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SYNTHESIS AND PROPERTIES OF COMB-LIKE
POLYLACTIDES
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XUWEI JIANG
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SYNTHESIS AND PROPERTIES OF COMB-LIKE POLYLACTIDES
By
quei Jiang
A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
Department of Chemistry
2006
ABSTRACT
SYNTHESIS AND PROPERTIES OF COMB-LIKE POLYLACTIDES
By
quei Jiang
Because of their biodegradability and biocompatibility, lactide based polymers
are extensively studied for biomedical applications. To have the broad range of
physical properties that make them suitable for these applications, certain
modifications of polylactides are necessary. This objective can be partially
accomplished by synthesizing substituted polylactides.
A series of substituted glycolides, substituted with n-alkyl groups of various
lengths (n (number of carbons in the alkyl group) = 6, 8, 10, 12, 14, 16), were
synthesized and subsequently polymerized to high molecular weight polymers.
Depending on the side chain length, low Tg polylactides and side chain crystalline
polylactides were obtained. Hydrolytic degradation rates are independant of side
chain length within experimental error. Thermal degradation temperatures of
these alkyl comb polylactides are around 320 °C. Kinetic studies showed that
lactide polymerizations are first order reactions in both melt and solution
processes. The apparent polymerization rates initially decrease with the increase
of side chain length. When side chain exceeds a critical length, the
polymerization rates became independant of side chain length. For side chain
crystalline polylactides, X—ray data revealed the formation of hexagonally packed
side chain crystallites and lamellar structure in bulk. The melting temperature of
the polymer can be easily tuned through copolymerization.
Novel glycolides with oligo(ethylene oxide) containing substituent groups
were synthesized and polymerized to yield PEG-grafted polylactides with well-
defined architecture. The introduction of PEO pendant groups onto the
polylactide backbone improved its hydrophilicity and eventually made the
polymer water-soluble. Aqueous solutions of water-soluble PEO grafted
polylactides underwent reversible phase transitions when the temperature is
above or below a critical point. The phase transition was studied by cloud point
measurements, variable temperature 1HNMR analysis, and variable temperature
DLS measurements.
Amphiphilic substituted lactide monomers were synthesized by coupling of
PEG containing a-hydroxy acids and 2-bromo-octadecanoyl chloride. DSC
analysis of the polylactides derived from these amphiphilic monomers suggested
side chain crystallization. Azobenzene encapsulation study by solvent
displacement method showed that water solubility of azobenzene can be
improved using the amphiphilic polylactide.
An acetylene functionalized glycolide was successfully synthesized.
Subsequent homopolymerization and copolymerization led to pendant acetylene
group containing polylactides. These functional polylactides were used as
substrates for introduction of functional moieties onto polylactide backbone by
click chemistry. PEG, alkyl, and PEG/alkyl grafted polylactides have been
prepared through this approach. Among those grafted polymers, DiEG and
DiEG/alkyl grafted polylactides exhibit lower critical solution temperature (LOST)
in aqueous solution at ~80 °C and ~30 °C respectively.
ACKNOWLEDEMENTS
I would like to sincerely thank my advisor Greg Baker for his guidance. It is
because of him I decided to come to MSU, it is because of him I had the chance
to stay at MSU, and it is also because of him I chose to stay as a Spartan. I value
tremendously his training and encouragements in all these years.
Secondly, I would like to thank Prof. Mitch Smith for his invaluable scientific
guidance and discussions, and for his free lunches. I would like to thank
Professor Maleczka and Blanchard for helpful discussions and suggestions, as
well as Professor Mackay and his group members for use of their equipments.
Special thanks go to Jon for his help with my language and research, as well
as for his interesting jokes. I would like to thank former and current group
members Tianqi, JB, Feng, Qin, Ying, Bao, Erin, Leslie, D.J., and Ping for their
friendship and profitable discussions.
Finally and most importantly, I would like to thank Guangyan, my wife, for
your love and support, as well as our coming daughter for the anticipation you
bring me. I would also like to thank my parents, sister, brother-in-law, and all
other family members for their support and encouragements during my graduate
career.
TABLE OF CONTENTS
List of Figures ..................................................................................................... vii
List of Schemes ................................................................................................. xvii
List of Tables ..................................................................................................... xviii
List of Abbreviations ........................................................................................... xix
Chapter 1 Introduction ...................................................................................... 1
Structure and Properties of Comb-like Polymers ............................................... 1
Alkyl Comb Polymers with flexible backbone .................................................... 1
Poly(acrylate)s, poly(methacrylates), poly(acrylamides) ................................ 1
Poly(vinyl ethers) and poly(vinyl esters) ......................................................... 3
Poly(q-olefins), polyaldehydes, and poly(oxiranes) ........................................ 4
Polystyrenes, poly(1,3-butadienes), and polyitaconates ................................ 7
Alkyl comb polymers with rigid backbone .......................................................... 9
Polypeptides .................................................................................................. 9
Poly(3-alkyl thiophene)s ............................................................................... 12
Stiff-chain polyesters, polyamides, and polyimides ...................................... 13
Other stiff-chain alkyl comb polymers .......................................................... 15
PEG comb polymers ....................................................................................... 17
Poly(vinyl ethers) ......................................................................................... 17
Poly(methacrylates) ..................................................................................... 20
Polystyrenes ................................................................................................ 21
PEG/Alkyl comb polymers ............................................................................... 23
Application of Click Chemistry in polymer synthesis and functionalization ...... 27
Chapter 2 Alkyl Comb Polylactides ................................................................ 39
Introduction ..................................................................................................... 39
Results and Discussion ................................................................................... 41
Monomer Synthesis ..................................................................................... 41
Bulk Polymerizations .................................................................................... 44
Solution Polymerizations .............................................................................. 48
Homopolymer Properties ............................................................................. 49
Polymer Degradation ................................................................................... 63
Alkyl Comb Copolymers ............................................................................... 66
Experimental Section ...................................................................................... 69
Chapter 3 PEG-grafted Comb Polylactides .................................................... 78
Introduction ..................................................................................................... 78
Results and Discussion ................................................................................... 80
Monomer synthesis ...................................................................................... 80
Bulk polymerization ...................................................................................... 84
Polymer properties ....................................................................................... 86
Aqueous solubility and solution properties of PEG-grafted polylactides ...... 87
Conclusions ..................................................................................................... 92
Experimental Section ...................................................................................... 92
Chapter 4 Functionalization of Polylactides by “Click” Chemistry ................. 103
Introduction ................................................................................................... 103
Results and Discussion ................................................................................. 105
Monomer synthesis .................................................................................... 105
Polymerization ........................................................................................... 1 07
“Click” functionalization .............................................................................. 1 1 1
Conclusions ................................................................................................... 121
Experimental Section .................................................................................... 122
Chapter 5 PEG/AlkyI-Grafted Comb Polylactides ......................................... 129
Introduction ................................................................................... 129
Results and Discussion ................................................................................. 131
Conclusions ................................................................................................... 139
Experimental Section .................................................................................... 140
Appendicies ...................................................................................................... 148
Appendix A. NMR Spectra ............................................................................ 149
Appendix B. FT-IR Spectra ........................................................................... 232
References ........................................................................................................ 247
vi
List of Figures
Figure 1. Chemical structures of comb-like poly(acrylates), poly(methacrylates),
and poly(acrylamides) ........................................................................................... 2
Figure 2. Possible side chain packing motifs for poly(acrylates) and
poly(methacrylates) as proposed by Jordan et al .................................................. 3
Figure 3. Chemical structures of comb-like poly(vinyl ester)s and poly(vinyl
ether)s ................................................................................................................... 4
Figure 4. Chemical structures of comb-like poly(q-olefin)s, poly(oxiranes)s, and
polyaldehydes ....................................................................................................... 5
Figure 5. Packing of comb polymers with parallel main chains and fully extended
side chains as proposed by Turner-Jones ............................................................ 5
Figure 6. Possible packing arrangements for comb polymers with side chains
tilted to main chain axis as proposed by Turner-Jones ......................................... 6
Figure 7. Chemical structures of comb-like polystyrenes, poly(1,3—butadiene)s,
and polyitaconates ................................................................................................ 8
Figure 8. Chemical structures of comb-like polypeptides ...................................... 9
Figure 9. Model for the packing of poly(a-glutamates) at low temperatures ........ 10
Figure 10. Schematic model illustrating the structural changes as function of
temperature for side chain crystalline poly(B-aspartate)s .................................... 11
Figure 11. Chemical structure and proposed possible molecular packing of
poly(3—alkyl thiophene)s ...................................................................................... 12
Figure 12. Chemical structures of comb-like rigid-rod polyesters, polyamides, and
polyimides l (R represents linear alkyl groups) ................................................... 14
Figure 13. Chemical structures of comb-like rigid-rod polyesters, polyamides, and
polyimides II (R represents linear alkyl groups) .................................................. 15
Figure 14. Chemical structures of several other alkyl comb-like polymers .......... 16
Figure 15. Chemical structures of PEG comb-like poly(vinyl ether)s .................. 17
Figure 16. Chemical structures of PEG comb-like poly(vinyl ether)s block
copolymers .......................................................................................................... 18
vii
Figure 17. Chemical structures of comb-like PEG poly(methacrylate)s .............. 20
Figure 18. Chemical structure of comb-like PEG polystyrenes ........................... 21
Figure 19. Chemical structures of PEG/alkyl comb polymers with well-defined
structures ............................................................................................................ 23
Figure 20. Chemical structures of PEG/alkyl comb polymers with ill-defined
structures ............................................................................................................ 25
Figure 21. A proposed model for a hypothetical bilayer structure formed by the
graft copolymers poly(PEOMA-ran-ODMA). ....................................................... 26
Figure 22. Mechanism of click chemistry proposed by Sharpless et al. .............. 27
Figure 23. Structure of a divergent dendrimer synthesized by Hawker and
Wooley et al. ....................................................................................................... 28
Figure 24. Structure of an unsymmetrical dendrimer synthesized by Lee et al. ..29
Figure 25. 500 MHz 1H NMR spectra of hexadecyl glycolide and its polymer....43
Figure 26. Bulk polymerization kinetics of substituted glycolides. Polymerization
conditions: 130°C, [Sn(2-ethylhexanoate)2]/[tert-butylbenzyl alcohol] = 1,
[monomer1/[catalyst] = 50. Each data point is the average of three independent
runs and corrected for equilibrium ....................................................................... 45
Figure 27. Relationship between apparent rate constant and the length of side
chains for bulk polymerization of substituted glycolides. ..................................... 46
Figure 28. Solution polymerization kinetics of substituted glycolides.
Polymerization conditions: 90°C in toluene, [Sn(2-ethylhexanoate)2]/[tert-
butylbenzyl alcohol] = 1, [monomer]/[catalyst] = 100. Each data set corresponds
to a single kinetics run. ....................................................................................... 47
Figure 29. Relationship between apparent rate constant and the length of side
chains for solution polymerization of substituted glycolides. ............................... 48
Figure 30. TGA results for substituted polyglycolides. (10 °Clmin in air, no aging)
............................................................................................................................ 50
Figure 31. DSC scans for substituted polyglycolides. The data are second
heating scans, taken after heating to 70 °C and flash cooled. Heating rate: 10 °C
/min in N2. ........................................................................................................... 51
Figure 32. The relationship between AH, and side chain length ......................... 52
viii
Figure 33. WAXS profiles of flash-cooled polyC14 and polyC16 (polyC14-1 and
polyC14-2, polyC16-1 and polyC16-2 are two different runs from the same
polyC14 and polyC16 sample, respectively.) ...................................................... 54
Figure 34. DSC traces of polyC14 samples with different thermal histories. First
heating scan. 10 °Clmin in N2. (black line: flash cooled in freezer for 8 minutes;
pink line: annealed at 27 °C for four hours; blue line: annealed 32 °C for six
weeks) ................................................................................................................ 56
Figure 35. WAXS profiles of polyC14 samples with different thermal histories.
(black line: flash cooled in freezer for 8 minutes; pink line: annealed at 27 °C for
four hours; blue line: annealed 32 °C for six weeks) ........................................... 56
Figure 36. DSC traces of polyC16 samples with different thermal histories. First
heating scan. 10 °Clmin in N2. (black line: annealed at room temperature for 12
hours; pink line: annealed at 45 °C for two weeks; blue line: annealed at 45 °C for
two months) ........................................................................................................ 57
Figure 37. WAXS profiles of polyC16 samples with different thermal histories.
(black line: annealed at room temperature for 12 hours; pink line: annealed at 45
°C for two weeks; blue line: annealed at 45 °C for two months) ......................... 57
Figure 38. DSC traces of annealed alkyl comb polyglycolides. 10 °Clmin in N2.
(black line: polyC10, annealed at room temperature for a year; pink line: polyC12,
annealed at room temperature for a year; red line: polyC14, annealed at 32 °C
for six weeks; blue line: polyC16, annealed at 45 °C for two weeks) .................. 60
Figure 39. WAXS profiles of annealed alkyl comb polyglycolides. (black line:
polyC10, annealed at room temperature for a year; pink line: polyC12, annealed
at room temperature for a year; red line: polyC14, annealed at 32 °C for six
weeks; blue line: polyC16, annealed at 45 °C for two weeks) ............................. 60
Figure 40. Evolution of d-spacings with side chain length. (I crystalline polymer
samples; A melt polymer samples) .................................................................... 61
Figure 41. Proposed molecular packing of annealed alkyl comb polylactides ....62
Figure 42. WAXS profiles of alkyl comb polyglycolides ....................................... 63
Figure 43. Molecular weight change of polyglycolides during hydrolytic
degradation in pH = 7.4 phosphate buffer at 55 °C ............................................. 65
Figure 44. Molecular weight change of polyglycolides during hydrolytic
degradation fitted to random chain scission model ............................................. 65
Figure 45. DSC heating scans of C14 and C16 random copolymers. Second
heating scan,10 °lmin in N2. ................................................................................ 67
Figure 46. DSC heating traces of polyC14 and polyC16 blends. Second heating
scan,10 °Clmin in N2. .......................................................................................... 68
Figure 47. DSC heating scan of polyC16 - block - polyC14). Second heating
scan, 10 °Clmin in N2. ......................................................................................... 69
Figure 48. 1H NMR spectra for 4b, 5b, and poly(5b). .......................................... 82
Figure 49. GPC traces of PEG-grafted polylactides ............................................ 85
Figure 50. TGA of PEG-grafted polylactides (10 °Clmin in air, samples were held
at 135 °C for 30 min prior to run. Pink line: poly(Sa); red line: poly(5b); black line:
poly(5c); blue line: poly(5d)) ................................................................................ 86
Figure 51. DSC traces of PEG-grafted polylactides (second heating scan, 10
°Clmin in N2) ....................................................................................................... 87
Figure 52. 500 MHz 1H NMR spectra of poly(5c) (Mn = 59,800 glmol, PDI = 1.16)
in D20 (15 mg/mL) at different temperatures. ..................................................... 88
Figure 53. 500 MHz 1H NMR spectra of poly(5d) (Mn = 10,600 glmol, PDI = 1.12)
in D20 (15 mglmL) at different temperatures. ..................................................... 89
Figure 54. DLS results of poly(5c) (Mn = 59,800 glmol, PDI = 1.16) in water (3
mglmL) at different temperatures. ....................................................................... 91
Figure 55. DLS results of poly(5d) (Mn = 10,600 glmol, PDl = 1.12) in water (3
mg/mL) at different temperatures. ....................................................................... 91
Figure 56. 300 MHz 1H NMR spectra of propargyl glycolide and poly(propargyl
glycolide) ........................................................................................................... 107
Figure 57. Relationship between Mn and the degree of polymerization for
propargyl glycolide bulk polymerization. ........................................................... 108
Figure 58. 75 MHz 13C NMR carbonyl region of propargyl glycolide homopolymer,
copolymers, and polylactide .............................................................................. 110
Figure 59. GPC traces of the PPGL macroinitiator, and PPGL-block-polylactide.
(black line: PPGL; pink line: PPGL-block-polylactide) ....................................... 1 11
Figure 60. GPC traces of PPGL and C10-grafted PPGL. (pink line: PPGL; black
line: C10-grafted PPGL) .................................................................................... 113
Figure 61. GPC traces from a control reaction where PPGL was exposed to click
conditions, but without added azide. (black line: PPGL before the reaction; pink
line: PPGL after the reaction) ............................................................................ 114
Figure 62. GPC traces of a polylactide sample exposed to “click” conditions.
