Synthesis of 14: Compound 12 (0.4 g, 0.96 mmol) and CpRu(PPh 3)2 C1 (69 mg, 0.096
mmol) were suspended in 9 mL of dry Dioxane under argon. 1-Decyne (0.68 g, 0.8 mL,
4.98 mmol) was added and the flask was sealed and heated at 105
0C
for 12 h. The
volatiles were removed in vacuo and the residue was purified by column chromatography
(7:3, Hexanes:DCM) to give 14 (85%). 'H NMR (400 MHz, CDC13): 6 7.68 (m, 2H),
7.57 (d, J=7.6, 11H), 7.51 (d, J=1.2, 1H), 7.19 (dd,. J=5.2, 3.2, 2H), 7.00 (s, 2H), 6.99 (dd,
J=7.6, 1.6, 1H), 4.55 (s, 1H), 4.51 (s, 1H), 2.59 (pseudo t, J=8, 2H), 1.58 (m, 2H), 1.25
(m, 10H), 0.88 (t, J=7.2, 3H). 13C NMR (125 MHz, CDCl3) 6 144.8, 144.7, 143.7, 143.6,
143.4, 141.5, 140.8, 133.6, 133.5, 126.3, 126.2, 126.1, 120.2, 120.03, 120.0, 119.94,
114.4, 114.3, 80.82, 80.77, 36.2, 32.1, 31.8, 29.7, 29.6, 29.4, 22.9, 14.3. HRMS (ESI)
calcd. for C28H28Br 2 O2 [M+H] 555.0529, found 555.0535.
Synthesis of 15: Compound 12 (0.4 g, 0.96 mmol) and CpRu(PPh 3)2C1 (69 mg, 0.096
mmol) were suspended in 9 mL of dry Dioxane under argon. 1-Dodecyne (0.68 g, 4.98
mmol) was added and the flask was sealed and heated at 105
0
C for 12 h. The volatiles
were removed in vacuo and the residue was purified by column chromatography (7:3,
Hexanes:DCM) to give 15 (86%). 1H NMR (400 MHz, CDCl3): 6 7.70 (m, 2H), 7.59 (d,
J=7.6, 1H), 7.54 (d, J=1.2, 1H), 7.20 (dd, J=5.6, 3.2, 2H), 7.01 (dd. J=7.6, 1.6, 1H), 6.98
(s, 2H), 4.58 (s, 1H), 4.54 (s, 1H), 2.60 (pseudo t, J=7.8, 2H), 1.59 (m, 2H), 1.27 (m,
14H), 0.91 (t, J=6.8, 3H).
13C
NMR (125 MHz, CDCl3) 6 144.8, 144.7, 143.7, 143.6,
143.4, 141.5, 140.9, 133.5, 133.4, 126.3, 126.2, 126.1, 120.2, 120.03, 120.0, 119.9, 114.4,
114.3, 80.8, 80.7, 36.2, 32.1, 31.8, 29.8, 29.7, 29.6, 29.5, 22.9, 14.4. HRMS (ESI) calcd.
for C30 H 32 Br 2 O 2 [M+H] 583.0842, found 583.0832.
Synthesis of 16: Compound 12 (0.4 g, 0.96 mmol) and [Rh(cod)Cl] 2 (12 mg, 0.024
mmol) were suspended in 9 mL of dry toluene under argon. Norbornadiene (0.88 g, 1.03
116
mL, 9.57 mmol) was added and the flask was sealed and heated at 105
0
C for 15 h. The
volatiles were removed in vacuo and the residue was purified by column chromatography
(3:2, Hexanes:DCM) to give 16 (87%).'H NMR (400 MHz, CDCl3): 6 7.69 (dd, J=5.6,
3.2, 4H), 7.19 (dd, J=5.6, 3.2, 4H), 7.02 (s, 2H), 4.56 (s, 2H). 13C NMR (125 MHz,
CDCl3) 6 144.6, 143.5, 133.6, 126.3, 120.1, 114.4, 80.8. HRMS (ESI) caled. for
C2 0H1 2 Br 2 O 2 [M+H] 442.9277, found 442.9292.
Synthesis of 22: Compound 16 (0.2 g, 0.45 mmol), Pd(PPh3)2Cl 2 (20 mg, 0.027 mmol),
Cul (10 mg, 0.054 mmol) was suspended in 2.25 mL dry Toluene under argon. TMS
acetylene (0.124 g, 1.28 mmol) was added by syringe along with 2.25 mL NEt 3 . The
reaction was sealed and heated at 85 C for 12 h. The volatiles were removed in vacuo
and the residue was purified by silica gel chromatography (1:3, DCM:Hexanes) to give
22 (94%). 1H NMR (400 MHz, CDCl3): 6 7.73 (dd, J=5.6, 3.2, 4H), 7.16 (dd, J=5.6, 3.2,
4H), 5.93 (s, 2H), 0.38 (s, 18H). 13 C NMR (125 MHz, CDC13) 6 147.1, 144.2, 130.9,
125.9, 120.2, 115.5, 104.8, 101.9, 80.8, -0.11. HRMS (ESI) calcd. for C30 H30 O2 Si 2
[M+H] 479.1857, found 479.1869.
