Synthesis and Characterization of Repeating Sequence Copolyesters by Ryan Michael Weiss ...

300 Pages·2016·7.19 MB·English

Synthesis and Characterization of Repeating Sequence Copolyesters
by
Ryan Michael Weiss
Bachelor of Arts, Wittenberg University, 2008
Submitted to the Graduate Faculty of the Kenneth P.
Dietrich School of Arts and Sciences in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy in Chemistry
University of Pittsburgh
2017
UNIVERSITY OF PITTSBURGH
DIETRICH SCHOOL OF ARTS AND SCIENCES
This thesis was presented
by
Ryan Michael Weiss
It was defended on
August 5th, 2016
and approved by
Alexander Star, Professor, Chemistry
W. Seth Horne, Associate Professor, Chemistry
Kacey G. Marra, Associate Professor, School of Medicine
Dissertation Advisor: Tara Y. Meyer, Associate Professor, Chemistry
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Synthesis and Characterization of Repeating Sequence Copolyesters
Ryan Michael Weiss, PhD
University of Pittsburgh, 2017
Copyright © by Ryan Michael Weiss
2017
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Synthesis and Characterization of Repeating Sequence Copolyesters
Ryan Michael Weiss, PhD
University of Pittsburgh, 2017
Sequence in copolymers is underexploited in synthetic copolymer design despite the
overwhelming evidence of the importance of sequence in controlling polymer properties that is
seen in biological polymers. A series of poly(α-hydroxy acid)s consisting of lactic (L); glycolic
(G) and caprolactone-derived (C) units has been prepared using segmer assembly polymerization
(SAP). The segmers, which consist of the targeted repeat unit, e.g. LGC, are first prepared by
the coupling of orthogonally protected building blocks. The periodic copolymers, e.g., (LGC)n
were then prepared by a step-growth condensation reaction. The retention of the sequence in the
copolymers was confirmed by NMR analysis and the chemical shifts were compared with those
previously assigned based on the analysis of statistical copolymers. Thermal properties, Tg and
Tm were found to depend both on composition and, in a few cases, sequence. Selected
poly(lactic-co-glycolic acid)s (PLGAs) with embedded stereosequences (LS vs. LR), were found
to form crystalline stereocomplexes, in some cases as blends and in others as homopolymers that
included both stereoisomers as mini-blocks. The sequence fidelity of PLGAs was defined and
determined for a series of copolymers with controlled levels and types of errors. Both NMR and
Matrix-Assisted Laser Desorption/Ionization (MALDI) mass spectrometry were used to quantify
the error level. An alternate synthetic method for sequenced PLGAs, based on Entropy-Driven
Ring-Opening Metathesis Polymerization (ED-ROMP) was developed. Embedding the target
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sequence in an unstrained macrocycle bearing an olefinic reactive group allowed for ED-ROMP
and produced sequenced copolymers with improved molecular weight control relative to SAP.
Kinetic studies were consistent with an entropy-driven process. Copolymers comprised of
repeating sequences were synthesized by SAP and ED-ROMP and their properties were then
characterized.
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TABLE OF CONTENTS
LIST OF TABLES ...................................................................................................................... XI
LIST OF FIGURES ................................................................................................................. XIII
LIST OF SCHEMES ............................................................................................................ XXIV
LIST OF ABBREVIATIONS ................................................................................................ XXV
PREFACE ........................................................................................................................... XXVIII
1.0 INTRODUCTION ........................................................................................................ 1
1.1 SYNTHESIS OF SEQUENCED COPOLYMERS ........................................... 1
1.1.1 Poly(lactic-co-glycolic acid)s: importance as a material in biomedical
applications ................................................................................................................... 2
1.1.2 Sequenced copolymers and their preparation .............................................. 4
1.1.3 Repeating sequence copolymers prepared via segmer assembly
polymerization .............................................................................................................. 5
1.1.4 Entropy-driven ring-opening polymerization ............................................... 8
2.0 SYNTHESIS OF REPEATING SEQUENCE COPOLYMERS OF LACTIC,
GLYCOLIC AND CAPROLACTIC ACIDS ............................................................................. 9
2.1 INTRODUCTION ............................................................................................... 9
2.2 RESULTS AND DISCUSSION ........................................................................ 10
2.2.1 Naming conventions ...................................................................................... 10
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2.2.2 Synthesis of sequenced copolymers containing L, G, and C ...................... 12
2.2.3 NMR analysis of sequenced copolymers containing L, G, and C.............. 14
2.2.4 Thermal data and analysis of sequenced copolymers containing L, G, and
C ...................................................................................................................... 23