(black line: polylactide before the click reaction; pink line: polylactide after
reaction) ............................................................................................................ 116
Figure 63. GPC traces for the poly(propargyl glycolide-co—Iactide) click
PEGylation. The concentration of propargyl glycolide in the copolymer was 7.9
mol %. (black line: copolymer before the click reaction; pink line: copolymer after
click reaction) .................................................................................................... 116
Figure 64. DLS of DiEG/alkyl-grafted PPGL (5 mg/mL in water) ....................... 119
Figure 65. DLS of PEGylated PPGL-block-polylactide in water ........................ 120
Figure 66. 300 MHz 1H NMR spectra of PEG containing q-hydroxy acids ........ 133
Figure 67. 500 MHz 1H NMR spectra of amphiphilic glycolide monomers ........ 134
Figure 68. 500 MHz 1H NMR spectra of amphiphilic polyglycolides .................. 135
Figure 69. GPC traces of amphiphilic polyglycolides (pink line: poly(4a); black
line: poly(4b) ..................................................................................................... 136
Figure 70. DSC heating traces of amphiphilic polylactides (second heating scan,
10 °Clmin in N2) ................................................................................................ 136
Figure 71. DLS of polymeric micelles and azobenzene loaded polymeric micelles
(5mg/mL in water, pink line: polymer only; black line: polymer + azobenzene).137
Figure 72. UV-vis spectra of polymeric micelles, azobenzene loaded polymeric
micelles, and azobenzene in water. (black line: azobenzene; pink line: poly(4a);
blue line: poly(4a) + azobenzene) ..................................................................... 138
Appendix A 1. 1H NMR spectrum of C6-a-hydroxy acid .................................... 150
Appendix A 2. 13C NMR spectrum of C6-q-hydroxy acid ................................... 151
Appendix A 3. 1H NMR spectrum of C6 dimer .................................................. 152
Appendix A 4. 13C NMR spectrum of C6 dimer ................................................. 153
Appendix A 5. 1H NMR spectrum of C8-a-hydroxy acid .................................... 154
xi
Appendix A 6. 13C NMR spectrum of C8-q-hydroxy acid ................................... 155
Appendix A 7. 1H NMR spectrum of C8 dimer .................................................. 156
Appendix A 8. 13C NMR spectrum of C8 dimer ................................................. 157
Appendix A 9. 1H NMR spectrum of C10 q-hydroxy acid ................................. 158
Appendix A 10. “C NMR spectrum of C10 a-hydroxy acid ............................... 159
Appendix A 11. 1H NMR spectrum of C10 dimer .............................................. 160
Appendix A 12. 13c NMR spectrum of C10 dimer ............................................. 161
Appendix A 13. 1H NMR spectrum of C12 q-hydroxy acid ................................ 162
Appendix A 14. ”C NMR spectrum of C12 a-hydroxy acid ............................... 163
Appendix A 15. 1H NMR spectrum of C12 dimer .............................................. 164
Appendix A 16. ”C NMR spectrum of c12 dimer ............................................. 165
Appendix A 17. 1H NMR spectrum of C14 q-hydroxy acid ................................ 166
Appendix A 18. 13c NMR spectrum of C14 d-hydroxy acid ............................... 167
Appendix A 19. 1H NMR spectrum of C14 dimer .............................................. 168
Appendix A 20. 13C NMR spectrum of C14 dimer ............................................. 169
Appendix A 21. 1H NMR spectrum of C16 q-hydroxy acid ................................ 170
Appendix A 22. 13c NMR spectrum of C16 d-nydroxy acid ............................... 171
Appendix A 23. 1H NMR spectrum of C16 dimer .............................................. 172
Appendix A 24. ”C NMR spectrum of C16 dimer ............................................. 173
Appendix A 25. 1H NMR spectrum of polyC6 .................................................... 174
Appendix A 26. 1H NMR spectrum of polyCB .................................................... 175
Appendix A 27. ‘H NMR spectrum of polyC10 .................................................. 176
Appendix A 28. 1H NMR spectrum of polyC12 .................................................. 177
xii
Appendix A 29.
Appendix A 30.
Appendix A 31.
Appendix A 32.
Appendix A 33.
Appendix A 34.
Appendix A 35.
Appendix A 36.
Appendix A 37.
Appendix A 38.
Appendix A 39.
Appendix A 40.
Appendix A 41.
Appendix A 42.
Appendix A 43.
Appendix A 44.
Appendix A 45.
Appendix A 46.
Appendix A 47.
Appendix A 48.
Appendix A 49.
Appendix A 50.
Appendix A 51.
1H NMR spectrum of polyC14 .................................................. 178
1H NMR spectrum of polyC16 .................................................. 179
1H NMR spectrum of MonoEG-C6 bromide ............................. 180
130 NMR spectrum of MonoEG-C6 bromide ............................ 181
1H NMR spectrum of MonoEG-C6-d-hydroxy acid ................... 182
13C NMR spectrum of MonoEG-C6-d-hydroxy acid ................. 183
1H NMR spectrum of MonoEG-C6 dimer ................................. 184
13C NMR spectrum of MonoEG-C6 dimer ................................ 185
1H NMR spectrum of DiEG-C6 bromide ................................... 186
13c NMR spectrum of DiEG-CG bromide ................................. 187
1H NMR spectrum of DiEG-C6-o-hydroxy acid ........................ 188
13C NMR spectrum of DiEG-C6-a-hydroxy acid ....................... 189
1H NMR spectrum of DiEG-C6 dimer ....................................... 190
13c NMR spectrum of DiEG-C6-dimer ..................................... 191
‘H NMR spectrum of TriEG-C6 bromide .................................. 192
13c NMR spectrum of TriEG-C6 bromide ................................. 193
1H NMR spectrum of TriEG-CB-d-hydroxy acid ....................... 194
13c NMR spectrum of TriEG-C6-d-hydroxy acid ...................... 195
1H NMR spectrum of TriEG-CG dimer ...................................... 196
13c NMR spectrum of TriEG-C6 dimer ..................................... 197
1H NMR spectrum of TetraEG-C6 bromide .............................. 198
1H NMR spectrum of TetraEG-C6-q-hydroxy acid ................... 199
13c NMR spectrum of TetraEG-C6-q-hydroxy acid .................. zoo
xiii
Appendix A 52. 1H NMR spectrum of TetraEG-C6 dimer .................................. 201
Appendix A 53. 13C NMR spectrum of TetraEG-C6 dimer ................................ 202
Appendix A 54. 1H NMR spectrum of poly(MonoEG-C6) .................................. 203
Appendix A 55. 1H NMR spectrum of poly(DiEG-C6) ........................................ 204
Appendix A 56. 1H NMR spectrum of poly(TriEG-C6) ....................................... 205
Appendix A 57. 1H NMR spectrum of poly(TetraEG-C6) ................................... 206
Appendix A 58. 1H NMR spectrum of propargyl-q-hydroxy ethyl ester .............. 207
Appendix A 59. 13C NMR spectrum of propargyl-a-hydroxy ethyl ester ............ 208
Appendix A 60. 1H NMR spectrum of propargyl-d-hydroxy acid ........................ 209
Appendix A 61. 13C NMR spectrum of propargyl-a-hydroxy acid ...................... 210
Appendix A 62. 1H NMR spectrum of propargyl glycolide ................................. 211
Appendix A 63. 13C NMR spectrum of propargyl glycolide ................................ 212
Appendix A 64. 1H NMR spectrum of poly(propargyl glycolide) ....................... 213
Appendix A 65. 130 NMR spectrum of poly(propargyl glycolide) ....................... 214
Appendix A 66. 1H NMR spectrum of poly(propargyl glycolide) — ran - polylacgdg
Appendix A 67. 13'C NMR spectrum of poly(propargyl glycolide) - ran - polylacgdg
Appendix A 68. 1H NMR spectrum of poly(propargyl glycolide) — block -
polylactide ......................................................................................................... 217
Appendix A 69. 13C NMR spectrum of poly(propargyl glycolide) -block —
polylactide ......................................................................................................... 218
Appendix A 70. 1H NMR spectrum of DiEG-grafted poly(propargyl glycolide) ..219
Appendix A 71. 1H NMR spectrum of 2-bromooctadecanoyl chloride ............... 220
Appendix A 72. 13C NMR spectrum of 2-bromooctadecanoyl chloride .............. 221
xiv
Appendix A 73. 1H NMR spectrum of TriEG-C6-C16 dimer .............................. 222
Appendix A 74. 13C NMR spectrum of TriEG-C6-C16 dimer ............................. 223
Appendix A 75. 1H NMR spectrum of TriEG-monobenzyl-ether—C6 bromide ....224
Appendix A 76. 13C NMR spectrum of TriEG-monobenzyl-ether-C6 bromide...225
Appendix A 77. 1H NMR spectrum of TriEG-monobenzyl-ether-C6-q-hydroxy acid
.......................................................................................................................... 226
Appendix A 78. 13C NMR spectrum of TriEG-monobenzyl-ether-C6-q-hydroxy
acid ................................................................................................................... 227
Appendix A 79. 1H NMR spectrum of TriEG-monobenzyl-ether-CG-C16 dimer 228
Appendix A 80. 13C NMR spectrum of TriEG-monobenzyl-ether-C6-C16 dimer
.......................................................................................................................... 229
Appendix A 81. 1H NMR spectrum of poly(TriEG-monomethyl-ether—CG-C16) .230
Appendix A 82. 1H NMR spectrum of poly(TriEG-monobenzyl-ether-C6-C16) .231
Appendix B 1. FT-IR spectrum of C6 dimer ...................................................... 233
Appendix B 2. FT-IR spectrum of C8 dimer ...................................................... 234
Appendix B 3. FT-IR spectrum of C10 dimer .................................................... 235
Appendix B 4. FT-IR spectrum of C12 dimer .................................................... 236
Appendix B 5. FT-IR spectrum of C14 dimer .................................................... 237
Appendix B 6. FT-IR spectrum of C16 dimer .................................................... 238
Appendix B 7. FT-IR spectrum of MonoEG-C6 dimer ....................................... 239
Appendix B 8. FT-IR spectrum of DiEG-C6 dimer ............................................. 240
Appendix B 9. FT-IR spectrum of TriEG-C6 dimer ............................................ 241
Appendix B 10. FT-IR spectrum of TetraEG-C6 dimer ...................................... 242
Appendix B 11. FT-IR spectrum of propargyl-a-hydroxy acid ........................... 243
Appendix B 12. FT-lR spectrum of propargyl glycolide ..................................... 244
XV
Appendix B 13. FT-IR spectrum of TriEG-monomethyl-ether-C6-C16 dimer ....245
Appendix B 14. FT-IR spectrum of TriEG-monobenzyI-ether-C6-C16 dimer ....246
Images in this dissertation are presented in color
List of Schemes
Scheme 1. Convergent approach toward triazole dendrimers by Hawker et al...28
Scheme 2. Synthesis of amphiphilic dendrimer (Fokin, Sharpless, and Hawker et
al.) ....................................................................................................................... 29
Scheme 3. Preparation of block copolymers by combination of ATRP and Click
Chemistry. ........................................................................................................... 30
Scheme 4. Synthesis and structure of dendronized linear polymers (Fréchet et
al.) ....................................................................................................................... 32
Scheme 5. Click functionalization of polymethacrylate ....................................... 33
Scheme 6. synthesis functional poly(p-phenyleneethynylene)s ......................... 33
Scheme 7. Simultaneous click functionalization of terpolymer ............................ 34
Scheme 8. Preparation of chain-end functional polymers by Click Chemistry ....35
Scheme 9. Click functionalization of aliphatic polyesters .................................... 35
Scheme 10. structure of mannose—functionalized dendrimer .............................. 37
Scheme 11. Synthesis of alkyl substituted lactide monomers ............................. 41
Scheme 12. Synthesis of PEG-grafted polylactides ............................................ 81
Scheme 13. Synthetic route to propargyl glycolide and its polymers ................ 106
Scheme 14. Synthesis of amphiphilic lactide monomers .................................. 132
xvii
List of Tables
Table 1. Properties of alkyl comb polylactides .................................................... 49
Table 2. X-ray Diffraction Spacings (A) of Comb-like PolyLactides ..................... 59
Table 3. properties of C14 and C16 copolymers ................................................. 67
Table 4. Representative bulk polymerization results of PEO containing glycolides.
............................................................................................................................ 84
Table 5. Bulk polymerization results of propargyl glycolide ............................... 108
xviii
BBA
br
dd
DLS
DMA
DMF
DSC
GPC
LCST
LS
Mn
Mw
MS
NMR
PDI
PEO
PEG
List of Abbreviations
4-tert-Butylbenzylalcohol
Broad
Doublet
Doublet of doublet
Dynamic light scattering
Dynamic mechanical analysis
N,N-Dimethyl-formamide
Differential scanning calorimetry
Gel permeation chromatography
Coupling constant
Lower critical solution temperature
Light scattering
Multiplet
Number average molecular weight
Weight average molecular weight
Mass spectroscopy
Nuclear magnetic resonance
Pentet
Polydispersity index
Poly(ethylene oxide)
Poly(ethylene glycol)
xix
PolyC6
PolyCB
PolyC1 0
PolyC12
PolyC14
PolyC1 6
PPGL
q
RT
s
Sn(Oct)2
t
T9
Tm
TGA
THF
UV-Vis
WAXS
Poly(hexylglycolide)
Poly(octylglycolide)
Poly(decylglycolide)
Poly(dodecylglycolide)
Poly(tetradecylglycolide)
Poly(hexadecylglycolide)
Poly(propargyl glycolide)
Quartet
Room temperature
singlet
Tin(ll)-2-ethylhexanoate
Triplet
Glass transition temperature
Melting temperature
Thermal gravimetric analysis
Tetrahyd rofu ran
Ultraviolet-Visible
VWde angle X-ray scattering
XX
Chapter 1 Introduction
Structure and Properties of Comb-like Polymers
Comb-like polymers with long, linear side chains in each repeat unit are a
bridge between branched polymers and linear polymers. Comb polymers have
attracted a great deal of attention because the nature of the side chains leads to
dramatically different polymer properties."2 For example, comb-like polymers
with linear alkyl side chains have lower melt and solution viscosities than linear
polymers, and decreased glass transition temperatures. Because of these
properties, comb-like polymers have found numerous applications such as pour-
point depressants for lubricants, viscosity modifiers, or additives in petroleum
products. The side chain crystalline character of these polymers has also led to
applications as temperature—triggered release matrices for the delivery of
agricultural insecticides and herbicides.3 In contrast to hydrophobic crystalline
combs, some comb-like polymers with oligo(ethylene oxide) side chains are
water soluble and exhibit lower critical solution temperature (LCST) behavior,
making them attractive “smart” materials for biotechnology.
Alkyl Comb Polymers with flexible backbone
Poly(acrylate)s, poly(methacrylates), poly(acrylamides)
In 1944 Rehberg and Fisher reported poly(n—alkyl acrylates) (1), the first alkyl
comb polymers.4 The “brittle points” of these poly(n-alkyl acrylates) decreased
with increasing side chain length up to poly(n—octyl acrylate), and then reversed
as the chains became progressively longer. Later, the higher alkyl polyacrylates
were identified as crystalline materials5 and the increase in brittle points was
attributed to the higher melting points of polymers with longer alkyl side chains.6
Crystallographic studies of these polymers by X-ray diffraction revealed that the
long alkyl side chains are hexagonally packed and that the arrangement of the
. . Hi 0
CnH2n+1 CnH2n+1 CnH2n+1
1 2 3
poly(acrylates) p0ly(methacrylates) poly(acrylamides)
Figure 1. Chemical structures of comb-like poly(acrylates), poly(methacrylates),
and poly(acrylamides)
side chain crystallites was independant of the stereoregularity of the polymer
backbone.7'9 Furthermore, studies suggested that comb polymers form lamellar
structures with amorphous regions formed by the polymer backbone and a
portion of the side chains separated by sheets of side-chain crystallites. For
poly(methacrylates) (2) and poly(acrylamides) (3), side chains of adjacent
polymers intercalate to form the side-chain crystallites (Figure 2a),10 while in
case of poly(acrylates), the crystallites are formed by the double layer packing of
side chains pointing in opposite directions (Figure 2b).10 In both cases, the side
chains are perpendicular to the polymer backbone. Systematic thermodynamic
studies of side-chain crystallization further concluded that, depending on the
flexibility of the main-chain structure, about nine to twelve methylene groups in
the side chain are in the amorphous state, and only the part of the side chain that
extends beyond that limit participates in crystallization.10 These studies also
showed that, in all cases, copolymers melt somewhere between the melting
points of the two homopolymers. X-ray data suggested the side chains of the
copolymers also packed into a hexagonal pattern.
(a) intercalated side chain packing (b) double-layered side chain packing
Figure 2. Possible side chain packing motifs for poly(acrylates) and
poly(methacrylates) as proposed by Jordan et al.‘°
Because of the unique rheological properties result from the introduction of
alkyl side chains, these polymers have long been used as viscosity index-
improving and pour point-depressing additives in lubricating oils."'“ Side-chain
crystallization has also lead to the formation of thermally reversible gels from
dilute solutions of these comb-like polymers.15
Poly(vinyl ethers) and poly(vinyl esters)
Swern and Jordan described the first side chain crystalline poly(vinyl esters)
(4) as white wax-like solids.16 Later, the same team conducted a systematic
study of poly(vinyl esters) and concluded that their side chains are able to
crystallize when the length of the chain exceeds twelve carbon atoms.17
However, no detailed structural data were available regarding the molecular
packing. In the following years, X-ray diffraction revealed that they crystallized in
hexagonal cells, regardless of the stereoregularitywm In addition, ten carbon
atoms was the minimal length of side chain required for crystallization, again
regardless of the stereoregularity of the backbone chains. Based on calorimetric
data, Jordan et al. further concluded that, similar to poly(acrylates), a double-
layered structure formed with only the outer part of the side chain included in the
crystal lattice (Figure 2b).10 Although poly(vinyl alkyl ethers) (5) are also known
to be capable of side chain crystallization, which has lead to applications such as
shape-memory materials?“22 the structural data of this series are rather limited
compared to poly(vinyl esters).
M...
m
0 C H O\
T n 2n+1 CnH2n+1
0
4 5
Poly(vinyl ester)s poly(vinyl ether)s
Figure 3. Chemical structures of comb-like poly(vinyl ester)s and poly(vinyl
ether)s
Poly(a-olefins), polyaldehydes, and poly(oxiranes)
A series of isotactic poly(a-olefins) (6) were studied by Turner-Jones using X-
ray diffraction and the results lead to the conclusion that there must be at least
seven carbon atoms in the side chains for them to be crystallizable?3 Depending
on the thermal history of the sample, three different crystalline forms were
observed.