Synthesis of 23: Compound 22 (0.150 g, 0.31 mmol) was dissolved in 4 mL THF, TBAF
(0.69 mmol, IM in THF) was added and the reaction was left to stir for 2 h. The reaction
mixture was diluted with brine and washed with DCM twice. The combined organic
fractions were dried over Na 2SO 4 and the volatiles were removed in vacuo. The residue
was purified by silica gel chromatography (6:4, Hexanes:DCM) to give 23 (87%). 1H
NMR (400 MHz, CDCl3): 6 7.73 (i, 2H), 7.58 (in, 2H), 7.17 (d, J=8, 1H), 7.14 (m, 2H),
7.12 (m, 2H), 7.08 (d, J=8, 1H), 5.06 (d, J=2.8, 1H), 4.78 (s, 1H), 4.75 (d, J=2.8, 1H),
3.56 (s, 1H). 13C NMR (125 MHz, CDCl3) 6 162.8, 150.4, 145.0, 141.8, 140.4, 132.8,
127.5, 126.0, 125.8, 120.7, 119.5, 118.4, 114.0, 89.8, 85.4, 83.7, 82.6, 80.6. HRMS (ESI)
calcd. for C24H1 40 2 [M+H] 335.1067, found 335.1059.
Synthesis of 24: Compound 16 (0.2 g, 0.45 mmol), Pd(PPh3)2 Cl 2 (20 mg, 0.027 mmol),
Cul (10 mg, 0.054 mmol) was suspended in 2.25 mL dry Toluene under argon.
Phenylacetylene (0.138 g, 0.148 mL, 1.35 mmol) was added by syringe followed by 2.25
117
mL NEt 3. The reaction was sealed and heated at 85 C for 12 h. The volatiles were
removed in vacuo and the residue was purified by silica gel chromatography (1:4,
DCM:Hexanes) to give 24 (93%). 1H NMR (400 MHz, CDCl3): 6 7.76 (dd, J=5.6, 3.2,
4H), 7.66 (m, 4H), 7.45 (m, 6H), 7.19 (s, 2H), 7.17 (dd, J=5.6, 3.2, 4H), 5.68 (s, 2H).
13
C
NMR (125 MHz, CDCl3) 6 146.5, 144.2, 131.8, 130.9, 129.6, 128.9, 126.0, 122.1, 120.2,
115.5, 98.3, 86.1, 81.0. HRMS (ESI) calcd. for C3 6H2 2 0 2 [M+H] 485.1547, found
485.1556.
Synthesis of 25 using
12:
Compound 24 (0.05 g, 0.1 mmol) and NaHCO 3 (0.052 g, 0.6
mmol) were suspended in 2 mL MeCN. Iodine (0.16 g, 6 mmol) was added and the
reaction was stirred at rt for 15 h. Saturated Na 2S2O3 was added and left for 10 min. The
reaction was diluted with water and washed with DCM (2x). The volatiles were removed
in vacuo and the. residue was purified by silica gel chromatography (6:4, Hexanes: DCM)
to give 25 (24%).
-using IC: Compound 24 (0.02 g, 0.4 mmol) dissolved in 3.2 mL dry DCM and cooled
to -78
0C.
ICl (0.014 g, 0.086 mmol) was added dropwise and the reaction was allowed
to warm to rt. After 10 min saturated Na 2S2O3 was added and left for a further 10 min.
The reaction was diluted with water and washed with DCM (2x). The volatiles were
removed in vacuo and the residue was purified by silica gel chromatography (6:4,
Hexanes: DCM) to give 25 (86%). 1H NMR (400 MHz, CDCl3): 6 7.84 (in, 4H), 7.60 (in,
10H), 7.15 (dd, J=5.6, 3.2, 4H), 6.92 (s, 2H).
13 C
NMR (125 MHz, CDCl3) 6 153.3,
144.1, 138.4, 131.2, 130.0, 129.8, 128.5, 127.1, 126.9, 126.0, 120.2, 83.1, 70.1. HRMS
(ESI) calcd. for C3 6H20 12 0 2 [M+H] 737.9547, found 737.9565.
Synthesis of 26 and 27: Compound 24 (72 mg, 0.15 mmol) and AuCl 3 (6 mg, 0.02
mmol) were dissolved in 1.6 mL THF and 0.4 mL MeCN. The solution was initially clear
but a yellow solid precipitated after a few minutes and stirring was continued at rt for 12
h. The volatiles were removed in vacuo and the residue was purified by silica gel
chromatography (7:3, Hexanes:DCM) to give 27 (40%) and 26 (29%).
27: 1H NMR (400 MHz, Cl 2CD-CDCl2): 6 8.06 (dd, J=7.6, 1.2 4H), 7.71 (dd, J=5.6, 3.2,
4H), 7.56 (m, 4H), 7.49 (in, 2H), 7.19 (dd, J=5.6, 3.2, 4H), 6.70 (s, 2H), 6.30 (s, 2H).
118
13C
NMR (125 MHz, Cl 2 CD-CDCl2) 6 150.8, 144.2, 134.5, 131.9, 129.0, 128.6, 125.5,
124.7, 124.3, 120.9, 120.0, 96.1, 82.5. HRMS (ESI) calcd. for C3 6H2 2 0 2 [M+H]
487.1693, found 487.1701.
26: 1H NMR (600 MHz, CDC3): 6 8.08 (dd, J=8.4, 1.2, 2H), 7.80 (dd, J=7.8, 1.2, 2H),
7.64 (dd, J=7.5, 2.1, 2H), 7.61 (dd, J=6.9, 0.6, 2H), 7.55 (in, 2H), 7.49 (in, 1H), 7.43 (in,
3H), 7.17 (ddd, J=7.8, 7.2, 1.2, 2H), 7.13 (ddd, J=7.2, 7.2, 1.2, 2H), 7.10 (d, J=7.8, 1H),
6.72 (d, J=7.8, 1H), 6.26 (s, 1H), 5.67 (s, 1H).