2.3 CONCLUSIONS ................................................................................................ 25
2.4 EXPERIMENTAL ............................................................................................. 26
2.4.1 General procedure for DCC/DPTS coupling reactions.............................. 27
2.4.2 General procedure for the silyl deprotections. ........................................... 38
2.4.3 General procedure for benzyl deprotection of diprotected oligomers. ..... 45
2.4.4 General procedure for benzyl deprotection of benzyl protected oligomers.
......................................................................................................................... 49
2.4.5 General procedure for the polymerization of the sequenced segmers ...... 56
3.0 DETERMINING SEQUENCE FIDELITY IN REPEATING SEQUENCE
POLY(LACTIC-CO-GLYCOLIC ACIDS) .............................................................................. 64
3.1 INTRODUCTION ............................................................................................. 64
3.1.1 Sequence and effects on properties .............................................................. 64
3.1.2 Calculation of sequence fidelity in copolymers ........................................... 65
3.2 RESULTS AND DISCUSSION ........................................................................ 68
3.2.1 SAP of sequenced PLGAs ............................................................................. 68
3.2.2 MALDI-ToF analysis of repeating sequence PLGAs ................................. 69
3.2.3 Synthesis and analysis of sequenced PLGA “errormers” .......................... 75
3.2.4 Segmer relative reactivity study ................................................................... 85
3.3 CONCLUSIONS ................................................................................................ 87
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3.4 EXPERIMENTAL ............................................................................................. 88
3.4.1 Materials ......................................................................................................... 88
3.4.2 Characterization ............................................................................................ 88
3.4.3 Errormer Synthesis ....................................................................................... 90
3.4.4 Reactivity of monomers study. ..................................................................... 94
4.0 SEQUENCE-CONTROLLED COPOLYMERS PREPARED VIA ENTROPY-
DRIVEN RING-OPENING METATHESIS POLYMERIZATION ..................................... 95
4.1 INTRODUCTION ............................................................................................. 95
4.1.1 Recent advances in sequenced copolymers ................................................. 95
4.1.2 Segmer assembly polymerization of PLGAs ............................................... 96
4.1.3 Entropy-driven ring-opening metathesis polymerization .......................... 96
4.2 RESULTS AND DISCUSSION ........................................................................ 98
4.2.1 Synthesis of sequenced macrocycles and subsequent ED-ROMP ............. 98
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4.2.2 H NMR spectroscopy characterization of synthesized copolymers ....... 102
4.2.3 ED-ROMP polymerization kinetic study .................................................. 106
4.2.4 Copolymer thermal properties ................................................................... 112
4.3 CONCLUSIONS .............................................................................................. 112
4.4 EXPERIMENTAL ........................................................................................... 113
4.4.1 General information .................................................................................... 113
4.4.2 Compound characterization ....................................................................... 114
4.4.3 Synthesis of cyclic macromonomers and copolymers .............................. 115
5.0 SYNTHESIS AND PREPARATION OF SEQUENCED PLGA
STEREOCOMPLEXES ........................................................................................................... 136
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5.1 INTRODUCTION ........................................................................................... 136
5.1.1 Sequence matters ......................................................................................... 136
5.1.2 Poly(α-hydroxy acid)s and tacticity ........................................................... 137
5.1.3 Formation of stereocomplexes .................................................................... 139
5.1.4 Sequenced copolyesters prepared by SAP................................................. 141
5.1.5 Preliminary evidence for the stereocomplex formation in sequenced
PLGAs ....................................................................................................................... 141
5.2 RESULTS AND DISCUSSION ...................................................................... 142
5.2.1 Naming conventions .................................................................................... 142
5.2.2 Synthesis and characterization of repeating sequence copolymers towards
the creation of copolymer stereocomplexes ........................................................... 143
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5.2.3 Characterization of isotactic and mini-block sequenced copolymers by H
NMR spectroscopy ................................................................................................... 145
5.2.4 Characterization of sequenced PLGA copolymers by differential scanning
calorimetry ................................................................................................................ 149
5.2.5 Stereocomplex formation of sequenced PLGAs ....................................... 149
5.3 CONCLUSIONS .............................................................................................. 153
5.4 FUTURE WORK ............................................................................................. 154
5.5 EXPERIMENTAL ........................................................................................... 155
5.5.1 General information .................................................................................... 155
5.5.2 Characterization of synthesized compounds ............................................. 156
5.5.3 Synthesis of sequenced PLGAs for stereocomplex formation ................. 157
5.5.3.1 DCC/DPTS coupling reactions ........................................................ 157
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5.5.3.2 Silyl deprotection of di-protected segmers...................................... 165
5.5.3.3 Hydrogenolysis of di-protected segmers ......................................... 171
5.5.3.4 Hydrogenolysis of mono-protected segmers ................................... 174
5.5.3.5 SAP of sequenced segmers ............................................................... 179
5.5.4 Preparation of mixed polymer samples with opposing stereochemistry 184
APPENDIX A ............................................................................................................................ 185
REFERENCES .......................................................................................................................... 261
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