O
N... “to/Yin. 1( Yin.
CnHZnH CnH2n+1 CnH2n+1
6 7 8
poly(q-olefins) poly(oxiranes) polyaldehydes
Figure 4. Chemical structures of comb-like poly(o-olefin)s, poly(oxiranes)s, and
polyaldehydes
main chain side chain
/ \
g 4.2A
Figure 5. Packing of comb polymers with parallel main chains and fully extended
side chains as proposed by Turner-Jones. 3
In a common crystalline form adopted by isotactic, side chain crystallizable
polyolefins, the main chains align in planes with side chains fully extended on
either side of the main chain axis and pack hexagonally (Figure 5). A second
crystalline form is seen for polyolefins having more than twelve carbon atoms in
the side chains, in which the side chains tilt ~130° relative to the axis defined by
the main chain and pack in a double-layered structure. As shown in Figure 6,
three different side chain packing modes are possible for this crystalline form.
Unlike other comb-like polymers, the isotactic backbone participates in the
crystallization of the above mentioned crystalline forms. A third form was formed
6.7A
*1
Q
N
3,.
/////9§ -
o
co
>
o
«a
V
//////
\\\\\ -.
//////
//////
\.\\\\\ .
/////§€T
//////
6.7A
>>>>>
.//////
\\\\\\
\\\\\\.
//////
.1
Figure 6. Possible packing arrangements for comb golymers with side chains
tilted to main chain axus as proposed by Turner-Jones.
by efficient quenching from the melt. Only hexagonal side chain crystallites
formed and no lamellar structure was observed.24 Further study of isotactic
polyolefins confirmed Turner-Jones’s conclusions.”27 In contrast, the structure
of atactic polyolefins is characterized by highly disordered main chains and
hexagonally packed side chains.28 A calorimetric study of both isotactic and
atactic polyolefins carried out by Magagnini et al. suggested that the calorimetric
properties of these comb polymers largely depend on the length of the side
chains and are almost independent on the stereoregularity of the backbone.28
The crystal structure of poly(oxiranes) (7) are very similar to those of poly(a-
olefins). For atactic poly(octadecylethylene oxide), a single crystalline phase was
observed, characterized by the efficient hexagonal packing of the side chains
and main chains in regularly spaced, parallel planes perpendicular to the
direction of the side chain. However, the side chains in the crystal structure of
isotactic poly(octadecylethylene oxide) are oriented at 120° with respect to the
plane defined by the main chain.29'3° The poly(oxirane) stereoregularity had a
negligible influence on their enthalpies and entropies of fusion.28
Vogel et al. proposed a supramolecular structure in which both main chain
and side chains play important roles to explain the complex melting of
polyaldehydes (8).”35 In this family of comb polymers, only six carbon atoms are
necessary for the side chain to crystallize. The resulting polymers have two
melting transitions, the lower typical of side chain crystallization and the higher
due to melting of the backbone. Based on IR absorption bands, the authors
concluded that the parafflnic side chains are arranged in a regular hexagonal
structure within the tetragonal crystal lattice of the polymer.32 However, no
detailed X-ray data have been reported for polyaldehydes.
Polystyrenes, poly(1,3-butadienes), and polyitaconates
Poly(p—alkyl styrenes) (9) were known as early as 1953.36 For atactic
polymers, thermal analysis suggested side chain crystallinity in polymers with
more than ten carbon atoms in the side chain?6 The comparison between atactic
and syndiotactic polystyrenes revealed that side chain crystallinity is strongly
influenced by tacticity.37 For example, the melting point of the side chains in
atactic poly(p-n-dodecylstyrene) was reported to be around -30 °C,38 while that of
syndiotactic poly(p-n-dodecylstyrene) was ~90 °C.37 However, there has been
m 0 OH 0 OMe o oc,,H2n+1
CnH2n+1
M m m in
O O O
CnH2n+1 0C:nHZnH OCnHZn+1 OCnH2n+1
9 1O 11 12 13
polystyrenes poly(1 ,3-butadienes) polyitaconates
Figure 7. Chemical structures of comb-like polystyrenes, poly(1,3-butadiene)s,
and polyitaconates
no detailed structural characterization for this series, resulting in incomplete
information on supramolecular packing. Although thermal analysis suggest that
side chain crystallization in poly(2-n-decyl-1,3-butadiene) is similar to
polystyrenes,39 no structural information is currently available for poly(1,3-
butadienes) (10).
Because of their similarity to poly(alkyl acrylates) and poly(alkyl
methacrylates), comb-like poly(itaconates) (11-13) have been extensively
studied.4048 When there are twelve or more carbon atoms in the side chain, the
side chains of poly(mono n-alkyl itaconates) (11, 12) and poly(di n-alkyl
itaconates) (13) crystallize.“°""'44 The crystalline side chains of poly(mono n-alkyl
itaconates) melt at lower temperatures than the corresponding poly(di n-alkyl
itaconates).“4 X-ray data suggested that, like in most of the comb-like polymers,
the side chains crystallized in hexagonal lattices.“
Alkyl comb polymers with rigid backbone
Polypeptides
The alkyl comb polypeptides reported to date include poly(q,L-aspartates)
(14), poly(a,L-glutamates) (15), poly(B,L-aspartates) (16), and poly(y-glutamates)
(17). Their chemical structures are shown in Figure 8. Similar to
poly((meth)acrylates), the linear alkyl side chain in these polypeptides is attached
to the backbone through an ester bond. The first report on the solid state
structure of comb-like poly(a-glutamates) appeared in 1978.49 Watanabe et al.
then systematically studied the supramolecular structure of comb-like
polyglutamates by X—ray diffraction, differential scanning calorimetry (DSC), and
dynamic mechanical analysis (DMA). Their data suggested that regardless of the
CH2COOCnH2n+1 CH2CH2COOCnH2n+1
H O H O
14 15
poly(d-aspartates) poly(o—glutamates)
o cooanz".1 cogent-r2",1
trim WNi’m
H o H
16 1 7
poly(B-aspartates) poly(v-glutamates)
Figure 8. Chemical structures of comb-like polypeptides
Layer
1-Helix
Figure 9. Model for the packing of poly(q-glutamates) at low temperatures
(a) view parallel to the main chain axes; (b) view parallel to the side chain axis
and perpendicular to the main chain axis; (c) view perpendicular to both the layer
and the chain axis of the d-helices. (Reprinted with permission from
Macromolecules 1822141, 1985. Copyright 1985 American Chemical Society)
side chain length, the conformation of the main chain was an a-helix,50'51 and the
side chain crystallized when its length exceeded ten carbon atoms. As a
consequence of the side chain crystallization, the polymers formed a lamellar
structure characteristic of comb-like polymers with the d-helices forced to align
into sheets separated by side-chain crystallites. The X-ray data further suggested
that the side chains are interdigitated and aligned perpendicular to the planes
defined by the sheets of d-helices (Figure 9). Their conclusions were supported
by dielectric measurements.52
10
For comparison, poly(B—L-aspartates) were also systematically studied.53'5‘
This family of poly(B-peptides) are also helical and they closely follow the general
behavior characteristic of poly(a-L—glutamates). The major difference is that the
side chain crystallization requires at least twelve carbon atoms in the side chains
instead of ten for poly(a-L—glutamates), likely due to the additional methylene
spacer in the backbone. Three different phases were observed for these comb-
like polypeptides as function of temperature. As schematically represented in
Figure 10, when the temperature is below T1, the side chain melting
temperature, the backbone helices are immobilized by the crystallized side
chains. A cholesteric arrangement may form when the temperature is between T1
and T2 and temperature > T2 can lead to the formation a nematic phase.
mu ~.' ~
79"?“
digit
:8
."(
0% <
0;;-
a
Figure 10. Schematic model illustrating the structural changes as function of
temperature for side chain crystalline poly(B-aspartate)s.
(Reprinted with permission from Macromolecules 28:5535, 1995. Copyright 1995
American Chemical Society)
Recently, comb-like poly(y-glutamates) with different backbone
stereoregularities were reported.”56 Again, the layered structure characteristic of
comb-like polymers was observed regardless of the backbone stereoregularity.
The additional methylene spacer in the backbone further increased the minimum
side chain length for crystallization to fourteen carbon atoms and this minimum
length was also independant of backbone regularity.
Poly(3-alkyl thiophene)s
Because of potential applications in light-emitting diodes, batteries, sensors,
and electrochromic devices, polythiophenes have attracted a great deal of
attention over the past two decades. Alkyl comb-like polythiophenes are
particularly interesting because the introduction of flexible alkyl side chains leads
to improved solubility, fusibility, and processability with retention of their stability
and electrical conductivity.57457 When there are twelve or more carbon atoms in
the side chain, a first order transition associated with the side chain crystallization
can be observed.59'6° Like other alkyl comb polymers, poly(3-alkyl thiophene)s
have a lamellar structure, with alkyl side chains functioning as spacers between
01”“ ///////
fl //////// ////
18
(a) (b) (c)
Figure 11. Chemical structure and proposed possible molecular packing of
poly(3-alkyl thiophene)s
the stiff main chains. Depending on the thermal history, molecular weight, and
regioregularity of the sample, the side chains can adopt several different packing
12
patterns. In the most common phase, the side chains are packed into a double-
layered structure and are strongly tilted such that the side chains can pack into
).58 A less common phase is
an approximately hexagonal lattice (Figure 11b
characterized by the side chain interdigitation (Figure 11c),61 which can coexist
with the double-layered phase.65 The appearance of several other phases has
also been reported, but the structural details are incomplete. Upon heating to a
certain temperature range, a nematic mesophase has also been reported for
polythiophenes with long alkyl side chains.58'6"‘55'67
Stiff-chain polyesters, polyamides, and polyimides
Aromatic polyesters, polyamides, and polyimides are very attractive because
of their unusual mechanical properties. However, like polythiophenes, their
processability and solubility are limited by chain stiffness. The introduction of
flexible alkyl side chains onto the stiff backbone has been proved to be an
effective strategy for improving solubility and lowering melting temperatures.”87
Shown in Figure 12 and Figure 13 are the chemical structures of these families
of comb-like polymers that have been reported in the literature. The first comb-
like aromatic polyester, the polyester of terephthalic acid and a 2-n-
alkylhydroquinone (19), was reported by Lenz et al. in 1983. Its melting
temperature decreased continuously with increasing side chain length, which
eventually led to the appearance of liquid-crystalline phases over a conveniently
accessible temperature range.87 When the side chain length is more than twelve
carbon atoms, mesophases characteristic of layered structures were observed.
There also is evidence of side chain crystallization in these rigid-rod comb
13
polymers when the side chains are longer than twelve carbon atoms.68'72'73'77'78
The detailed supramolecular packing depends on the substitution pattern in the
polymer. Based on the available X-ray data, polymers that have substituents
R 0R
9 9 9 9
‘EC—Q—C-O O)‘ ‘<‘C C-O O)‘
R0
19 20
R0 OR OR
9 9 9 9
(o—Q—o-c c) (c c-o 0)-
OR R0 R0
21 22
OR OR
0 8
O
H H H II
- O O-C
i000 C t t i.
O 0
R0
23 R0 24
OR OR
II 91 9 II
. oi ioHo—c i
R0 R0
26
25
R R0 OR RO
.. 9 9
‘(O 9; ‘(O O-C C
RO OR OR
27 28
Figure 12. Chemical structures of comb-like rigid-rod polyesters, polyamides,
and polyimides l (R represents linear alkyl groups)
14
R0 R0 R0
31 32
8 ii “0
(~< KI My)
9 f or:
O
33
Figure 13. Chemical structures of comb-like rigid-rod polyesters, polyamides,
and polyimides II (R represents linear alkyl groups)
limited to one phenyl ring in the repeat unit ( 20, 21, 23, 24, 25, 26, 29, 30, 32)
pack into interdigitated layered structures with the side chains either
perpendicular or tilted relative to the backbone plane‘sfi'n'n'n'78 When both
phenyl rings of the repeat unit are substituted as in case of polyamide 31 in
Figure 13, a double-layer structure is formed.‘58
Other stiff-chain alkyl comb polymers
There are several other stiff-chain alkyl comb polymers in addition to the
examples cited above (Figure 14). Other examples include
) 88,89
’
(hydroxypropyl)cellulose-based polymers (34 polydiacetylenes (35),90 and
15
2-alkylbenzimidazoIe-based polymers (36).91 Like other alkyl comb polymers,
both side chain crystallization and formation of a lamellar structure are observed
once the side chain reaches a minimum length.
H2n+1CnHNOCO
0—)— EHZnH
o o H2n+1cn N’ NH
O / Q
0 m m
c:nHZnM m
H2n+1CnHNOCO OCONHCnH2n+1
34 35 36
Figure 14. Chemical structures of several other alkyl comb-like polymers
16
PEG comb polymers
Because of its hydrophilicity, biocompatibility, and resistance to protein
adsorption, poly(ethylene glycol) (PEG) based polymers have attracted a great
deal of attention for industrial and biomedical applications.”93 Comb-like
polymers with PEG grafts are particular interesting because these polymers can
efficiently inhibit cell or protein adsorption even when the side chains are short
PEG segments.“95 Additionally, polymer properties can be easily tuned by
changing the PEG segment length. However, the number of PEG comb polymers
with well-defined structures are very limited, possibly due to the tedious synthetic
procedures for the synthesis of exact length oligo(ethylene glycol)s.
Poly(vinyl ethers)
Shown in Figure 15 are the chemical structures of well-defined PEG comb
poly(vinyl ethers) terminated with either methyl or ethyl groups. Poly(vinyl ethers)
with PEG pendant groups were known as early as 1950s96 and were found to be
97.98
water-soluble and show lower critical solution temperature (LCST) behavior.
However, a systematic study of solution properties of these poly(vinyl ethers)
30M}:
9 atomic;
37
Figure 15. Chemical structures of PEG comb-like poly(vinyl ether)s
17
was not reported until 1992.99 In their study, Kobayashi et al. found that LCST of
poly(vinyl ethers) can be controlled either by the length of the PEG chain or the
m-alkyl group at the terminus of the chain. The LCST is also affected by the
molecular weight and molecular weight distribution.99 For the case of PEG chains
terminated with an w-methyl group (37), the LCST was 70, 82, and 100 °C for
n=1, 2, and 3, respectively. For an w-ethyl group (38), the LCST was 20, 44, and
60 °C for n=1, 2, and 3, respectively. The temperature range for the phase
transition is only ~0.3 °C for polymers with narrow molecular weight distributions
(PDI = 1.1) increasing to ~3 °C when PDI increased to ~3.99
Figure 16. Chemical structures of PEG comb-like poly(vinyl ether)s block
copolymers
Stimulated by the thennoresponsive properties of PEG comb poly(vinyl
ethers), the block copolymers of poly(vinyl ethers) with PEG pendant groups
were extensively studied during the last decade.""“08 Arrnes et al. prepared
18
diblock copolymers of methyl vinyl ether (MVE) and methyl triethylene glycol vinyl
ether (MTEGVE) by living cationic polymerization (39).”8 The cloud points of
poly(MVE) and poly(TTEGVE) are 8 and 83.5 °C. respectively. By simply
changing the relative length of the individual blocks, the phase transition
temperature of the block copolymer was tuned over the entire 18 — 80 °C range.
Dynamic light scattering measurements showed that these block copolymers
form micelles upon heating.
Related materials such as the block copolymer of ethyl diethylene glycol vinyl
ether (EOEOVE) and methyl ethylene glycol vinyl ether (MOVE) (40), EOEOVE
and ethyl ethylene glycol vinyl ether (EOVE) (41), EOVE and MOVE (42), and
EOVE and ethylene glycol vinyl ether (HOVE) (43) were reported by Aoshima et
al.1°2'1°4"°7 The block copolymer EOEOVE2oo-b-MOVE400 is soluble in water at
temperatures <40 °C. A 20 wt% solution of this block copolymer transformed to a
transparent gel when warmed to 42-55 °C due to the phase transition of the
EOEOVE2oo block. Further heating led to a clear solution and eventually polymer
precipitation, because of the phase transition associated with MOVE4oo block.
These materials were termed “double therrnosensitive” materials.‘°“"°7 Further
studies of EOEOVE-b—EOVE and MOVE-b—EOVE revealed similar phase
transition behavior, and that the gelation temperature is determined by the phase
transition temperature of the less hydrophilic block, which is easily tunable.“°7] In
the case of EOVE-b-HOVE block copolymers, only a gelation temperature was
observed above the LCST of the EOVE block because HOVE block is soluble in
water over the entire temperature range.‘°2"°5-‘°‘5
19
Poly(methacrylates)
Polymethacrylates with pendant PEG groups have long been used as the
polymeric component of polymer electrolytes.")9‘112 Smid et al. reported that the
cloud points of polymethacrylates with an average of 4, 8, and 22 ethylene oxide
Ems
O
f
8,
'1H
44
a towel;
Figure 17. Chemical structures of comb-like PEG poly(methacrylate)s
repeat units in the side chain were 54.5, 83.5, and 102 °C respectively.113
However, the PEG chains of the oligo(ethylene glycol) methacrylates were
polydisperse with a distribution of side chain length. The first linear water soluble
PEG comb polymethacrylates with well-defined structures and at least two
ethylene glycol units in the side chain (44) were not reported until 2003. lshizone
and coworkers synthesized poly(diethylene glycol methacrylate) and
poly(triethylene glycol methacrylate) using living anionic polymerization.114 Both
polymers were readily soluble in water at normal temperatures. The same group
later reported the living anionic polymerization of ditheylene glycol monomethyl
ether methacrylate (PDEGMMA) and triethylene glycol monomethyl ether
methacrylate (PTEGMMA) (45).“5 Like the PEG comb poly(vinyl ethers),
PDEGMMA and PTEGMMA showed very sharp and reversible phase transitions
20
at 26 and 52 °C respectively. Employing the thermoresponsive properties of
PDEGMMA and PTEGMMA, Zhao et al. developed thermoresponsive hairy
nanoparticles by using surface-initiated ATRP to grow PDEGMMA and
PTEGMMA brushes from initiator-functionalized silica nanoparticles.116
Compared to analogous polymer solutions, the transition temperatures of
polymer brushes were lower and the temperature range broader.