13
C NMR (125 MHz, CDCl3) 6 151.9,
144.3, 143.8, 142.8, 135.0, 134.4, 131.9, 131.7, 129.6, 129.2, 128.9, 128.8, 126.9, 125.9,
125.8, 125.2, 122.5, 120.9, 120.7, 119.8, 112.6, 96.3, 95.8, 86.6, 83.1, 81.5. HRMS (ESI)
caled. for C3H22O2 [M+H] 487.1693, found 487.1713.
Synthesis of 28: Compound 14 (0.2 g, 0.36 mmol), Pd(PPh 3)2Cl 2 (15 mg, 0.022 mmol),
Cul (10 mg, 0.054 mmol) was suspended in 2.25 mL dry Toluene under argon.
Phenylacetylene (0.11 g, 0.118 mL, 1.08 mmol) was added by syringe followed by 2.25
mL NEt 3. The reaction was sealed and heated at 85 C for 18 h. The volatiles were
removed in vacuo and the residue was purified by silica gel chromatography (1:4,
DCM:Hexanes) to give 28 (93%). 1H NMR (400 MHz, CDCl3): 6 7.56 (in, 2H), 7.687.63 (in, 5H), 7.59 (d, J=1.2, 1H), 7.46-7.44 (in, 6H), 7.19-7.15 (m, 4H), 6.98 (dd, J=7.6,
1.2, 1H), 5.68 (s, 1H), 5.63 (s, 1H), 2.59 (pseudo t, J=8, 2H), 1.59 (in, 2H), 1.25 (in,
10H), 0.86 (t, J=6.8, 3H).
13
C NMR (125 MHz, CDCl3) 6 146.8, 146.7, 144.4, 144.3,
144.1, 141.55, 141.1, 131.8, 130.9, 130.8, 129.5, 128.9, 125.9, 125.8, 125.7, 122.2, 120.3,
120.1, 120.0, 115.4, 98.24, 98.22, 86.3, 86.2, 81.1, 81.0, 36.3, 32.1, 31.9, 29.8, 29.7, 29.5,
22.9, 14.3. HRMS (ESI) calcd. for C44 H3 8 0 2 [M+H] 599.2945, found 599.2935.
Synthesis of 29: Compound 28 (0.1 g, 0.167 mmol), Ph 3PAuCl (5 mg, 0.01 mmol) and
AgSbF 6 (3.5 mg, 0.01 mmol) were dissolved in 3 mL of THF:1,2-dichloroethane (1:1)
and stirred at rt for 4 h. The volatiles were removed in vacuo and the residue was purified
by silica gel chromatography (9:1, Hexanes:DCM) to give 29 (85%).1H NMR (400 MHz,
CDC13): 6 8.06 (m, 4H), 7.66 (in, 2H), 7.57-7.43 (in, 8H), 7.12 (dd, J=5.4, 3, 2H), 6.92
(dd, J=7.6, 1.2, 1H), 6.62 (s, 2H), 6.26 (s, 1H), 6.25 (s, 1H), 2.55 (pseudo t, J=8, 2H),
1.54 (m, 2H), 1.26-1.23 (in, 10H), 0.85 (t, J=6.8, 3H). 13C NMR (125 MHz, CDC13) 6
119
151.1, 151.0, 145.0, 144.9, 144.6, 140.8, 135.2, 129.1, 128.9, 128.8, 125.6, 125.5, 125.3,
125.1, 125.0, 124.5, 121.1, 120.3, 120.1, 120.0, 119.9, 96.6, 96.5, 83.0, 36.2, 32.1, 32.0,
29.7, 29.6, 29.5, 22.9, 14.3. HRMS (ESI) caled. for C44 H38 0 2 [M+H] 599.2945, found
599.2963.
Synthesis of 30: Compound 14 (50 mg, 0.113 mmol), 1,4-diethynylbenzene (14.3 mg,
0.113 mmol), Pd(PPh3)Cl 2 (2.38 mg, 3.4 gmol), Cul (15 mg, 79 ptmol) were dissolved in
1 mL dry toluene and 0.7 mL NEt 3 under argon. The reaction was stirred at 85 *C for 3 d
and partitioned between DCM and sat. NH 4Cl. The reaction was extracted with sat.
NH 4 C1 twice and the organic portion was dried over Na 2 SO 4 and evaporated to dryness in
vacuo. The residue was dissolved in a minimum amount of DCM, filtered to remove
insoluble material, and precipitated from MeOH. The precipitation procedure was
repeated twice more to give 30 (32%). 1H NMR (400 MHz, THF-d 8): 6 7.75-7.55 (m,
6H), 7.23 (m, 2H), 7.09 (m, 2H), 6.93 (d, J=7.6, 1H), 6.21 (br, 2H), 5.98 (s, 1H), 5.96 (s,
1H), 2.58 (br, 2H), 1.57 (br, 2H), 1.28 (br, 1OH), 0.88 (br t, 3H). GPC: Ma = 12,500, PDI
= 1.44, DP = 24.
Synthesis of 31: Polymer 30 (50 mg, 0.123 mmol) was dissolved in 1 mL THF:1,2dichloroethane (1:1). A solution of Ph 3PAuCl (6.5 mg, 13 [tmol) and AgSbF 6 (4.4 mg, 13
tmol) was premixed in 1 mL THF: 1,2-dichloroethane (1:1) and filtered through celite
into the reaction mixture. After 12 h of stirring at room temperature, a second preparation
of catalyst solution was added and left to stir for an additional 12 h. The reaction mixture
was diluted with IM HCl and extracted with fresh DCM twice. The combined organic
fractions were dried over Na 2 SO4 and evaporated to dryness in vacuo. The residue was
dissolved in a minimum amount of DCM and precipitated from MeOH. The precipitation
procedure was repeated twice more to give 31 (74%). 1H NMR (400 MHz, CDCl3): 6
8.174 (br, 2H) 7.77-7,48 (m, 4H), 7.19 (br, 2H), 7.01 (br, 1H), 6.59 (br, 1H), 6.32 (br,
1H), 4.82 (s, 1H) 4.79 (s, 1H), 2.61 (br, 2H), 1.59 (br, 2H), 1.26 (br, 1OH), 0.85 (br, 6H).
3
C NMR (125 MHz, CDCl3, partial) 6 125.8, 125.0, 124.4, 120.2, 32.0, 29.6, 29.4, 22.8.
GPC: Ma = 14,700, PDI = 1.16, DP = 28.
120
Synthesis of 32: Compound 16 (0.15 g, 0.34 mmol), phenylboronic acid (0.84 g, 1.01
mmol), Pd(PPh3 )2 Cl 2 (14 mg, 0.02 mmol) were dissolved in 2 mL degassed THF and 2
mL K3 PO 4 (0.5 M, degassed) under argon. The reaction was sealed and heated at 60 C
for 6 h. The reaction was diluted with sat. NH4 Cl and washed with DCM twice. The
combined organic layers were dried over Na2 SO 4 and volatiles were removed in vacuo.
The residue was purified by silica gel chromatography (6:4, Hexanes:DCM) to give 32
(98%). 1H NMR (400 MHz, CDC13): 6 7.52 (m, 10H), 7.38 (m, 4H), 7.13 (dd, J=5.4, 3,
4H), 6.81 (s, 2H), 3.04 (s, 2H). 13C NMR (125 MHz, CDCl3) 6 145.0, 142.7, 141.0,
135.2, 129.4, 128.8, 128.4, 128.3, 125.7, 119.6, 81.0. HRMS (ESI) calcd. for C3 2 H2 2 0 2
[M+H] 439.1693, found 439.1687.
Synthesis of 33: Compound 32 (85 mg, 0.19 mmol), K2S208 (0.21 g, 0.78 mmol),
CuOAc 2 (0.31 g, 1.56 mmol) and KOAc (0.30 g, 3.1 mmol) was suspended in 2 mL of
AcOH and heated at 113 0C for 6 h. Once cool the reaction was diluted with 10% NaOH.
The mixture was extracted with DCM (3x) and the combined organic fractions were dried
over Na2 SO 4 and volatiles were removed in vacuo. The residue was triturated with
EtOAc (2 mL) and filtered to give 33 (77%). 1H NMR (400 MHz, CDCl3): 6 7.67 (dd,
J=5.6, 3.2, 4H), 7.64 (dd, J=8, 1.6, 2H), 7.40 (s, 2H), 7.39 (dd, J=8, 1.2, 2H), 7.35 (ddd,
J=8, 7.2, 1.6, 2H), 7.12 (dd, J=5.6, 3.2, 4H), 7.03 (ddd, J=8, 7.2, 1.2, 2H).
13
C NMR
(125 MHz, CDCl3) 6 153.1, 143.9, 138.6, 134.3, 130.2, 125.8, 124.1, 122.7, 122.2, 120.3,
118.5, 117.8, 81.8. HRMS (ESI) caled. for C32Hi 8 0 2 [M+H] 435.1380, found 435.1360.
Synthesis of 36: Compound 16 (0.05 g, 0.113 mmol), Pd cat. (4.5 mg, 5.7 mmol) and 2thiophene boronic acid (0.043 g, 0.338 mmol) were dissolved in 1 mL degassed THF
under argon. Following, 2 mL of degassed 0.5 M K3 PO 4 was added by syringe and the
reaction was stirred at 40 "C for 12 h. The reaction was diluted with water and extracted
with DCM (3x). The combined organic extracts were dried over Na2 SO 4 and the volatiles
were removed in vacuo. The residue was purified by silica gel chromatography (6:4,
Hexanes:DCM) to give 36 (98%). 1H NMR (400 MHz, CDCl3): 6 7.58 (dd, J=5.6, 3.2,
4H), 7.53 (dd, J=5.2, 1.2, 2H), 7.19 (dd, J=5.2, 3.2, 2H), 7.15 (dd, J=5.6, 3.2, 4H), 7.09
(dd, J=3.2, 1.2, 2H), 3.74 (s, 2H).
13 C
NMR (125 MHz, CDCl3) 6 144.6, 141.1, 129.6,
121
128.3, 128.1, 127.6, 127.4, 125.9, 119.8, 80.9. HRMS (ESI) caled. for C2 8 Hi 8 0 2 S2
[M+H] 449.0675, found 449.0657
Synthesis of 37: Compound 16 (0.1 g, 0.226 mmol), Pd cat. (4.5234 mg, 5.7 mmol) and
5-methyl-2-thienylboronic acid (0.123 g, 0.338 mmol) were dissolved in 1 mL degassed
THF under argon. Following, 2 mL of degassed 0.5 M K3 PO 4 was added by syringe and
the reaction was stirred at 40 C for 12 h. The reaction was diluted with water and
extracted with DCM (3x). The combined organic extracts were dried over Na2 SO 4 and
the volatiles were removed in vacuo. The residue was purified by silica gel
chromatography (6:4, Hexanes:DCM) to give 37 (70% plus unreacted 16) 1H NMR (400
MHz, CDCl3): 6 7.62 (dd, J=5.6, 3.2, 4H), 7.15 (dd, J=5.6, 3.2, 4H), 6.89 (s, 2H), 6.87
(d, J=3.2, 2H), 6.84 (m, 2H), 4.10 (s, 2H), 2.60 (s, 6H).