Polystyrenes
Like PEG comb polymethacrylates, polystyrenes with pendant PEG groups
"7419 and as polymer electrolytes.120
have been used in phase transfer catalysis
As part of a study of their cation and anion binding properties, Smid et al.
synthesized the first well-defined PEG comb polystyrenes with either one or two
pendant PEG groups in each repeat unit.121 Some of these polymers strongly
bound organic solutes such as picrate anions in aqueous solution. These
polymers were reported to exhibit inverse temperature solubility in water but no
detailed solution properties were reported at that time.121 Recently, Zhao et al.
0K0
ax
96A?"
(«)0
/§0
8’
"H
49
a 1M.
46 47
Figure 18. Chemical structure of comb-like PEG polystyrenes
21
reported the detailed aqueous solution properties of PEG comb polystyrenes
synthesized by living radical polymerization.122 The reported polymers had three,
four, and five ethylene oxide units in the pendant PEG group and the LCST for
these polymers were 13, 39, and 55 °C respectively. They also showed that the
cloud point of block copolymers can be easily tuned by changing the polymer
composition, and that the experimental data agree well with theoretically
calculated values.
PEG comb polystyrenes also are promising materials for applications in
biotechnology. Results from the Sommerdijk group proved the biocompatibility of
polystyrenes with pendant tetra(ethylene glycol) groups as well as its
effectiveness in tuning cell proliferation rate, and suggested its potential
application as a protective coating for in vivo sensors.95 Through surface initiated
living radical polymerization, Ober and coworkers reported PEG comb
polystyrene brushes grafted to SiOx surface.94 This modified surface inhibited
protein and cell adhesion better than surface assemblies with the same PEG
length, suggesting potential applications in the fabrication of biological micro- and
nanodevices.
22
PEG/Alkyl comb polymers
Because of a potentially broad range of applications, the synthesis and
characterization of amphiphilic polymers has been one of the most popular
research areas. Most amphiphilic synthetic polymers are block copolymers which
undergo interesting self—assembly processes. A relatively new class of
amphiphilic polymers is comb polymers with hydrophilic PEG groups and
hydrophobic alkyl groups on the same polymer backbone. Their structure
suggests interesting possibilities for self-assembly. However, only a few well-
defined structures have been reported so far. McCullough et al. reported the
CnH2n+1 C H2 +1
n n
S / \
\ l S p p
O f
”g 0
0
:6 T‘
50 51
OCnH2n+1 CnH2n+1
53
Figure 19. Chemical structures of PEG/alkyl comb polymers with well-defined
structures
23
synthesis and self-assembly of regioregular, amphiphilic polythiophenes (50).123
By using a self-assembly approach; ultrathin films of amphiphilic polythiophene
were manipulated and processed on the nano- and micrometer scales. Three
melting temperatures, assigned to the melting of tetraethylene glycol side chains
(~5 °C), melting of dodecyl side chains (~55 °C), and melting of the backbone
(~120 °C) were observed for amphiphilic polythiophenes having dodecyl and
tetraethylene glycol monomethyl ether as substitutents.124 Amphiphilic poly(p-
phenylene), with one linear alkyl side chain and one PEG side chain per repeat
unit (51), self-organized into fibrous aggregates in micellar surfactant
solutions.‘25'126 The synthesis of other PEG/alkyl-substituted amphiphilic
polyphenylenes (52 and 53) was recently reported, but the bulk and solution
properties of these polymers have not yet been studiedm'128
In addition to the well-defined amphiphilic comb polymers described above,
amphiphilic combs with less well-defined structures have also been the topic of
several recent publications. Allcock et al. synthesized poly(organophosphazenes)
having roughly an equimolar mixture of PEG and alkyl groups (54).129 With nine
or more carbon atoms in the linear alkyl group, the polyphosphazene side chains
crystallized, similar to the properties of alkyl comb polymers. Side chain
crystallization in mixed-substitutent comb polymers was exploited to prepare
stimuli-responsive reversible physical networks. Reversible physical gels were
obtained upon cooling aqueous solutions of poly(vinyl ether) (55) shown in Figure
130,131
20 due to alkyl side chain crystallization. The copolymerization of
poly(ethylene glycol) methyl ether methacrylate (PEOMA) with octadecyl
24
O n m
o q 0
? C18H37 /? C18H37
O O
‘76 ‘73
56 57
Figure 20. Chemical structures of PEG/alkyl comb polymers with ill-defined
structures
methacrylate or acrylate (ODMA, ODA) also leads to amphiphilic comb polymers
(56 and 57).132 Both the PEG and alkyl side chains are crystallizable. X-ray data
suggests that the alkyl side chains in the copolymers are hexagonally packed,
and that the PEG side chains are segregated from alkyl side chains and
assembled on one side of the backbone. In the proposed structure, PEG side
chains pack into a double-layer structure as shown in (Figure 21).
25
illl rliill ll‘llllr
III IIIii
iIIIIli
il'IiIl“
Il"liil“l.;
" Israemy‘ “it We 59.3?" i"
2 2222 “s 22‘. 222.» 2 ,2. .
. .2:
Crystallized section
ofOD side chains
, _ .. ,. ... . ,2 B 2 2. 2 2 2. ‘_ ,.
2722‘ 9‘22; #2" 2.52 “1'”? 25%: I “1);: :2er “22912,.
- 2.9.2.2, 5’s.“ “3.: r“ «245 >359: ‘35“-
. '3: it .0. 1.8"~..'...M ‘8 {19‘ J
' \
~ Crystallized section
I T 2. _, : f of PEO side chains
22‘ _ 1:“ "V '3' h. 3' l
“as 42:: 22“ 3,25 ' sigkfl’iafl (“”71 .,_.rt‘3-i.-w2
s. ‘16:? § ‘3 (“flick-w 2. '2 ‘92.. 2 6th
Figure 21. A proposed model for a hypothetical bilayer structure formed by the
graft copolymers poly(PEOMA-ran-ODMA).
(Reprinted with permission from Neugebauer D. et al. Macromolecules 39:584.
2006. Copyright 2006 American Chemical Society)
26
Application of click chemistry In polymer synthesis and functionalization
The Huisgen 1,3-dipolar cycloaddition of azides and terminal alkynes to form
triazole compounds has been known for about a hundred years but the
regioselectivity of this reaction was poor until the discovery of the Cu(l)-mediated
variant?”134 This reaction was proposed to start with the formation of Cu(l)
acetylide, and according to theoretical calculations, follow a stepwise pathway to
exclusively generate 1,4-disubstituted 1,2,3-triazoies (Figure 22)?“ Since then,
this reaction has become the most popular type of click chemistry.‘35
R1
R1 CuLn I.“
R1 -
\(squLn 33 H ”W” 92
NeN,N‘R2 * NéN’N‘RZ product
C
B-2
reductant
R‘ : CuLn B-direct [LnCu]+ CUSO“
N2 ,iv—R?
=53 3-1 A R‘ : H
R‘ : CuLn
NSN’N‘RZ
4.
Figure 22. Mechanism of click chemistry proposed by Sharpless et al.““
Because of its high selectivity, near-perfect reliability, nearly quantitative
yields, and tolerance to a wide scope of functional groups and reaction
conditions, click chemistry has been used as the key step in the synthesis or
27
_ "N ~ '
r—— r '1. r 8.. xr—— a. U
+ Cl/—\—= u’ n r / IIINI Cl/—\———: N
R ,N: A \ N N N A N I i
N N N X X
x x \ r
kCI kN: an< \N"IN
N N
"k
Cl
R IR R
r5 N‘ ”A: “N |
H N H
m U~
X ’N _ N—N N-
R- ,N:N N’ ‘14—}? /—: R “N N N
K N’NN N,N‘N 0' \__-: N’ I J
R “
R\ X—\ \ / /"X N’ N X N
'W/ N 3 I) N V}; f
N: N \ I N N
N N X X N ,N N\
U M
NH, If, X
N N k
x N3
kCl
Scheme 1. Convergent approach to triazole dendrimers by Hawker et al.136
0 O
N
— ..N
s .N N-N
N 10 /_J
K/0
Figure 23. Structure of a divergent dendrimer synthesized by Hawker and
Wooley et al.137
28
0 O
HO
138
Figure 24. Structure of an unsymmetrical dendrimer synthesized by Lee et al.139
29
or functionalization of various polymers in last three years. Hawker, Sharpless,
Fokin and coworkers first introduced click chemistry to polymer chemistry
through the synthesis of dendrimers.136 Triazole—based dendrons were
convergently synthesized following the procedure outlined in Scheme 1, where X
0 O O N=N
0 0
Br 0 N
Br
Scheme 3. Preparation of block copolymers by combining ATRP and click
chemistry.“‘°'“‘1
and R stand for a number of different internal repeat units and chain-end groups
respectively. These dendrons were then convergently anchored to a variety of
polyacetylene cores to generate dendrimers. A similar strategy was applied by
Hawker and Wooley for the divergent synthesis of triazole-based dendrimers
(Figure 23) where R represents either azido or hydroxy groups.137 The use of
click chemistry to couple dendritic blocks containing an acetylene group with
dendritic blocks containing an azido group at the focal point has proved to be a
powerful tool for the generation of unsymmetrical dendrimers. For example, the
facile synthesis of amphiphilic dendrimers was accomplished by the coupling of a
hydrophilic dendron with a hydrophobic dendron as shown in Scheme 2.138 The
30
same strategy has been successfully utilized to synthesize unsymmetrical
dendrimers such as those shown in Figure 24.139
In addition to the synthesis of dendrimers, click chemistry is also very useful
for the synthesis of other types of polymers. As shown in Scheme 3a, the click
coupling of telechelic polystyrene prepared by ATRP yielded linear polystyrene
containing ester bonds in the backbone140 which renders the polymer partially
biodegradable. A similar strategy is a versatile approach for the synthesis of
various block copolymers from building block precursors prepared by ATRP
(Scheme 3b).141
The advantages of click chemistry also provided polymer chemists with a
powerful tool for attaching functional pendant groups onto various polymer
backbones. Fréchet et al. reported the quantitative anchoring of dendrons onto
the poly(vinylacetylene) backbone,142 fully covering the polymer backbone with
Fréchet-type dendrons up to GB, and yielding dendronized linear polymers for
nanoscale applications (Scheme 4a). In a related example, they started with
acetylene functionalized bis(hydroxymethyl)propionic acid dendrons anchored to
a linear poly(p-hydroxystyrene), and then used click chemistry to further
elaborate the structure with F réchet-type benzyl ether dendrons.”3 The resulting
structure has the microstructure of a radial dendritic diblock copolymer and is
shown in Scheme 4b, where the R groups correspond to benzyl ether dendrons.
Matyjaszewski used click chemistry to introduce different side groups to poly(3-
azidopropyl methacrylate), resulting in poly(methacrylates) with high degrees of
functionalization (Scheme 5).144 Functional poly(p-phenylene ethynylene)s were
31
(a) (If? @fi J51
Sonar“? 4. Synthesis and structure of dendronized linear polymers (Fréchet et
al.) '
%o r -CH20H
Br” 53h
'—CH2P\+’Ph
R = 4 pn
—CH2CH2COOH
O
K —CH20J>
.OCH3 (c12) Y‘LO
o
CH2(CH2)12CH3 (C14), CH2(CH2)14CH3(C16) R
0
Scheme 11. Synthesis of alkyl-substituted glycolide monomers
41
since common names based on glycolide as the base structure clearly describe
the length of the alkyl chain. Two synthetic approaches to substituted glycolide
monomers were employed. In route 1, the reaction of alkyl Grignard reagents
with diethyl oxalate at low temperature provided the corresponding d-keto
esters.179 The crude products were obtained in >90% yields, with no detectable
contamination from addition of a second Grignard equivalent to the substrate.
Catalytic hydrogenation of the crude keto ester at 1500 psig using Pt on carbon
yielded the o-hydroxy ester, but since purification of the ester proved difficult, the
crude a-hydroxy ester was hydrolyzed and isolated as the o-hydroxy acid.
Crystallization of the acid three times from hexane gave white crystals in an
overall yield of 68-84% from diethyl oxalate. ln route 2, the reaction of fatty acids
with thionyl chloride and bromine generated the corresponding d-bromoacyl
chlorides.180 Without further purification, the crude products were hydrolyzed and
isolated as the o-hydroxy acids. Three crystallizations from petroleum ether gave
the acids as white crystals in an overall yield of ~70% from the fatty acids. Some
of the q-hydroxy acids were isolated or prepared earlier and the limited physical
data reported in the literature match the data for our compounds.
Dimerization of the o-hydroxy acids in refluxing toluene using p-
toluenesulfonic acid as a catalyst yielded a mixture of the R,S and R,R/S,S
diastereomers in ~45% yield. The byproducts primarily consisted of linear
oligomers which could in principle be recycled or thermally cracked to yield
additional monomer. A representative 1H NMR, that of hexadecyl glycolide, is
shown in Figure 25. The methine protons of the 3,6-disubstituted glycolide ring
42
appear as a doublet of doublets at 4.88 and 4.83 ppm; integration of the 1H NMR
spectrum of the crude product confirms the 1:1 ratio of the mesa (R,S) to rac
(RR/SS) diastereomers expected for the statistical coupling of a racemic mixture
of hydroxy acids. Crystallization altered the diasteomeric ratio to 2:1 (meso :
rac). Similar results were obtained for the other glycolides. We note that 1H NMR
also provides a convenient method for monitoring the polymerization reaction. As
shown in Figure 25 for hexadecyl glycolide, the methine peaks at 4.85 evolve
into a broad peak at ~5.10 ppm during polymerization allowing straightforward
calculation of the conversion of monomer to polymer.
fl ,. U2
W0
OWWVWW
Jl LL?
'1' T rfT T T T T I T I T T I T 7 T T I T T T T I r T
‘l"‘T7""l""l“'
5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
mm
Figure 25. 500 MHz 1H NMR spectra of hexadecyl glycolide and its polymer
43
Bulk Polymerizations
Compared to lactide, glycolide monomers having substituents larger than
methyl would be expected to polymerize more slowly due to the added steric bulk
of the substituent. For a homologous series of n-alkyl-substituted monomers,
only those methylenes close to the glycolide ring should influence the ring
opening step and glycolides with alkyl chains beyond a critical number of
methylenes should polymerize at the same rate. We tested this notion by
measuring the polymerization kinetics for each of the monomers at 130 °C. using
the polymerization of lactide under identical conditions as a control. The data
were collected from bulk polymerizations run in sealed tubes using t-butylbenzyl
alcohol as the initiator and Sn(2-ethylhexanoate); as the catalyst. Since having
pure and scrupulously dry monomer is a key to high molecular weights, low
polydispersities, and repeatable kinetics, the monomer was crystallized several
times and dried overnight under vacuum before used.
Ring—opening polymerizations of lactides are typically first-order in
monomer181 and can be expressed as
R, = -d[M]/dt = kp[M][cat] (1)
where [M] and [cat] are the concentration of monomer and catalyst respectively
and kp is the rate constant for propagation. Integration of (1) and assuming the
catalyst concentration is constant provides (2)
-|n([M]t l [M]o) = kp[cat]o t (2)
44
where the subscripts 0 and t refer to initial concentrations and at time = t. Data
from such a polymerization can be linearized by plotting -ln([M]. / [M]o) vs time.
Lactide polymerizations run to high conversions (or low monomer concentrations)
often deviate from linearity due to the reversibility of the polymerization.
Eventually polymerization ceases due to the establishment of an equilibrium
between the propagation and depropagation steps, leaving an equilibrium
monomer concentration [M]... unpolymerized.176 To simplify evaluation of
experimental data, equation 2 can be modified to account for effects of
equilibrium polymerization by subtracting [M],, from [M]o, giving eq 3.
-ln{([Mh - [Mlel/(lMlo - [M]e)}=kplcat]ot
3.5
3 5
2
A. ,
a 2‘5 // /A
JP. /
E: 2 ~ 13] / ,
>. /’ A
.2 ,/ / .
E 1_5. )5
T! 1 1 0 "
1' ,
0.5]
o T
o 5 10
time (min)
15
o lactide
C] 06
A08
xC1O
0 C12
0 014
+ C16
(3)
Flgure 26. Bulk polymerization kinetics of substituted glycolides. Polymerization
conditions: 130 °C. [Sn(2-ethylhexanoate)2]/[tart-butylbenzyl alcohol] = 1,
[monomerMcatalyst] = 50. Each data point is the average of three independent
runs and corrected for equilibrium.
45
Kinetic data for the polymerization of lactide and alkyl-substituted glycolides
are shown in Figure 26. Plots of -In(([M]t - [M]e)/([M]o-[M]e)) versus t should be
linear, which are the experimental results as shown in Figure 26. Polymerization
and depolymerization reactions under the same conditions show that all of the
apparement rate constant, kg...