3
C NMR (125 MHz, CDCl3) 6
144.8, 144.4, 142.4, 138.5, 129.6, 128.5, 128.1, 125.8, 125.5, 119.8, 80.9, 15.6. HRMS
(ESI) calcd. for C3 0H22 0 2 S2 [M+H] 477.0988, found 477.0995.
Synthesis of 40: Compound 16 (0.1 g, 0.225 mmol), Pd cat. (8.8 mg, 11.2 pmol) and
thiophene (0.162 g, 0.675 mmol) were dissolved in 2 mL degassed THF under argon.
Following, 4 mL of degassed 0.5 M K3 PO 4 was added by syringe and the reaction was
stirred at rt for 12 h. The reaction was diluted with water and extracted with DCM (3x).
The combined organic extracts were dried over Na 2 SO4 and the volatiles were removed
in vacuo. The residue was purified by silica gel chromatography
(6:4->2:8,
Hexanes:DCM) to give 40 (good yield). 1H NMR (400 MHz, CDC3): 6 7.58 (br m, 4H),
7.37 (d, J=5.6, 2H), 7.13 (br m, 4H), 6.98 (d, J= 5.6, 2H), 6.90 (s, 2H), 4.69 (br m, 2H),
3.82 (br s, 6H). 13 C NMR (125 MHz, CDCl)(Partial) 6 145.6, 144.6, 130.8, 125.6 (broad),
125.0, 120.2-119.5 (broad), 116.6, 80.8, 59.1. HRMS (ESI) calcd. for C30 H2 2 0 4 S2 [M+H]
511.1032, found 511.1035.
Synthesis of 38: Compound 40 (38.5 mg, 75.4 pmol) and a catalytic amount of ptoluenesulfonic acid monohydrate were dissolved in 1 mL toluene and heated at 85 0C
overnight. The reaction was diluted with DCM and washed with sat. NaHCO 3 twice. The
organic fraction was dried over Na 2SO4 and volatiles removed in vacuo. The residue was
122
purified by silica gel chromatography (8:2, Hexanes:DCM) to give 41 (71%). 1H NMR
(400 MHz, CDCl3): 6 7.67 (dd, J=5.6, 3.2, 4H), 7.18 (d, J=5.2, 2H), 7.14 (dd, J=5.6, 3.2,
4H), 7.08 (d, J=5.2, 2H), 6.78 (s, 2H).
13
C NMR (125 MHz, CDCl3) 6 151.6, 143.7,
132.7, 125.9, 122.9, 122.5, 120.4, 119.4, 117.7, 112.0, 84.3. HRMS (ESI) caled. for
C 30 H22 0 4 S2 [M+H] 447.0508, found 447.0525.
4.8 References
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1999, 5, 3103-3106. (e) Trost, B. M.; Rhee, Y. H. J Am. Chem. Soc. 1999, 121, 1168011683. (f) Compain, P.; Gord, J.; Vatele, J.-M. Tetrahedron 1996, 52, 10405-10416. (g)
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G. C. J. Am. Chem. Soc. 1999, 121, 7787-7799.
123
13. Sandros, K.; Sundahl, M.; Wennerstrom, 0.; Norinder, U. J. Am. Chem. Soc. 1990,
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124
125
Chapter 4 Appendix
H-NMR, "C-NMR,
IR Data, and
X-ray Structures
126
o
Br
O
Br
I
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm
Figure 4.A.1: H NMR spectrum of 10 in CDC13 (400 MHz)
O
Br
O
Br
vwTr- R-111"r-ri
Fly-mr
200
180
Figure 4.A.2:
13C
160
140
120
100
80
60
40
20
0
ppm
NMR spectrum of 10 in CDC13 (125 MHz)
TIPS
OH Br
I~
N
OH Br
TIPS
I
8.0
iII
7.5
I
7.0
6.5
6.0
5.5
Figure 4.A.3: lH NMR spectrum of
4.5
4.0
3.5
3.0
in CDC 3 (400 MHz)
127
2.5
2.0
1.5
.
1.0
0.5 ppm
TIPS
OH Br
OH Br
TIPS
11 I
--i -l.I---J.---A200
180
Figure 4.A.4:
13
160
140
120
100
80
,A. -L-~.iAj
-
L .v
60
40
20
0
.
ppm
C NMR spectrum of 11 in CDC13 (125 MHz)
H
OH Br
OH Br
H
-1
.
8.0
7.5
7.0
...
....
6.5
....
6.0
....
5.5
...