1.2
14
0.8 ~
0.6 ~
0.4 ~
0.2 ~
O
l
4
T
6
l l T l i i
8 10 12 14 16 18
Number of carbon atoms in side chain
Figure 27. Relationship between apparent rate constant and the length of side
chains for bulk polymerization of substituted glycolides.
lactides have similar equilibrium monomer concentrations (~1.4 mol% based on
NMR). These results indicate that bulk polymerizations of the alkyl substituted
lactides follow the same kinetic pattern as lactide and that ring-opening
polymerization of glycolides substituted with linear alkyl groups is facile. The
apparent rate constant values (kp[cat]) were extracted from the slopes of the
plots and then plotted as a function of the length of the side chain (Figure 27).
46
We found that the apparent rate constant decreases until the side chain length
reaches ten methylene groups and then remained constant. However, the
polymerization rates are not necessarily directly related to the length of the side
chains. Since the monomer:initiator:catalyst ratios are constant, the side chains
act as a diluent in these melt polymerizations and both the catalyst and monomer
concentrations decrease with increasing side chain length; the trend in apparent
polymerization rates is more likely the result of the combination of decreased
catalyst and monomer concentrations and increased steric effects.
<> lactide
l
l
l
-ln[M]/[M]o
60
tlme (min)
Figure 28. Solution polymerization kinetics of substituted glycolides.
Polymerization conditions: 90 °C in toluene, [Sn(2-ethylhexanoate)2]l[tert-
butylbenzyl alcohol] = 1, [monomer]/[catalyst] = 100. Each data set corresponds
to a single kinetics run.
47
Solution Polymerizations
We further studied the polymerization kinetics by carrying out solution
polymerizations in toluene at 90 °C with an initial monomer concentration of 0.2
M and [monomer]:[catalyst]:[initiator] ratio of 100:1 :1. Again, the polymerization
0.06
3 O
:3 0.05 -
‘E
in
in” 0.04 5
i:
O
o
a:
E 0.03 ~
‘5
E 0.02 —
2 o
in
Q 0.01 —
g- Q . . . .
0 l l l l l i l l
number of carbon atoms in side chain
Figure 29. Relationship between apparent rate constant and the length of side
chains for solution polymerization of substituted glycolides.
of lactide under identical conditions was used as a control. Solution
polymerizations of glycolides should also follow first order kinetics described by
eq. 2, and plots of —|n[M]t / [M]o vs t should be linear for low monomer
conversions. The apparent rate constant values were again extracted from the
slopes of the plots and plotted as a function of the length of side chain. As
shown in Figure 29, the apparent rate constant decreased with increasing side
48
chain length, becoming constant at 28 carbon atoms in the side chain. However,
since the solution data correspond to a single polymerization for each monomer,
the differences in polymerization rates could have been complicated by trace
amounts of impurities in the monomers. A more reliable way to compare the
polymerization rates is to determine their reactivity ratios.
Homopolymer Properties
We determined the properties of the alkyl glycolide homopolymers using
samples prepared by bulk polymerizations at 130 °C with the monomer to initiator
ratio set at 200:1 (Table 1). These colorless polymers have molecular weights
(Mn) between 55,000 and 70,000 glmol and ranged from sticky liquids to waxy
solids at room temperature. The polymers are soluble in common solvents such
as toluene, THF and CHzClz and were purified by washing with 2M HCI, and then
precipitated from CH20I2 into 2-propanol and dried under vacuum.
Table 1. Properties of alkyl comb glycolides
AHm
Polymer M, x 10'3 PDl Tg (°C)a 7... (°C) n.b
(cal/mol)
polyCG 56.9 1.22 -37 ~ ~ ~
polyCB 56.4 1 .21 —46 ~ ~ ~
polyC10 60.7 1.37 nd -18 417 0.7
polyC12 67.7 1.28 nd 8 1676 2.9
polyC14 70.0 1.19 nd 28 2795 4.8
polyC16 55.9 1.13 nd 45 3912 6.7
a. nd indicates that the T9 was not detected. b. number of crystalline methylenes
(see equation 5).
49
The polymer decomposition temperatures measured by thermal gravimetric
analysis (T GA) estimate the limiting use temperatures of the polymers. As shown
in Figure 30, the TGA profiles for all of the polymers are similar, with the onset
for decomposition shifting to higher temperatures and the residue at 360 °C
increasing as the length of the alkyl group increases. Alkyl substituted
polyglycolides thermally decompose by depolymerizing to the volatile monomers,
with some aldehydes formed by elimination reactions.176 Consequently, the
100
80 -
Si"
35
w 60 .
O
I-
0
Q
a
.C
,9 40 ~
8
3
20 -
0 T T I l
200 250 300 350 400 450
temperature (°C)
Figure 30. TGA results for substituted polyglycolides. (10 °Clmin in air, no aging)
increase in residual mass percentage at 360 °C does not necessarily imply
increased thermal stability for the polymers with longer side chains, but it more
50
likely is a char that reflects the increasing importance of reactions other than
depolymerization as the monomer volatility decreases.
Differential scanning calorimetry (DSC) was used to measure the glass
transition (To) and/or melting (Tm) temperatures for the polymers, and the results
are displayed in Figure 31. When the substituted linear alkyl group is shorter
— polyC16 1.0 W/g l
— polyC14
— polyC12
— polyC10
- polyCB
-po|y06 L ]
-80 -60 -4O -20 0 20 4O 60 80
temperature (°C)
Figure 31. DSC scans for substituted polyglycolides. The data are second
heating scans, taken after heating to 70 °C and flash cooled. Heating rate: 10 °C
/min in N2.
than decyl, the T‘' decreased with increasing side chain length. In these cases
the flexible pendant group is thought to reduce T" by acting as an internal
plasticizer, thereby lowering the frictional interaction between different main
chains. After the alkyl group reached decyl, the glass transition was not detected
by DSC. Instead, a first order transition corresponding to melting of the side
51
chain crystalites appeared with melting points ranging from —18 °C for polyC10 to
45 °C for polyC16.
4500 l
4000- O,
3500 - "
3000 9
2500 —
2000 J
1500 -
1000 — ,
500 — ,fi"
0 l l l l
8 10 12 14 16 18
AH; (cal/moi)
number of carbon atoms in the side chain
Figure 32. The relationship between AHf and side chain length
The enthalpy of fusion (AHf) for comb-like polymers bearing crystallizable
linear alkyl side chains is indicative of the number of methylenes (nc) participating
in the paraffinic crystalline phase. Plotting AHf as a function of the number of
carbon atoms in the side chains (Figure 32) yields a straight line where the x-
intercept is interpreted in the literature as the minimum number of side chain
atoms required for side-chain crystallization of comb-like polymers. 1°
AM=AMyHm (0
In equation 4, Aer is a constant representing the end methyl group’s contribution
to the enthalpy, and k is the average melting enthalpy for each crystallized
52
methylene group. The value of k extracted from the slope of the line in Figure 32
is ~580 cal/moi CH2, which is far from the 950-1000 cal/mol CH2 reported for the
rhombic-to-liquid transition of crystalline parafins,1° but fairly close to the ~520
cal/mol CH2 melting enthalpy measured for the crystalline alkyl side-chains in
comb-like poly(D-glutamic acid esters).56
I.10 showed that each methylene in a crystalline side chain
Jordan et a
contributes a fixed enthalpy, and thus the number of crystalline CH2 groups in a
side chain, no, is given by the equation
no = AHf/ k (5)
Although equation 5 only allows a rough estimation of no clue to the assumptions
involved during its derivation, calculation of no is commonly used in studies of
side chain crystallzation.‘°"5°'56 The no data listed in the last column of Table 1
vary from 0.7 for polyC10 to 6.7 for polyC16, suggesting that ~9 methylene
groups in the side chain are in a disordered state, and only those methylene
groups beyond this limit participate in crystallization. The values of no in Table 1
are close to those reported for flexible main chain polymers with linear alkyl side
chains.10
To further elucidate the structure of flash-cooled comb-like polylactides, samples
of polyC14 and polyC16 were melted, quickly transferred to a -40 °C freezer for
eight minutes, and then their wide angle X-ray scattering (WAXS) profiles were
recorded at room temperature. WAXS results for two independent runs of
polyC14 and two independant runs of polyC16 are shown in Figure 33. Although
the DSC melting points for both polyC14 runs are 28 °C. their diffraction patterns
53
—— polyC16-2
polyC16-1
— polyC14-2
— polyC14-1
relative intensity
i l
l l V r 1
13 5 7 91113151719212325
2 9 (°)
Figure 33. WAXS profiles of flash-cooled polyC14 and polyC16 (polyCl4-1 and
polyC14-2, polyC16-1 and polyC16-2 are two different runs from the same
polyC14 and polyC16 sample, respectively.)
are only repeatable in the wide angle region, with a strong diffraction peak at d =
4.17 A and a broad, weak peak at d = 12 A. Sample to sample variation in the
WAXS data also is often seen for polthe as shown in Figure 33. According to
current understanding of comb-like polymers, the peak at 4.17 A indicates a
hexagonally crystallized paraffinic phase as has been reported for other comb-
like polymers}56 while the poor reproducibility of the low angle X-ray data for
both polyC14 and polyC16 indicates the absence of a well-defined layered
structure.182 DSC analysis shows that both polyC12 and polyC10 crystallize, but
we were unable to record WAXS profiles of flash-cooled samlples of crystalline
polyC12 and polyC10 due to their low melting points. Although the presence or
54
absence of a lamellar structure cannot be verified for these two polymers, we
expect that the alkyl side chains in these two polymers are also hexagonally
packed because of their structural similarity to polyC14 and polyC16.
(1,9'5°'56'89 a two—dimensional supramolecular structure
As previously reporte
consisting of a layered arrangement of alternating paraffinic and polymer
backbone phases is commonly observed for comb-like polymers. Obviously the
results obtained for flash-cooled comb-like polylactides do not necessary lead to
the same conclusion due to the irreproducible X-ray diffraction patterns in the low
angle region. The appearance of hexagonal side chain crystallites and the lack of
a layered structure was previously reported for quenched poly(o-olefin)s and was
attributed to the formation of a phase in which backbone is highly disorderedm’]
Annealing experiments proved to be helpful in forming well-defined layered
structures.
The DSC traces in Figure 34 show the effect of annealing on polyC14. The
melting temperature shifted from 28 °C to 37 °C after annealing the flash-cooled
sample at 27 °C for 4 hours. Further annealing at 32 °C increased the melting
point to 47 °C. The WAXS patterns of these polyC14 samples are shown in
Figure 35. After annealing at 27 °C, an irreproducible low intensity broad peak in
the low angle region disappeared and a strong sharp reflection appeared at 34.2
A. Second and third order reflections (17.7 A and 11.9 A respectively) also
appeared after annealing, with the third order reflection more intense.
Enhancement in odd-order diffraction patterns has been observed in other comb-
like polymers.”89
55
0 10 20 30 40 50 60 70
temperature (°C)
Figure 34. DSC traces of polyC14 samples with different thermal histories. First
heating scan. 10 °Clmin in N2. (black line: flash cooled in freezer for 8 minutes;
pink line: annealed at 27 °C for four hours; blue line: annealed 32 °C for six
weeks)
relative Intensity
1 3 5 7 9 11 13 15 17 19 21 23 25
29 (°)
Figure 35. WAXS profiles of polyC14 samples with different thermal histories.
(black line: flash cooled in freezer for 8 minutes; pink line: annealed at 27 °C for
four hours; blue line: annealed 32 °C for six weeks)
56
l l l l l l l
0 1 0 20 30 40 50 60 70 80
Temperature (°C)
Figure 36. DSC traces of polyC16 samples with different thermal histories. First
heating scan. 10 °Clmin in N2. (black line: annealed at room temperature for 12
hours; pink line: annealed at 45 °C for two weeks; blue line: annealed at 45 °C for
two months)
relative Intensity
.
l
l l r f l l
13 5 791113151719212325
29(°)
Figure 37. WAXS profiles of polyC16 samples with different thermal histories.
(black line: annealed at room temperature for 12 hours; pink line: annealed at 45
°C for two weeks; blue line: annealed at 45 °C for two months)
57
Interestingly, the sharp diffraction peak at 4.17 A seen in the flash-cooled
sample broadens and shifts to 4.25 A, which suggests looser packing of the alkyl
chains in the annealed sample than in the flash-cooled sample. Although further
annealing at 32 °C led to a 10 °C increase in the melting point, the X-ray patterns
of both annealed polyC14 samples are almost identical with the only difference
being a decrease in the relative intensity of the diffraction peak at 4.25 A.
Annealing polyC16 at 45 °C first shifted the melting point from 45 °C to 55 °C
and after further annealing, DSC detected a new melting transition at 60 °C
(Figure 36). The effect of annealing on the WAXS profile is very similar to that
seen for polyC14, with the peak in the wide angle region broadened and shifted
from 4.17 A to 4.23 A (Figure 37). The broad weak reflection peaks in the low to
medium angle region sharpened, with associated spacings of 38.7 A, 19.6 A,
13.3 A, and 8.0 A, indicating a well-defined lamellar structure.
PolyC12 and polyC10 were subjected to similar thermal treatments, and while
DSC traces showed an increase in melting point, attempts to track changes in
the WAXS profile failed due to the low melting points. It should be stressed that
within experimental error, the enthalpy of melting for all crystalline samples
remains constant during annealing, which suggests that according to equation 5,
annealing does not appreciably increase the number of crystalline methylenes in
side chains. This observation is helpful in understanding the broadening and
shifting of the X-ray diffraction peak at ~4.2 A. Since the observed AH is
essentially constant, AS must increase for AG for this process to be negative.
Since X-ray reflections in low angle region suggest the formation of a more
58
ordered two-dimensional structure, the side chain packing must disorder to
compensate for the decrease in entropy.
Table 2. X-ray diffraction spacings (A) of comb-like polyglycolides
polyC6 polyC8 polyC10 polyCl 2 polyC14 polyC16
melt annealed melt annealed
13.6 16.2 18.9 26.8 21.1 30.5 34.2 38.7
15.7 17.7 19.6
9.1 10.5 11.9 13.3
7.2 8.0
4.6 4.6 4.6 4.5 4.6 4.3 4.25 4.23
“melt” means the side chains are in disordered state; “annealed” means the side
chains are crystalline.
Shown in Figure 38 are the DSC traces from the first heating scan of
annealed samples; the corresponding X-ray diffraction patterns taken at room
temperature are shown in Figure 39 and the spacings measured for the whole
series are listed in Table 2. Because of the extremely slow annealing process,
DSC scans of both polyC10 and polyC12 showed two melting temperatures even
after being annealed at room temperature for a year. Apparently, an amorphous
phase crystallizes as the samples are cooled to start the X-ray analysis, leading
to two distinct melting transitions. The X-ray diffraction patterns of these samples
are the result of diffraction from a minor side chain crystalline phase and
substantial scattering from an ill-defined layered structure in which side chain is
in disordered state, as seen from the broad peak at 18.6 A for polyC10 and at
20.2 A for polyC12.
59
temperature (°C)
Figure 38. DSC traces (10 °C/min in N2) of annealed alkyl comb polyglycolides.
(black line: polyC10, annealed at room temperature for a year; pink line: polyC12,
annealed at room temperature for a year; red line: polyC14, annealed at 32 °C
for six weeks; blue line: polyC1 6, annealed at 45 °C for two weeks)
38.-7 A
135791113151719212325
20 (°)
Figure 39. WAXS profiles of annealed alkyl comb polyglycolides. (black line:
polyC10, annealed at room temperature for a year; pink line: polyC12, annealed
at room temperature for a year; red line: polyC14, annealed at 32 °C for six
weeks; blue line: polyC16, annealed at 45 °C for two weeks)
60
Diffraction from the crystalline phases can be readily interpreted as arising
from a well-defined lamellar structure. The primary diffractions with associated
spacings between 25 A and 40 A are due to the layer periodicity of the structure,
whereas the reflections appearing at 4-4.6 A are from the paraffinic phase. For
polyC14 and polyC16, the ~4.2 A spacing demonstrates unambiguously the
formation of a hexagonally packed crystalline paraffinic phase. The broader
reflection peaks with longer d spacings in this region in the case of polyC12 and
polyC10 do not necessary mean the side chains are packed in a different
crystalline structure, but more likely results from the combination of a disordered
paraffinic phase with an average spacing reported to be 4.5 A56 and a hexagonal
paraffinic crystalline phase, as was expected by the DSC analysis and the broad
diffraction peaks in low angle region.
40 i
35 2
it: 30—
O
.s
8 25~
D.
in
u 20-
15 -«
10 l I T I l l
4 6 8 1o 12 14 16 18
number of carbon atoms in the side chain
Figure 40. Evolution of d-spacings with side chain length. (I crystalline polymer
samples; A melt polymer samples)
61
As seen in Figure 40, the periodicity of the layered structure seen in polyC10,
polyC12, polyC14, and polyC16 increases linearly with n, giving a slope of 1.97 A
per carbon, very close to values observed for poly(4-alkylthiazole)s (2.0 A per
carbon) and poly(3-alkylthiophene)s (1.8 A per carbon).182 Since this value is
much greater than the theoretical value of 1.26 A for each methylene in
interdigitated side chains, the alkyl side chains of comb-like polylactides most
likely are packed in a bilayer structure similar to that proposed by Wegner,77 in
which the side chains were tilted at an angle 6 to the main chain (Figure 41).
For the polymers described here, 6 is ~50°.
///////
////////
7777///
Figure 41. Proposed molecular packing of annealed alkyl comb polylactides
For comparison, the X-ray diffraction patterns of molten polyC6, polyC8,
polyC10 and polyC12 were measured at room temperature (Figure 42). The
broad reflection peak at ~4.6 A in all four samples is consistent with a disordered
paraffinic phase, as was expected by the DSC analysis. The broad primary
reflections with associated d spacings between 10 and 25 A and the absence of
62
higher order reflections suggests a poorly defined lamellar structure in the molten
samples. From the plot of d as a function of n shown in Figure 40, we can see
that the periodicity of the layered structure also increases linearly with n, but with
a slope of 1.27 A per methylene unit. This value perfectly matches the theoretical
value of 1.26 A per methylene expected for interdigitated side chains, and we
conclude that above the melting point, the alkyl side chains are most likely
perpendicular to the main chains and interdigitated.
21. 1 A 1 1,1,1
if 217‘ '1
NW NW WW ‘
WM”
Vrrmnmwvm’wbmw .W“ "
“10,18. 9 A
- M2,, m" WMWWWW‘M
162A ”N; M
29 (°)
Figure 42. WAXS profiles of alkyl comb polyglycolides
Polymer Degradation
The temperature chosen for hydrolytic degradation experiments, 55 °C, is
higher than the glass transition temperature of each polymer, and higher than the
melting transition for all crystalline polymers. Measuring the degradation
properties using this protocol should provide information about the intrinsic
hydrolytic degradation rate without complications posed by crystallization or
glassy phases. Shown in Figure 43 is the evolution in molecular weight during
degradation, where Mn(0) and mm are the intial and partially degraded number
average molecular weights respectively. All of the polymers show an apparent
induction time for degradation. Similar induction times were observed during the
degradation of poly(phenyllactide),177 lactic acid/mandelic acid183 and lactic
acid/phenyllactic acid copolymers. A plausible explanation is that initially the
equilibrium concentration of water in pristine polymer samples is low, but
hydrolysis renders the polymer increasingly hydrophilic and accelerates the
degradation. Near the end of the experiment, all polymers appear to degrade
slower. The likely reason is that the low molecular weight oligomers are soluble
in the buffer solution and are not recovered during the experiment. Thus the
molecular weights were overestimated.
To better evaluate the degradation rates, the molecular weight data were
plotted according to random chain scission model as (Mn(O)/Mn(t)-1)/Pn(0) vs.
time,184 where Pn(0) is the initial degree of polymerization (Figure 44). All of the
data sets were then shifted to the left by subtracting the induction time so that
each data set passes through the origin. Surprisingly, all of the data sets yielded
linear plots, and all data sets had roughly the same slope. These data show that
while the gross physical properties of the polymers are dependant on the length
of the alkyl side chain, their degradation rates (slope of the data) are remarkably
64
120-7——-~ _-_-H,,,__, ——- —
o polylactide
100 w ‘3‘ I - polyce
A
o 3 i A polyCB
:3 8° 5 Q X polyC10
: 0 x I
96 60 _ ’ >A< I x polyC12
i . 3 x o polyC14
3: o A
E 40 O. x .3 ‘r polyC16
20 — i i!
'1.....*..i..i.i i i i
0 l l
0 5 10 15 20 25 30
time (days)
Figure 43. Molecular weight change of polyglycolides during hydrolytic
degradation in pH = 7.4 phosphate buffer at 55 °C
0.07 —
0 polylactide
0-06 ‘ I polyC6
8 0.05 - A polyC8
~g - polyC10
g 0.04 — x polyC12
15E 0 03 o polyC14
g ' “ + polyC16
9' o 02 j
g .
0.01 1
l l l I
0 5 10 15 20
time minus induction tlme (days)
Figure 44. Molecular weight change of polyglycolides during hydrolytic
degradation fitted to random chain scission model
65
similar to that of polylactide. Prior to the degradation experiment we thought that
the longer alkyl side chains, being hydrophobic, might shield the polymer
backbone decreasing the rate of hydrolysis. Clearly the length of the side chain
appears to have only a minor effect on the degradation rate, and apparently the
rubbery nature of each polymer ensures that the diffusion rate of water through
these polymers is high enough that it is not rate limiting.
Alkyl Comb Copolymers
The melting points of poly(alkyl glycolide)s span a range including ambient to
physiologically relevant temperatures. We prepared C16/C14 copolymers with
different monomer loading ratios to assess physical properties expected for
poly(alkyl glycolide) copolymers. The copolymers were prepared by melt co-
polymerization using conditions identical to those used to prepare the
homopolymers. The polymerizations were run at 130 °C for two hours with a
monomer/initiator ratio of 100 and reached 2 92% conversions. GPC data
showed that all of the copolymers have high molecular weights and narrow
molecular weight distribution (PDI < 1.2) (Table 3). Both DSC and GPC results
suggest a random distribution of monomer repeat units along the polymer
backbone.
The DSC traces shown in Figure 45 reveal a single melting transition for
each copolymer, which was dependant on the monomer loading ratio and ranged
from 29.4 °C for the C14 homopolymer to 45.7 °C for the C16 homopolymer. A
similar relationship between melting temperature and polymer composition was
previously reported for comb-like acrylate copolymers.1o
66
Table 3. Properties of 014/016 copolymers
mol% of C14 in the copolymer Mnx 10'3 PDI Tm (°C)
100 39.2 1.12 29
90 51.9 1.19 31
80 74.7 1 .19 33
65 53.6 1 .18 34
50 69.3 1.15 37
35 47.7 1 .17 39
20 55.0 1.12 43
10 46.2 1 .16 43
0 39.6 1.10 45
2.5 Mg
A — C14 homopolymer
ék\ — 90 mol% C14
M — 80 mol% C14
A —- 65 mol% C14
A — 50 mol% C14
k — 35 mol% C14
_ WW -. A — 20 mol% C14
A — 10 mol% C14
— C16 homopolymer
10 20 30 40 50
temperature (°C)
Figure 45. DSC heating scans of C14 and C16 random copolymers. Second
heating scan,10 °lmin in N2.
67
-— C14 homopolymer
— 90 mol% polyC14
A 2.5 w/g
M — 78 mol% polyC14
ML... — 65 mol% polyC14
. — 50 mol% polyC14
— 35 mol% polyC14
’F—x—J/k—a' — 20 mol% polyC14
~WL — 10 mol% polyC14
A —- C16 homopolymer
T T i
1 0 20 30 4O 50
temperature (°C)
Figure 46. DSC heating traces of polyC14 and polyC16 blends. Second heating
scan,10 °Clmin in N2.
We carried out two experiments to rule out the formation of simple blends or
blocky copolymers. We prepared polymer blends with compositions matching
those used in the copolymerizations. The DSC traces of the blends (Figure 46)
all show distinct melting points for polyC14 and polyC16 homopolymer phases,
indicating the formation of two different crystalline phases in these blends. A
C16/C14 block copolymer was prepared by sequential addition of C16 to C14.
Figure 47 shows two melting temperatures for the block copolymer, suggesting
the formation of two different crystalline phases. Finally, the polymerization
kinetics for the C16 and C14 monomers also support the conclusion that the
copolymers are not blocky. Since the effect of the side chain length on
68
polymerization rates saturates at 28 chain atoms, the two carbon difference in
the C14 and C16 side chains would not be expected to affect the rate at which
the two monomers enter the polymer.
0.5 Mg
0 10 20 30 40 5O 60
temperature (°C)
Figure 47. DSC heating scan of polyC16 — block - polyC14). Second heating
scan, 10 °Clmin in N2.
Experimental Section
Unless otherwise specified, ACS reagent grade starting materials and
solvents were used as received from commercial suppliers without further
purification. THF was distilled from CaHz and sodium. 1H NMR (300 MHz or 500
MHz) and 13C NMR (75 MHz or 125 MHz) spectra were recorded at room
temperature in CDCl3 using a Varian Gemini 300 or a Varian UnityPlus-500
69
spectrometer with chemical shifts referenced to residual proton signals from the
solvent. Mass spectral analyses were carried out on a VG Trio-1 Benchtop GC-
MS.
General procedure for the synthesis of q-hydroxy acids. The appropriate
alkyl bromide (0.26 mol) was dissolved in anhydrous THF (250 mL) in a 1 L
round bottom flask and stirred with magnesium turnings (9.4 g, 0.39 mol) at a
temperature appropriate for forming the Grignard reagent (0 °C for hexyl
bromide, 50 °C for hexadecyl bromide). After transferring the resulting Grignard
reagent to an addition funnel, the solution was added dropwise under nitrogen to
a 1-L three-neck round bottom flask containing a mechanically stirred solution of
diethyl oxalate (29.5 g, 0.20 mol) in anhydrous THF (100 mL) at —80 °c.‘79 The
reaction mixture was stirred for an additional half hour at -80 °C, and then was
quenched with 2M HCI (200 mL). The aqueous layer was extracted with ether or
hexanes (for C16 and 014) (3 x 300 mL) and the combined organic layers were
washed with saturated NaCl and dried over MgSO4. Filtration and removal of the
solvents by rotary evaporation gave a light brown oil. The oil was then poured
into chilled (0 °C) methanol (300 mL), the mixture was filtered, and the methanol
was removed by rotary evaporation to give a light brown oil. Without further
purification, the crude ketoester was dissolved in acetic acid (250 mL) and 0.5 g
of 5% Pt/A|203 was added. After hydrogenation at ~1500 psig for 5 days, the
solids were removed by filtration, ether was added, and the acetic acid was
removed by washing with water. The colorless oil was hydrolyzed in a refluxing
mixture of 15 wt % solution of KOH in 70% aqueous ethanol (500 mL) for 2 days,
70
after which the mixture was neutralized with 2M HCI and extracted with CH2CI2 (3
x 400 mL). The combined organic layers were dried over M9804, and after
filtration and removal of solvents by rotary evaporation, the crude o-hydroxy acid
was recrystallized from hexanes three times.
2-Hydroxyoctanoic acid (1a) Isolated as white crystals, mp 67-69 °C (lit. 70
°C).185 1H NMR: 6 4.23-4.27 (dd, 1H, J = 7.57 Hz, J = 4.15 Hz), 1.77-1.87 (m,
1H), 1.62-1.72 (m, 1H), 1.36-1.49 (br, 2H), 1.21-1.35 (br, 6H), 0.77-0.94 (t, 3H, J
= 6.84 Hz). "’0 NMR: 6 180.04, 70.28, 34.09, 31.58, 28.88, 24.66, 22.52, 14.00.
MS (m/z): 161.4 (M+1).
2-Hydroxydecanoic acid (1b) Isolated as white crystals, mp 71-72 °C (lit. 70-72
°C).186 1H NMR: 6 4.23427 (dd, 1H, J= 7.57 Hz, J = 4.15 Hz), 1.77-1.86 (m, 1H),
1.62-1.71 (m, 1H), 1.35-1.48 (br, 2H), 1.18-1.34 (br, 10H), 0.78-0.91 (t, 3H, J =
6.84 Hz). 136 NMR: 6 180.01, 70.28, 34.09, 31.81, 29.36, 29.23, 29.19, 24.72,
22.62, 14.05. MS (m/z): 189.3 (M+1).
2-Hydroxydodecanoic acid (1c) isolated as white crystals, mp 73-74 °C (lit. 73-
74 °C).187 1H NMR: 6 4.23-4.28 (dd, 1H, J = 7.57 Hz, J = 4.15 Hz), 1.78-1.87 (m,
1H), 1.62-1.72 (m, 1H), 1.37-1.49 (br, 2H), 1.18-1.35 (br, 14H), 0.78-0.91 (t, 3H,
J=6.84 Hz). 13C NMR: 8 180.10, 70.27, 34.14, 31.88, 29.57, 29.54, 29.42, 29.30,
29.24, 24.73, 22.66, 14.09. MS (m/z): 217.4 (M+1).
2-Hydroxytetradecanoic acid (1d) Isolated as white crystals, mp 81-82 °C (lit.
81.5-82 °C).188 1H NMR: 6 4.19-4.31 (dd, 1H, J = 7.57 Hz, J = 4.15 Hz), 1.78-
1.87 (m, 1H), 1.63-1.72 (m, 1H), 1.36-1.50 (br, 2H), 1.18-1.35 (br, 18H), 0.80-
71
0.89 (t, 3H, J = 6.84 Hz). 130 NMR: 5 179.92, 70.26, 34.17, 31.91, 29.65, 29.63,
29.61, 29.54, 29.42, 29.34, 29.24, 24.72, 22.68, 14.11. MS (mlz): 245.4 (M+1).
2-Hydroxyhexadecanoic acid (1e) Isolated as white crystals, mp 87-88 °C (lit.
86.5-87 °C).189 1H NMR: 6 4.03409 (dd, 1H, J = 7.57 Hz, J = 4.15 Hz), 1.66-
1.77 (m, 1H), 1.50-1.60 (m, 1H), 1.28-1.42 (br, 2H), 1.12-1.26 (br, 22H), 0.71-
0.86 (t, 3H, J = 6.84 Hz). 13c NMR: 6 176.66, 69.63, 33.85, 31.37, 29.14, 29.12,
29.11, 29.10, 29.06, 28.99, 28.87, 28.80, 24.44, 22.14, 13.64. MS (mlz): 273.5
(M+1).
2-Hydroxyoctadecanoic acid (1f) Isolated as white crystals, mp 89-90 °C (lit.
91-92 °C).189 1H NMR: 6 4.22-4.28 (dd, 1H, J = 7.57 Hz, J = 4.15 Hz), 1.79-1.88
(m, 1H), 1.63-1.73 (m, 1H), 1.37-1.49 (br, 2H), 1.20-1.33 (br, 26H), 0.78-0.91 (t,
3H, J = 6.84 Hz). 130 NMR: 6 176.99, 69.86, 34.07, 31.62, 29.39, 29.37, 29.35,
29.30, 29.23, 29.11, 29.05, 24.62, 22.39, 13.86. MS (mlz): 301.5 (M+1).
General procedure for the synthesis of substituted glycolides. The
appropriate a-hydroxy acid (0.11 mol) was placed in a 2 L round bottom flask,
along with 0.6 g p—toluenesulfonic acid and ~1600 mL of toluene. The solution
was heated at reflux for 4 days, with the water removed azeotropically using a
Barrett trap. After the toluene was removed by rotary evaporation, the residue
was dissolved in 500 mL dichloromethane, washed with saturated NaHCO3 (3 x
300 mL) and dried over M9804. Removal of the dichloromethane gave the
product as a light brown oil or solid which was purified by recrystallization three
times from hexanes.
3,6-Dihexyl-1,4-dioxane-2,5-dione (2a). Hexylglycolide (5.9 g, 38% yield) was
72
isolated as white crystals mp 77-80 °c (lit. 78-80 °C).176 1H NMR: 6 4.88 (dd, J =
8.05 Hz, J = 4.88 Hz), 5 4.83 (dd, , J = 7.81 Hz, J = 4.39 Hz, 2H total for the
signals at 4.88 and 4.83), 1.97-2.10 (m, 2H), 1.88-1.97 (m, 2H), 1.40-1.56 (br m,
4H), 1.22-1.36 (br m, 12H), 0.75-0.91 (t, 6H, J = 6.84 Hz). 13C NMR: 5 166.99,
165.84, 76.36, 75.56, 31.89, 31.41, 30.36, 30.06, 28.69, 28.52, 24.45, 24.28,
22.44, 22.41, 13.96, 13.93. MS (mlz): 285.2 (M+1).
3,6-Dioctyl-1,4-dioxane-2,5-dione (2b). Octylglycolide (8.8 g, 48% yield) was
isolated as white crystals, mp 77-80.5 °C. 1H NMR: 5 4.88 (dd, J = 8.05 Hz, J =
4.88 Hz), 5 4.83 (dd, J = 7.81 Hz, J = 4.39 Hz, 2H total for the signals at 4.88 and
4.83), 1.97-2.10 (m, 2H), 1.87-1.97 (m, 2H), 1.41-1.56 (br m, 4H), 1.19-1.36 (br
m, 20H), 0.75-0.94 (t, 6H, J = 6.84 Hz). 13C NMR: 6 166.98, 165.85, 76.37,
75.58, 31.92, 31.76, 31.73, 30.08, 29.21, 29.17, 29.10, 29.06, 29.05, 28.88,
24.51, 24.34, 22.59, 22.57, 14.04. MS (mlz): 341.3 (M+1).
3,6-DidecyI-1,4-dioxane-2,5-dione (2c). Decylglycolide (9.1 g, 42%) was
isolated as white crystals, mp 82-86 °C. 1H NMR: 5 4.88 (dd, J = 8.05 Hz, J =
4.88 Hz), 5 4.83 (dd, J = 7.81 Hz, J = 4.39 Hz, 2H total for the signals at 4.88 and
4.83), 1.97-2.10 (m, 2H), 1.87-1.96 (m, 2H), 1.40-1.57 (br m, 4H), 1.18-1.36 (br
m, 28H), 0.75-0.91 (t, 6H, J = 6.84 Hz). 13C NMR: 5 166.99, 165.84, 76.36,
75.56, 31.90, 31.83, 31.82, 30.06, 29.50, 29.47, 29.44, 29.40, 29.25, 29.23,
29.21, 29.05, 28.87, 24.51, 24.33, 22.61, 14.05. MS (mlz): 397.3 (M+1).