5.0
4.5
4.0
3.5
3.0
Figure 4.A.5: 'H NMR spectrum of 12 in CDC13 (400 MHz)
128
2.5
2.0
1.5
1.0
0.5 ppm
H
OH Br
OH Br
H
II
210
200
190
13
Figure 4.A.6:
180 170
160 150
140 130 120
110 100
90
80
60
50
40
30
20
ppm
C NMR spectrum of 12 in CDCl 3 (125 MHz)
jUL
7.5
70
I
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
Al
2.0
1.5
1.0
0.5 ppm
Figure 4.A.7: H NMR spectrum of 13 in CDC13 (400 MHz)
il~[
Br
200
Figure 4.A.8:
180
13 C
160
140
i
I~
120
100
80
60
NMR spectrum of 13 in CDC13 (125 MHz)
129
40
20
0
ppm
ilJ~iCi
7.5
7.0
6.5
6.0
Z
5.5
5.0
4.5
4.0
Ld
3.5
3.0
2.5
2.0
1.5
1.0
0.5 ppm
Figure 4.A.9: 1H NMR spectrum of 14 in CDC13 (400 MHz)
OH
HO
200
Br
180
Figure 4.A.10:
Br
_
13C
160
140
120
100
80
40
60
20
0
ppm
NMR spectrum of 14 in CDC13 (125 MHz)
C0OH
21
OH
Br
HO
Br
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
Figure 4.A.11: 1H NMR spectrum of 15 in CDC13 (400 MHz)
130
2.0
1.5
1.0
0.5 ppm
C1 0H2
OH
HO
1
Br
-
Br
200
180
Figure 4.A.12:
13
160
140
120
100
80
60
40
20
0
ppm
C NMR spectrum of 15 in CDC13 (125 MHz)
OH
Br
HO
Br
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
1.5
2.0
1.0
0.5 ppm
Figure 4.A.13: H NMR spectrum of 16 in CDC13 (400 MHz)
OH
Br
HO
Br
200
Figure 4.A.14:
180
3
160
140
120
100
80
60
C NMR spectrum of 16 in CDC13 (125 MHz)
131
40
20
0
ppm
SiMe3
/
OH
/0
s'HO
Me3 Si
IIII
I
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5 ppm
Figure 4.A.15: H NMR spectrum of 22 in CDC13 (400 MHz)
OH
SiMe3
/
HO
Me3Si"
150
140
130
Figure 4.A.16:
7.5
7.0
3
120
110
100
90
80
70
60
50
40
30
20
10
ppm
C NMR spectrum of 22 in CDC13 (125 MHz)
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
Figure 4.A.17: 'H NMR spectrum of 23 in CDC13 (400 MHz)
132
2.0
1.5
1.0
0.5 ppm
0
HO+
H
I
I
200
180
Figure 4.A.18:
160
140
120
100
80
60
40
Ii1~
0
ppm
I
I
7.5
7.0
Figure 4.A.19:
",0164
20
C NMR spectrum of 23 in CDCl 3 (125 MHz)
13
6.5
1H NMR
LL.""
200
Figure 4.A.20:
6.0
LJA
180
5.5
5.0
4.5
I
I
4.0
3.5
I''
I'
3.0
2.5
2.0
1.5
1.0
0.5 ppm
spectrum of 24 in CDC13 (400 MHz)
AALkjlkgjiw
160
-A'"
140
120
100
13
80
60
C NMR spectrum of 24 in CDC13 (125 MHz)
133
40
20
0
ppm
Ai
8.0
7.5
I
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
A
-,L.
1.5
1.0
0.5 ppm
Figure 4.A.21: 'H NMR spectrum of 25 in CDC13 (400 MHz)
L.
200
2
Figure 4.A.22:
180
13C
160
160
,
si LA"AALAAwmJL
140
1
,
120
1
100
8
60
6
40
4
220
0
ppm
NMR spectrum of 25 in CDC13 (125 MHz)
@400MHz
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
@600MHz
H
HO
8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1
0.5 ppm
-
7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1 6.0 5.9 5.8 5.7 ppm
Figure 4.A.23: 'H NMR spectrum of 26 in CDC13 (400 MHz and 600 MHz)
134
I
I
I
ppm
-5.5
-6.0
-6.5
-7.0
-7.5
-8.0
-8.5
8.5
8.0
7.5
6.5
7.0
6.0
ppm
5.5
Figure 4.A.24: gCOSY spectrum of 26 in CDCl 3 (600 MHz)
A
,.I
200
180
Figure 4.A.25:
13C
I
j .-
140
160
120
i-
100
40
60
80
20
0
NMR spectrum of 26 in CDC13 (125 MHz)
H
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
Figure 4.A.26: lH NMR spectru m of 27 in CL2CD-CDC12 (400 MHz)
135
1.5
1.0
0.5 ppm
200
Figure 4.A.27:
8.0
7.5
180
13
160
140
120
100
80
- AH
,.
L60
40
20
0
ppm
C NMR spectrum of 27 in CL2CD-CDC12 (125 MHz)
7.0
6.5
6.0
5.5
4.5
5.0
4.0
3.5
3.0
2.5
2.0
1.5
0.5 ppm
1.0
Figure 4.A.28: 'H NMR spectrum of 28 in CDC13 (400 MHz)
n-Oct
200
180
Figure 4.A.29:
160
13C NMR
140
120
100
40
60
20
0
spectrum of 28 in CDCl 3 (125 MHz)
0
-
H
-ii
8.5
80
it
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
Figure 4.A.30: 'H NMR spectrum of 29 in CDC13 (400 MHz)
136
2.5
2.0
1.5
1.0
ppm
j HI
KI5H
I L..
200
180
Figure 4.A.31:
8.5
8.0
I
I~
13
160
hi
140
120
.1.
I 11,1
100
a 0, 1. 1..- -AA.
80
. .1.
. 1 1.
40
.1
p
20
C NMR spectrum of 29 in CDC13 (125 MHz)
I
I
I
7.5
7.0
6.5
~
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.0
1.5
1.0
ppm
2.0
1.5
1.0
ppm
Figure 4.A.32: lH NMR spectrum of 30 in CDC13 (400 MHz)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
Figure 4.A.33: IH NMR spectrum of 31 in CDC13 (400 MHz)
137
2.5
n-Oct
n
\
/0
0
200
13
Figure 4.A.34:
-
150
100
/
[ppm]
OH
HO
-
1\
-J(t I
I
7.5
0
50
C NMR spectrum of 31 in CDC13 (125 MHz)
/
I
7.0
6.5
6.0
5.5
5.0
I
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5 ppm
Figure 4.A.35: 1H NMR spectrum of 32 in CDC13 (400 MHz)
/
HO
200
Figure 4.A.36:
180
13 C
160
140
120
100
NMR spectrum of 32 in CDC
138
80
3
60
(125 MHz)
40
OH
-
20
0
ppm
/O
0
0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
-
3.5
3.0
2.5
2.0
1.5
0.5 ppm
1.0
Figure 4.A.37: H NMR spectrum of 33 in CDCl 3 (400 MHz)
/0
0
jjAjA".A
-7
200
180
Figure 4.A.38:
13
160
140
L I-- -
-
l
TTF"VrW--T-I'F'W-
120
100
80
60
40
20
0
ppm
C NMR spectrum of 33 in CDC13 (125 MHz)
h i Ii
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
Figure 4.A.39: 'H NMR spectrum of 36 in CDC 3 (400 MHz)
139
2.0
1.5
1.0
0.5 ppm
200
160
Figure 4.A.40:
13
160
140
120
100
80
60
40
20
0
ppm
C NMR spectrum of 36 in CDC13 (125 MHz)
Me V,
I
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
0.5 ppm
1.0
Figure 4.A.41: 1H NMR spectrum of 37 in CDCl 3 (400 MHz)
HO
-
S
Me
T -
200
180
Figure 4.A.42:
1
3
I
1
160
1
140
120
IO
100
I
80
60
40
20
0
ppm
C NMR spectrum of 37 in CDC13 (125 MHz)
os
|
S
oue
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
Figure 4.A.43: H NMR spectrum of 40 in CDC13 (400 MHz)
140
2.0
1.5
1.0
0.5 ppm
\ MeO
/ OH|
SHO
S
S
OMe
200
180
Figure 4.A.44:
13
160
140
120
7.5
80
60
40
20
0
ppm
C NMR spectrum of 40 in CDCl 3 (125 MHz)
JL1
8.0
100
0
7.0
6.5
6.0
5.5
5.0
-
I
I
4.5
4.0
I
3.5
I
3.0
2.5
2.0
1.5
1.0
0.5 ppm
Figure 4.A.45: 1H NMR spectrum of 41 in CDC13 (400 MHz)
S
0
2
200
Figure 4.A.46:
6
180
13C
'
160
-p
'
140
2
'120
0
100
8
6
80
60
NMR spectrum of 41 in CDC13 (125 MHz)
141
2
40
20
0
ppm
84 -
82-
80-
78-
76-
400
3500
3000
25;0
Wavenumbers(cm-1)
Figure 4.A.47: FT-AT-IR spectrum of 39.
142
2000150
100
X-ray Crystal Structures:
a)
b)
c)
d)
Figure 4.A.48: Crystal Structure of 23.
(a) Suitable crystals were grown by vial-in-vial vapor diffusion using CHCl 3:Pentane as
the solvent:antisolvent mixture. b) Anisotropic thermal ellipsoids set at 50% probability.
c) and d) Crystal twins separated for clarity.
143
A
Figure 4.A.49: Crystal Structure of 27.
(a) Suitable crystals were grown by vial-in-vial vapor diffusion using (DCM and 1,1,2,2tetrachloroethane):MeOH as the (solvent): antisolvent mixture (solvent molecules
removed for clarity. b) Anisotropic thermal ellipsoids set at 50% probability.
Figure 4.A.50: Crystal Structure of 33.
Suitable crystals were grown by slow evaporation of CHCl3. Anisotropic thermal
ellipsoids set at 50% probability.
144
Figure 4.A.51: Crystal Structure of 38.
Suitable crystals were grown by vial-in-vial vapor diffusion using CHCl 3 :Pentane as the
solvent:antisolvent mixture.
145
BRETT VANVELLER
Department of Chemistry - Massachusetts Institute of Technology
77 Massachusetts Avenue, Bldg 18-031
Cambridge, MA 02139-4307 USA
(617) 452-2569 - bvv@mit.edu
EXPERIENCE
2006-2011
Graduate Student with Professor Timothy M. Swager
Massachusetts Institute of Technology
2005-2006
Researcher with Professor Alex Adronov
McMaster University
2004 (summer)
Researcher with Professor M6nica Barra
University of Waterloo
EDUCATION
2011
Ph.D., Chemistry, Massachusetts Institute of Technology
2006
B.Sc., Chemistry, McMaster University
ACADEMIC HONORS & AWARDS
2010
2008
2007
2007
2007
2006
2006
2006
2006
2005
2005
2005
2004
2004
2004
2004
2002
David A. Johnson Summer Graduate Fellowship
National Science and Engineering Research Council Postgraduate Scholarship
Massachusetts Institute of Technology Department of Chemistry Award for Outstanding
Teaching
David A. Johnson Award
Macromolecular Science and Engineering Division of the Chemical Institute of Canada
Undergraduate Research Thesis Award
National Science and Engineering Research Council Postgraduate Scholarship
The Society of Chemical Industry Merit Award
The Provost's Honour Roll Medal
The Robert S. Haines Memorial Scholarship
The Canadian Society for Chemistry Prize
The J. L. W. Gill Prize
The Donald G. McNabb Scholarship
National Science and Engineering Research Council Undergraduate Student Research Award
Reactive Intermediates Student Exchange Award
The Chemical Institute of Canada Prize
The University Senate Scholarship
The McMaster Honour Award
146
PUBLICATIONS
(5)
(4)
(3)
(2)
(1)
Polat, B. E.; Lin, S.; Mendenhall, J. D.; VanVeller, B.; Langer, R.; Blankschtein, D. An
Experimental and Molecular Dynamics Investigation into the Amphiphilic Nature of
Sulforhodamine B, J. Phys. Chem. B 2011, 115, 1394-1402. Cover Article
Andrew, T. L.; VanVeller, B.; Swager, T. M. Synthesis of Azaperylene-9,10-dicarboximides,
Synlett 2010, 3045-3048.