3,6-Didodecyl-1,4-dioxane-2,5-dione (2d). Dodecylglycolide (13.4 g 54% yield)
was isolated as white crystals, mp 83-86 °C (lit. 82.5-83.5 °C )1” 1H NMR: 5
4.88 (dd, J = 8.05 Hz, J = 4.88 Hz), 5 4.83 (dd, J = 7.81 Hz, J = 4.39 Hz, 2H total
73
for the signals at 4.88 and 4.83), 1.97-2.10 (m, 2H), 1.87-1.97 (m, 2H), 1.41-1.56
(br m, 4H), 1.18-1.36 (br m, 36H), 0.78-0.92 (t, 6H, J = 6.84 Hz). 130 NMR: 6
166.98, 165.85, 76.38, 75.58, 31.92, 31.87, 30.09, 29.61, 29.59, 29.56, 29.53,
29.46, 29.41, 29.31, 29.27, 29.23, 29.06, 28.89, 24.52, 24.35, 22.65, 14.08. MS
(mlz): 453.4 (M+1).
3,6-DitetradecyI-1,4-dioxane-2,5-dione (2e). Tetradecylglycolide (8.1 g, 29%
yield) was isolated as white crystals, mp 87-89 °c (lit. 86-87 °c )1” 1H NMR: 6
4.88 (dd, J = 8.05 Hz, J = 4.88 Hz), 5 4.83 (dd, J = 7.81 Hz, J = 4.39 Hz, 2H total
for the signals at 4.88 and 4.83), 1.98-2.11 (m, 2H), 1.88-1.97 (m, 2H), 1.41-1.55
(br m, 4H), 1.18-1.36 (br m, 44H), 0.77-0.90 (t, 6H, J = 6.84 Hz). 13C NMR: 5
166.96, 165.86, 76.39, 75.60, 31.94, 31.90, 30.11, 29.66, 29.64, 29.62, 29.60,
29.58, 29.55, 29.47, 29.42, 29.34, 29.28, 29.24, 29.07, 28.90, 24.53, 24.36,
22.66, 14.10. MS (mlz): 509.4 (M+1).
3,6-Dihexadecyl-1,4-dioxane-2,5-dione (21). Hexadecylglycolide (17.7 g 57%
yield) was isolated as white crystals, mp 89-92 °C ( 88.5-90.5 °C )1” 1H NMR: 5
4.88 (dd, J = 8.05 Hz, J = 4.88 Hz), 5 4.83 (dd, J = 7.81 Hz, J = 4.39 Hz, 2H total
for the signals at 4.88 and 4.83), 1.98-2.12 (m, 2H), 1.88-1.97 (m, 2H), 1.41-1.55
(br m, 4H), 1.20-1.37 (br m, 52H), 0.78-0.92 (t, 6H, J= 6.84 Hz). 13c NMR: 6
166.96, 165.87, 76.40, 75.61, 31.95, 31.91, 30.12, 29.69, 29.67, 29.66, 29.64,
29.63, 29.61, 29.58, 29.56, 29.48, 29.43, 29.35, 29.28, 29.25, 29.08, 28.91,
24.54, 24.37, 22.68, 14.11. MS (mlz): 565.4 (M+1).
Bulk polymerization of substituted glycolides. Solvent free
polymerizations were run in sealed tubes prepared from 3/8 in. diameter glass
74
tubing. A representative polymerization is described. Monomer (~150 mg) and a
small magnetic stir bar were added to a tube and then the tube was connected to
a vacuum line and evacuated at 12 mTorr for 12 hours. After backfilling with
argon, a syringe was used to add anhydrous toluene solutions of Sn(2-
ethylhexanoate); and t-butylbenzyl alcohol (~0.02M) to give the desired
monomer/catalyst/initiator ratio. After careful removal of the toluene under
vacuum, the tube was flame-sealed under vacuum and immersed into a
magnetically stirred oil bath at 130 °C. At the end of the polymerization, the tube
was removed from the bath, cooled in ice water and opened. The contents of the
tube were dissolved in dichloromethane. A portion of the solution was evacuated
to dryness and analyzed by 1H NMR to determine conversion. The remaining
solution was washed with 2M HCI three times, followed by precipitation into cold
2-propanol multiple times to ensure the removal of residual catalyst and
unreacted monomer. Typical polymer yields were > 60%. For kinetic runs,
multiple tubes were prepared. For each data point, three tubes were removed
from the heating bath at predetermined intervals, cooled in ice and opened, and
the contents were analyzed by NMR for conversion. The data reported are
averages of the three samples.
Solution polymerizations of substituted glycolides. Solution
polymerizations were run in Schlenk flasks with magnetic stirring. The general
procedure is as follows. The desired amount of glycolide was added to the flask,
weighed, and held under vacuum (10 mTorr) overnight. Using a syringe,
degassed anhydrous toluene, and catalyst and initiator solution in anhydrous
75
toluene were transferred into the Schlenk flask under argon ([M] = 0.2M, [Cat]/[l]
= 1, [M]l[l] = 100). The polymerizations were heated with an oil bath controlled to
9012? At various times, a syringe was used to remove small volumes of the
polymerization solutions and after the solvents were evaporated in vacuo,
conversion was measured by NMR.
Hydrolytic degradation experiments. Polymer degradation experiments
were carried out by placing ~25 mg of polymer in a test tube containing 15 mL of
buffer solution (pH = 7.4). Taking care not to introduce air, the tube was inverted
and sealed in a slightly larger second tube filled with buffer. The tubes were
placed in a constant temperature bath at 55 °C. At predetermined times, three
tubes were removed from the bath and the degraded polymer was recovered by
cooling the tip of the polymer-containing tube in dry ice to harden the polymer,
and decanting the buffer. After drying under vacuum, the molecular weights
were measured by GPC. The reported molecular weight data are the average of
three samples.
Polymer characterization. The molecular weights of polymers were
determined by gel permeation chromatography (GPC) at 35 °C using two PLgel
10p mixed-B columns in series with THF as the eluting solvent at a flow rate of 1
mL/min. A Waters 2410 differential refractometer was used as the detector, and
monodisperse polystyrene standards were used to calibrate the molecular
weights. The concentration of polymer solutions used for GPC was 1 mg/mL.
Differential scanning calorimeter (DSC) analyses of the polymers were obtained
using a TA DSC 0100. Samples were run under a nitrogen atmosphere at a
76
heating rate of 10 °Clmin, with the temperature calibrated with an indium
standard. Thermogravimetric analyses (TGA) were run in air at a heating rate of
10 °Clmin using a Perkin-Elmer TGA7. X-ray diffraction (WAXS) patterns were
recorded using a Rigaku RTP 300 RC X-ray generator (Cu Kq = 1.5418 A) with a
Rigaku diffractometer. Samples were obtained by heating bulk polylactides on a
glass slide above the melting points to form a uniform film, followed by various
thermal treatments.
77
Chapter 3 PEO-grafted Comb Polylactides
introduction
Therrnoresponsive polymers that exhibit a lower critical solution temperature
(LCST) at near-ambient temperatures have attracted a great deal of attention in
the past two decades. One of the most studied systems is aqueous solutions of
poly(N—isopropylacrylamide) which undergoes a rapid and reversible sol-gel
transition when heated through its LCST.“"*192 Besides N-isopropylacrylamide
and its copolymers, various POlymers such as poly(methacrylate)s,115
122 193-196 104,107
poly(styrene)s, poly(phosphazene)s, poly(vinyl ether)s, and
chitosan197 have been reported to exhibit LCST behavior. Although their unique
phase transition suggests potential applications in fields such as drug delivery
197499 smart surfaces,2°° bioseparations, and for controlling enzyme
systems,
activity, the vast majority of LCST polymers are non-biodegradable, limiting their
biomedical applications.
Lactide based polymers are an important class of degradable aliphatic
polyesters. Due to their biodegradability and biocompatibility, polylactides have
long been used in medical applications as degradable sutures and implants, and
are currently being developed for controlled drug delivery and degradable
scaffolds for tissue engineering.‘°'°"2°4 For these applications, it is important to
have access to polymers that exhibit a broad range of physical properties. The
properties of these polymers can typically be tailored by controlling of the
175,205
stereochemistry of lactic acid precursors, manipulating their crystallinity, or
78
creating copolymers.‘73'2°6'208 Not surprisingly, there also is substantial interest in
developing thermoresponsive polylactides. For example, thermoresponsive
injectable drug-delivery systems were developed from thermoresponsive
poly(ethylene oxide) and polylactide diblock and triblock copolymers (PEO-FLA
and PEO-PLA-PEO).208 A disadvantage of such systems is that practical
applications limit the allowable PEO block length and that manipulation of the
transition temperature requires precise control over the length of lactide block.
Furthermore, structural heterogeneity may lead to unpredictable degradation
profiles, resulting in complicated drug release kinetics.
An alternative method for tailoring the thermoresponsive properties of
polylactides is to replace the methyl group of the lactic acid repeat unit with
different substitutents and regulate polymer properties by the nature of the
substituents. The effectiveness of this approach was proved by the successful
synthesis of a various of substituted polylactides such as poly(phenyllactide),177
polymandelide,178 and alkyl substituted polylactides.‘76
Recent reports have shown that introducing pendant oligo(ethylene oxide)
groups onto a hydrophobic polymer backbone can lead to new water-soluble
104,107,115122,193194.196.197-209 For example
thermoresponsive polymers.
polymethacrylates that have two and three ethylene oxide units in the side chain
exhibit LCSTs at 26 and 52 °C, respectively,115 and PEO-grafted polystyrene with
three and four ethylene oxide units in the side chain shows LCST behavior at 13
and 39 °C, respectively.122 Additionally, the presence of PEO moieties can render
the polymer resistant to protein adsorption, making them attractive biomaterials.94
79
944504512102“ reported to date all suffer from
The few PEO-grafted polyesters
either a low grafting density, backbone degradation or a high polydispersity, and
none has been shown to be thermoresponsive.
This chapter describes the synthesis and ring opening polymerization of
lactide monomers that have been functionalized with exact length oligo(ethylene
glycol) chains. The resulting PEO-grafted-polylactides should have predictable
degradation behavior because of their inherent structural homogeneity. These
polymers are water-soluble and show LCST behavior, suggesting potential
applications in biotechnology such as localized drug delivery.
Results and Discussion
Monomer synthesis
Scheme 12 shows the synthetic route to the four substituted glycolides
described in this chapter. Our synthetic approach to all of the monomers follows
the same pattern, the reaction of oligo(ethylene glycol) monomethyl ether with
1,6-dibromohexane to generate the corresponding oligo(ethylene glycol)
monomethyl ether capped with hexyl bromides. The reaction of Grignard
reagents generated from these functionalized oligo(ethylene glycol)s with diethyl
oxalate at -78 °C provided the corresponding q-keto esters. Typically, the
conversion of diethyl oxalate is >85%, with no detectable contamination from
addition of a second Grignard equivalent to the substrate. Catalytic
hydrogenation of the crude ketoesters at 1500 psig using Pt/C yielded the a-
hydroxy esters, but since purification of the esters proved difficult, the crude a-
80
hydroxy esters were hydrolyzed and isolated as the q-hydroxy acids. To the best
of our knowledge, none of the a-hydroxy acids were previously reported.
Crystallization from ether at -80 °C and -40 °C gave the acids as colorless to light
brown oils in overall yields of 41-80% based on diethyl oxalate. A representative
1H NMR spectrum, that of compound 4b, is shown in Figure 48.
NaH/T HF 1. M IT HF
[(OW‘OH 1 6-dibromohexane 4OV‘X‘OW Br .9 7
1a. n = 1 ' 2a. n = 1 2. diethyl oxalate
1b. n = 2 2b. n = 2
1cn=3 20n=3
1d. n = 4 2d. n = 4
O 1 5°/ Pt/CIA OH OH
. 0 C
’(O\/)\nO/V\/\)l\’r0\/ : ’(O\/‘)fiO/\/\/\/KWOH
2. KOH/H 0
3a. n = 1 O 2 _ O
_ 4a. n - 1
3bn-2 _
- 4bn-2
3c. n - 3 4 _ 3
3dn=4 9"“
0 4d. n = 4
toluZTiiAreflux : \(ON'PWLO
’ OYK/W\O(’\/O%
0
5a. 11 = 1
50. n = 2
Scn=3
5d. 11 = 4
O
Oh/O)fi
Sn(2-ethylhexanoate)2 O
tart-butylbenzyl alcohol 0
4' O
(0% We
in
poly(5a). n = 1
poly(5b). n = 2
poly(5c). n = 3
poly(5d). n = 4
Scheme 12. Synthesis of PEO-grafted polylglycolides
81
an
md o4 m; QN Wm o.m Wm oé We. ow Wm 0.0 We as We 9w
LFt__PL—_—_p_—_berr£pF_b_—_VHEF|FCGB_bk;—p__——________b_b___—________F__—___
«J ‘1 - l“)
:0
IO4X/\/\/\/O\/\O/\/O\
O
as: s .l H 2
O
OE/_\/\/>\O/\/O\/\O/
/O\/\O/\/O\/\/\/}fio
0
all 1<1 3W
Figure 48. 1H NMR spectra for 4b, 56, and poly(5b).
82
The methine proton appears as doublet of doublets at 4.20 ppm and intense
signals between 3.50 ppm and 3.65 ppm are characteristic of the methylene
protons of the E0 units. The methylene protons of the hexyl spacer adjacent to
PEO segment appear as a triplet at 3.42 ppm and the w-methoxy protons as a
singlet at 3.35 ppm.
Dimerization of the q-hydroxy acids in refluxing toluene using p-
toluenesulfonic acid as a catalyst yielded a mixture of the R,S and R,R/S,S
diastereomers in ~45% yield before distillation. The major byproducts consisted
of linear oligomers, which could in principle be recycled or thermally cracked to
yield additional monomer. A representative 1H NMR, that of compound 5b, is
shown in Figure 48. The methine protons of the 3,6-disubstituted glycolide ring
appear as two sets of doublets of doublets centered at 4.88 and 4.83 ppm;
integration of these two peaks in the 1H NMR spectrum of crude product confirms
the 1:1 ratio of the mesa to rac diastereomers expected for the statistical
coupling of a racemic mixture of hydroxy acids. Crystallization from ether
significantly alters the diastereomeric ratio, favoring isolation of the mesa
diastereomer. Similar results were obtained for the other glycolides. We note that
1H NMR also provides a convenient method for monitoring the polymerization
reaction. As shown in Figure 48 for glycolide 5b, the methine peaks at 4.85
evolve into a broad peak at ~5.10 ppm during polymerization allowing
straightforward calculation of the conversion of monomer to polymer.
83
Bulk polymerization
Bulk polymerizations of PEO-functionalized glycolides at 130 °C using t-
butylbenzyl alcohol as the initiator and Sn(2-ethylhexanoate)2 as the catalyst
yielded PEO-grafted polylactides. The catalystzmonomer:initiator ratio for all
polymerizations was 500:1:1. Since residual alcohol or water in monomer can
also act as initiator and lead to lower than expected molecular weights, it is
essential to have pure and dry monomers to obtain high molecular weight
polymers. Because of the hydrophilic PEO segment in these PEO functionalized
monomers, much more stringent purification and drying processes are required
compared to hydrophobic glycolide monomers. All monomers were freshly
distilled by Kiigelrohr distillation after recrystallization and dried under vacuum at
>100 °C before polymerization. (During Kiigelrohr distillation, the monomer
epimerized to a statistical mixture of diastereomers). The conversion of monomer
to polymer was followed by 1H NMR. The crude polymers were purified by
dialysis against acetone and vacuum dried to give clear viscous liquids. Polymer
molecular weights were measured by GPC in THF, and are reported relative to
polystyrene standards.
Table 4. Bulk polymerization results for PEO functionalized glycolides.
Monomer Time (hr) Conversion (%)a Mn (theor Mnc PDIc
5a 4 97 209,500 148,500 1.28
5b 11 65 169,000 56,400 1.10
50 20 73 221,900 59,800 1.16
5d 20 74 257,500 10,600 1.12
a. Measured by 1H NMR; b. Corrected for conversion; c. Measured by GPC in THF
using polystyrene standards for calibration
84
poly(5d)
poly(5c)
A poly(5b)
A poly(5a)
i
12 13 14 15 16 17
elution time (min)
Figure 49. GPC traces of PEO-grafted polylactides
Typical polymerization results are listed in Table 4 and the corresponding
GPC traces are shown in Figure 49. The GPC molecular weights were lower
than the theoretical values in all cases. Although low apparent molecular weights
could be due to residual alcohol or water in the monomer, it is likely that the PEO
segments in the side chains alter the hydrodynamic size of the polymer in THF
leading to lower relative molecular weights. We also observed that multiple
distillations of monomer or higher distillation temperatures generally led to slower
polymerization rates and lower molecular weights, suggesting that thermal
decomposition may introduce impurities into the monomer. The relative
contributions of these effects and the origin of occasional shoulders seen on the
high molecular weight side of GPC GPC traces (see the data for poly(5a) peak
and poly(5c) in Figure 49) are unclear.
Polymer properties
The decomposition temperatures of polymers measured using TGA define the
limiting use temperatures of the polymers. As shown in Figure 50, the TGA
profiles for all polymers are similar, with the onset for decomposition at around
100
90-
80-
7o-
60-
50-
40-
301
20-
10—
0
weight percentage (96)
50 1 50 250 350 450 550
temperature (°C)
Figure 50. TGA of PEO-grafted polylactides (10 °Clmin in air, samples were held
at 135 °C for 30 min prior to run. Pink line: poly(5a); red line: poly(5b); black line:
poly(Sc); blue line: poly(5d))
300 °C. The weight loss at lower temperatures is most likely due to the loss of
hydrogen bonded water because the weight loss depended on the length of time
the sample was held at 135 °C prior to staring the run. The DSC scans displayed
in Figure 51 show no thermal transitions between -55 °C and 100 °C; the low
86
intensity and the consistency of the “peak" at ~ -15 °C suggests that it is a
baseline fluctuation.