VanVeller, B.; Swager, T. M. Biocompatible Post-Polymerization Functionalization of a Water
Soluble Poly(p-Phenylene Ethynylene), Chem. Comm un. 2010, 46, 5761-5763.
VanVeller, B.; Swager, T. M., Poly(aryleneethynylene)s. In Design and Synthesis of Conjugated
Polymers, Leclerc, M.; Morin, J., Eds. Wiley-VCH: Weinheim, 2010; pp 175-200.
VanVeller, B.; Miki, K.; Swager, T. M. Rigid Hydrophilic Structures for Improved
Properties of Conjugated Polymers and Nitrotyrosine Sensing in Water, Org. Lett. 2010, 12,
1292-1295.
PRESENTATIONS
2010
2010
2010
2004
VanVeller, B.; Swager, T. M. Design and synthesis of rigid 3D hydrophilic structures for
improved properties of conjugated polymers in water and post-polymerization strategies for
sensing of proteins and influenza. Presented at the 240t ACS National Meeting, Boston,
Massachusetts, USA.
VanVeller, B.; Swager, T. M. Rigid Hydrophilic Structures for Improved Properties of
Conjugated Polymers in Water and Applications in Biosensing. Presented at the 9 3 rd Canadian
Chemistry Conference and Exhibition, Toronto, Ontario, CAN.
VanVeller, B.; Swager, T. M. Rigid Hydrophilic Structures for Improved Properties of
Conjugated Polymers in Water and Applications in Biosensing. Presented at the 9 th
International Symposium on Functional nt-Electron Systems, Georgia Institute of Technology,
Atlanta, Georgia, USA.
VanVeller, B.; Barra, M. Synthesis of the Elusive 5-Deazariboflavin: a Probe for the Study of
Electron Transfer Mechanisms. Presented at Reactive Intermediate Student Exchange
Symposium, University of Saskatchewan, Emma Lake, Saskatchewan, CAN.
TEACHING EXPERIENCE
2006-2007
Massachusetts Institute of Technology, Department of Chemistry:
Classroom Teaching Assistant for Organic Chemistry and General Chemistry
Prepared lessons for two one hour tutorials and held office hours each week.
Received The MIT Department of Chemistry Award for Outstanding Teaching
2005-2006
McMaster University, Department of Chemistry:
Classroom Teaching Assistant for General Chemistry
Prepared lessons for two one hour tutorials and held office hours each week.
2004 (fall)
McMaster University, Department of Chemisty:
Laboratory Teaching Assistant for General Chemistry
Instruction for one three hour laboratory session each week.
OTHER RELEVENT EXPERIENCE
2009-2010
Executive planning committee, "Chemistry and Policy: Solving Problems at the
Interface" symposium. 2010 Fall ACS National Meeting, Boston, MA.
http: / /web.mit.edu / gsspc /. Press: Chemical & Engineering News 2011, 89, 54-55.
2007-2010
Assistant Editor of the journal Synfacts
147
Acknowledgements
The past five years in graduate school have been both challenging and enriching
in no small part thanks to the many wonderful people I had the pleasure of working with
here at MIT.
First and foremost, I must thank my advisor Tim Swager. He has been an
inspiring and imaginative mentor who always granted me freedom to explore whatever
chemical curiosity I could cook up. His wonderful creativity and sense of humor made it
a pleasure to work with him these past five years.
I would also like to thank my thesis committee, Profs. Stephen Buchwald and
Barbara Imperiali, for guiding my academic progress. I thank Prof. Buchwald in
particular for his advice and recommendation when selecting my future postdoctoral
position.
I am also indebted to my many coworkers in the Swager lab. There are far too
many people to name who made my experience at MIT so memorable. Jeewoo Lim was
my year mate and a great colleague to discuss chemistry with over a beer at the Muddy
Charles. Trisha Andrew taught me everything I know about photophysics and using the
instruments. Jason Cox, for the many conversations we shared, I will miss them once I
leave. I wish to thank my office mates Barney Walker, Joel Batson, and Scott Meek, for
all the wonderful discussions both chemistry and non-chemistry related. There are far too
many to thank and this document was supposed to be submitted to the registrar last week.
I gratefully acknowledge the organization s that financially supported my
research: the Institute for Soldier Nanotechnologies (ISN) and the Natural Science and
Engineering Research Council (NSERC) of Canada.
Finally, I thank my wife Courtney for filling my life with happiness. Without her
my life would not be as full. The last five years have been such a fun adventure and I
can't wait for the next chapter together as our family has expanded by one-our new
daughter Helena is now only 10 weeks old.
148