W ___ _ F i _ i _ poly(5a)
M W
poly(5b)
M
poly(5c) ;
M fi' l
| 0.02 W/g l
poly(5d) l
a _\ ‘
!
temperature (°C)
Figure 51. DSC traces of PEO-grafted polylactides (second heating scan, 10
°Clmin in N2)
Aqueous solubility and solution properties of PEO-grafted polylactides
Poly(5a) and poly(5b) are insoluble in water. Although hydration of the
hydrophilic side chains preclude a precise measurement of the contact angle, the
polymers are clearly more hydrophilic than poly(hexyl glycolide) (contact angles
of 50-75° compared to 100°). Poly(5c) and poly(5d) are water soluble and form
clear solutions at temperatures below their LCST. To determine the cloud points,
we prepared aqueous solutions of poly(5c) (Mmepc = 59,800, PDI = 1.16) and
poly(5d) (Mmepc = 10,600, PDI = 1.12) with a concentration of 15 mglmL.
87
C
p
19
_!—1
Ln.
LF‘
LO.
_(\l
o o 9 9 9 .0 .0 S3:
° ° N co co to o o__‘n,
V (D ‘- ‘- ‘- N CO V N
g r-
9 l 0, LC.
2 a) m
2 or
Q 0 C2) 5 g
I P Q
”:0.
_m
LO.
_<1’
2‘".
J J J j) j J % fi-V
01 1 j I
N
I _
l _C>.
<_In
L“.
in
Figure 52. 500 MHz 1H NMR spectra of poly(5c) (M. = 59,800 glmol, PDl = 1.16)
in D20 (15 mg/mL) at different temperatures.
88
15°C
-OMe
L
H20
-OMe
25 °C
-OMe
35 °C
38 °C
-OMe
uL
45 °C
-OMe
3L
1.0
1.5
2.0
50 °C
3.0 2.5
—OMe
4.0 3.5
4.5
JL
I I I I I I I i I I I I I I I I I T l i I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I
5.0
—-'_’—P
5.5
ppm
Figure 53. 500 MHz 1H NMR spectra of poly(5d) (M. = 10,600 g/mol, PDI = 1.12)
in D20 (15 mglmL) at different temperatures.
89
Solutions of poly(5c) were transparent below 19 °C, and suddenly turned cloudy
at 20 °C during the course of heating. After 24 hours at 25 °C, an obvious
precipitate settled, but the precipitate re-dissolved when the solution was cooled.
Similarly, solutions of poly(5d) exhibited a cloud point at 38 °C. Apparently, the
cloud point increases with the length of oligo(ethylene glycol) group, as has been
reported for other oligo(ethylene glycol)-grafted polymers.
We also used variable temperature 1H NMR measurements to study the
phase transitions of the two polymer solutions in D20. Figure 52 and Figure 53
show the 1H NMR spectra of poly(5c) and poly(5d) solutions (15 mg/mL) at
various temperatures, respectively. The height and position of water peak was
used as an internal reference. When a solution of poly(5c) was heated from 4 °C
to 18 °C, there were no visible changes in the height and shape of the proton
signal from the terminal methoxy group. When heated to 25 °C, the peak
broadened and the peak height noticeably decreased, indicating a phase
transition from a soluble to an insoluble state somewhere between 18 °C and 25
°C, consistent with the cloud point measurements. For poly(5d), the height of the
methoxy peak decreased and broadened between 35 °C to 45 °C, consistent
with cloud point measurements that place the transition at 38 °C. The
thermoresponsive behavior of the polymer solutions also can be monitored by
variable temperature dynamic light scattering measurements. Shown in Figure
54 are the DLS results for aqueous solutions of poly(5c) (3 mglmL) at different
temperatures. When the solutions were heated from 10 °C to 21 °C, the average
hydrodynamic radius of the particles in the solution remained constant at ~5 nm.
90
22 °C
21 °C
A
A
10°C
0.1 1 10 100 1000 10000
R). (nm)
Figure 54. DLS results for poly(5c) (Mn = 59,800 glmol, PDI = 1.16) in water (3
mglmL) at different temperatures.
A 38°C
25 °C
I I I I
0.1 1 10 100 1000 10000
Rh (nm)
Figure 55. DLS results for poly(5d) (M" = 10,600 glmol, PDI = 1.12) in water (3
mglmL) at different temperatures.
91
Further heating to 22 °C caused a drastic increase in the average hydrodynamic
radius to hundreds of nanometers, and the variability of this value is consistent
with polymer agglomeration. The DLS results for aqueous solutions of poly(5d) (3
mglmL) are shown in Figure 55. Between 25 and 38 °C, the average
hydrodynamic radius of the particles is essentially constant within experimental
error. But heating the solution to 39 °C induces an increase in hydrodynamic
radius to hundreds of nanometers, suggesting the polymer chains changed from
a hydrated state to an agglomerated insoluble state.
Conclusions
We successfully synthesized a series of lactides that have one oligo(ethylene
glycol) monomethyl ether chain per lactic acid residue. Their subsequent ring
opening polymerization yielded high molecular weight PEO-grafted polylactides
with narrow molecular weight distributions. Poly(5a) and poly(5b), having 1 and 2
PEO repeat units in the pendant chain, are hydrophilic but are not water soluble.
Poly(5c) and poly(5d) are water-soluble, and we detected lower critical solution
temperatures for both polymers. The cloud points of poly(5c) and poly(5d) in
aqueous solutions were 20 °C and 37 °C respectively, which we confirmed by
variable temperature 1H NMR and DLS measurements.
Experimental Section
Materials. Ethylene glycol monomethyl ether (99%), di(ethylene glycol)
monomethyl ether (99.6%), and tri(ethyiene glycol) monomethyl ether (95%)
92
were purchased from Aldrich and distilled before use. 1,6-Dibromohexane (96%),
NaH (60% dispersion in mineral oil), diethyl oxalate (99%) and 5 % platinum on
activated carbon were obtained from Aldrich and used as received.
Tetrahydrofuran (THF) was dried using an activated alumina column.
Characterization. The molecular weights of polymers were determined by
gel permeation chromatography (GPC) at 35 °C using two PLgel 10p mixed-B
columns in series with THF as the eluting solvent at a flow rate of 1 mUmin. A
Waters 2410 differential refractometer was used as the detector, and
monodisperse polystyrene standards were used to calibrate the molecular
weights. The concentration of polymer solutions used for GPC was 1 mg / mL.
Differential scanning calorimetry (DSC) analyses of the polymers were obtained
using a TA DSC 0100. Samples were run under nitrogen at a heating rate of 10
°Clmin, with the temperature calibrated using an indium standard.
Thermogravimetric analyses (TGA) were run in air at a heating rate of 10 °Clmin
using a Perkin-Elmer TGA-7. 1H NMR (300 or 500 MHz) and 136 NMR (75 or 125
MHz) spectra were acquired using either a Varian Gemini 300 spectrometer or a
Varian UnityPlus-500 spectrometer with the residual proton signals from the
CDCI3 solvent used as the chemical shift standard. Mass spectral analyses were
carried out on a VG Trio-1 Benchtop GC-MS. Variable temperature 1H NMR (500
MHz) spectra were recorded on a thermoregulated Varian UnityPlus-500
spectrometer using polymer solutions in 020 (D, 99.9%) with a concentration of
15 mglmL. For each temperature, the solution was equilibrated for 20 min before
acquiring the data. Variable temperature dynamic light scattering (DLS)
93
experiments were run on a temperature controlled Protein Solutions Dyna Pro-
MSIX system. All samples were filtered through a 0.2 pm Whatman PTFE
syringe filter. Samples were equilibrated in the instrument for 15 min at each
temperature before taking the data used to calculate the hydrodynamic radius
(R..). The uniformity of the particle sizes was determined by a monomodal curve
fit, which assumes a single particle size with a Gaussian distribution.
General synthetic procedure for PEO-functionalized hexyl bromides
The synthetic route to the desired monomers is summarized in Scheme 12.
A general procedure is described here. A 2 L round bottom flask containing 600
mL of dry THF was cooled between ~25 °C and -35 °C under a blanket of N2 and
charged with NaH (1.5 moi) and 1,6-dibromohexane (2.0 mol). The appropriate
ethylene glycol monomethyl ether (1 mol) was dissolved in 500 mL dry THF and
added dropwise into the strirred slurry over 5 hours. After the addition was
complete, the mixture was stirred at ~ -15 °C for 24 hours and at 0 °C for 2 days.
The solids were removed by filtration, and the solvent was removed by rotary
evaporation to give a light yellow oil, which was purified by fractional distillation.
1-Bromo-6-(2-methoxyethoxy)-hexane (2a). The distillate at 58-60 °C (50
mTorr) was collected to give 151 g of 2a (63%) as a colorless oil. 1H NMR 5 3.53
(m, 2H), 3.49 (m, 2H), 3.42 (t, 2H, J = 6.59 Hz), 3.38 (t, 2H, J = 6.84 Hz), 3.34 (s,
3H), 1.84 (p, 2H), 1.59 (p, 2H), 1.38-1.46 (br m, 2H), 1.29-1.38 (br m, 2H). 13C
NMR 5 71.93, 71.20, 69.95, 58.97, 33.71, 32.65, 29.33, 27.90, 25.22.
94
1-Bromo-6-[2-(2-methoxyethoxy)-ethoxy]-hexane (2b). The distillate at 83-86
°C (30 mTorr) was collected to give 195 g of 2b (69%) as a colorless oil. 1H NMR
5 3.60 (m, 4H), 3.56 (m, 2H), 3.52 (m, 2H), 3.42 (t, 2H, J = 6.59 Hz), 3.36 (t, 2H,
J = 6.84 Hz), 3.34 (s, 3H), 1.82 (p, 2H), 1.56 (p, 2H), 1.38-1.46 (br m, 2H), 1.30-
1.38 (br m, 2H). 130 NMR 6 71.94, 71.17, 70.63, 70.51, 70.08, 58.97, 33.75,
32.70, 29.40, 27.94, 25.27.
1-Bromo-6-{2-[2-(2-methoxyethoxy)-ethoxy]-ethoxy}-hexane (2c). The
distillate at 108-112 °C (30 mTorr) was collected to give 213 g of 2c (65%) as a
colorless oil. 1H NMR 5 3.61 (m, 8H), 3.51 (m, 4H), 3.41 (t, 2H, J = 6.59 Hz), 3.36
(t, 2H, J = 6.84 Hz), 3.33 (s, 3H), 1.82 (p, 2H), 1.54 (p, 2H), 1.37-1.45 (br m, 2H),
1.29-1.37 (br m, 2H). 136 NMR 6 71.88, 71.11, 70.56, 70.53, 70.45, 70.04, 58.93,
33.70, 32.65, 29.36, 27.90, 25.23.
1-Bromo-6-(2-{2-[2-(2-methoxyethoxy)-ethoxy]-ethoxy}-ethoxy)-hexane (2d).
After removal of excess 1,6-dibromohexane, the light brown residue was held
under vacuum (10 mTorr) at 145 °C overnight and used without further
purification because the attempts to distill this compound caused significant
decomposition. 1H NMR 5 3.57-3.64 (m, 16H), 3.48-3.55 (m, 5.5H), 3.39-3.43 (t,
2.7H, J = 6.59 Hz), 3.34-3.38 (t, 2.2H, J = 6.84 Hz), 3.32-3.34 (s, 3.8H), 1.77-
1.85 (p, 2H), 1.50-1.59 (p, 2.6H), 1.37-1.45 (br m, 2.6H), 1.28-1.37 (br m, 2H).
The integration of this compound was skewed due to contamination from by-
products.
95
Synthesis of PEO monomethyl ether substituted a-hydroxy octanoic acids.
The appropriate bromide (0.5 mol) was dissolved in 600 mL dry THF and
stirred with 24 g of magnesium turnings until the solution stopped boiling. The
Grignard reagent was then added dropwise under nitrogen to a 2 L round bottom
flask containing a stirred solution of diethyl oxalate (56 g, 0.38 mol) in dry THF
(500 mL) at -80 °C. The mixture was stirred for an additional hour at -80 °C, and
then was quenched by adding 300 mL 2M HCI into the reaction mixture. The
water layer was extracted with ether (5 x 200 mL) and the combined organic
layers were dried over MgSO4. Filtration and removal of the solvents by rotary
evaporation gave a light brown oil. After dissolving the oil in 500 mL ethanol and
adding 1 g of 5% PVC and 15 g NaHCOa, the a-keto ester was hydrogenated at
~1500 psi. When 1H NMR showed that the a-keto ester had fully reacted
(disappearance of the triplet at 2.80 ppm), the solids were removed by filtration
and the ethanol solution was concentrated by rotary evaporation to give a
colorless oil. Saturated aqueous NaHCO;; (1 L) was added and the mixture was
heated to reflux for 3 days. When 1H NMR showed the hydrolysis was complete
(disappearance of the quartet at 4.30 ppm), the basic solution was continuously
extracted with ether for 24 hours. The ether layer was discarded and the
aqueous layer was acidified with concentrated HCI to ~pH = 1. After continuous
extraction with ether for 48 hours, the ether layer was dried over MgSO4, filtered,
and evaporated to dryness to give the crude a-hydroxy acid. The final work up
depended on the particular q-hydroxy acid as noted below.
96
2-Hydroxy-8-(2-methoxy ethoxy)-octanoic acid (4a). Three recrystallizations
from ether at -40 °C followed by drying under vacuum (10 mTorr) at RT for 12
hours gave 71 g of 4a (80%) as white crystals. 1H NMR 5 4.21 (dd, 1H, J = 7.17
Hz, J = 4.39 Hz), 3.56 (m, 4H), 3.44 (t, 2H, J= 6.66 Hz), 3.37 (s, 3H), 1.80 (m,
1H), 1.67 (m, 1H), 1.56 (p, 2H), 1.24-1.50 (br m, 6H). 130 NMR 6 178.35, 71.89,
71.38, 70.06, 69.73, 58.88, 33.83, 29.27, 28.82, 25.69, 24.45.
2-Hydroxy-8-[2-(2-methoxy ethoxy)-ethoxy]-octanoic acid (4b). The crude
product was recrystallized once from ether at -80 °C and twice from ether at -40
°C. The resulting colorless oil was then dried under vacuum (10 mTorr) at RT for
12 h to give 72 g of 4b (67%) as a colorless oil at room temperature. 1H NMR 5
4.20 (dd, 1H, J = 7.17 Hz, J = 4.39 Hz), 3.62 (m, 4H), 3.56 (m, 4H), 3.43 (t, 2H, J
= 6.66 Hz), 3.35 (s, 3H), 1.78 (m, 1H), 1.66 (m, 1H), 1.55 (p, 2H), 1.24-1.48 (br
m, 6H). 13C NMR 5 177.55, 71.68, 71.24, 70.34, 70.15, 69.96, 69.77, 58.75,
33.81, 29.12, 28.79, 25.61, 24.45.
2-Hydroxy-8-{2-[2-(2-methoxy ethoxy)-ethoxy]-ethoxy}-octanoic acid (4c).
The crude product was recrystallized twice from ether at —80 °C and twice from
ether at -40 °C. The colorless oil was dried under vacuum (10 mTorr) at room
temperature for 12 h to give 76 g of 4c (61%). 1H NMR 5 4.20 (dd, 1H, J = 7.17
Hz, J = 4.39 Hz), 3.62 (m, 8H), 3.56 (m, 4H), 3.43 (t, 2H, J = 6.66 Hz), 3.35 (s,
3H), 1.78 (m, 1H), 1.66 (m, 1H), 1.55 (p, 2H), 1.24-1.48 (br m, 6H). 13C NMR 5
. 177.69, 71.77, 71.21, 70.44, 70.26, 69.97, 69.88, 33.83, 29.19, 28.78, 25.65,
24.47.
97
2-Hydroxy-8-(2-{2-[2-(2-methoxy ethoxy)-ethoxy]-ethoxy}-ethoxyi)-octanoic
acid (4d). The crude product was recrystallized five times from ether at -80 °C.
The light brown oil was dried under vacuum (10 mTorr) at room temperature for
12 h to give 57 g of 4c (41%). 1H NMR 5 4.20 (dd, 1H J = 7.08 Hz, J = 4.39 Hz),
3.62 (m, 12H), 3.56 (m, 4H), 3.43 (t, 2H, 2H, J= 6.59 Hz), 3.35 (s, 3H), 1.78 (m,
1H), 1.66 (m, 1H), 1.55 (p, 2H), 1.24-1.48 (br m, 6H). 13C NMR 5 177.37, 71.78,
71.21, 70.49, 70.43, 70.39, 70.26, 69.98, 69.91, 58.86, 33.84, 29.22, 28.79,
25.69, 24.46.
Synthesis of PEO monomethyl ether functionalized glycolides
The appropriate 2-hydroxy acid (0.1 mol) was placed in a 2 L round bottom
flask, along with 1 g PTSA and ~1800 mL toluene. The solution was refluxed for
3 days, with the water removed azeotropically using a Barrett trap. After the
toluene was removed by rotary evaporation, the residue was dissolved in 500 mL
diethyl ether, washed with saturated NaHC03 and dried over M9804. Filtration
and removal of the ether gave the product as a light brown oil, which was purified
by three recrystallizations from diethyl ether at low temperatures. These
compounds are oils at room temperature.
3,6-Bis-[6-(2-methoxy-ethoxy)-hexyl]-[1,4]dioxane-2,5-dione (5a). The
colorless oil was distilled (180 °C/3 mTorr) to give 9.6 g of 5a (41%). 1H NMR 5
4.88 (dd, J = 8.30 Hz, J = 4.88 Hz), 5 4.83 (dd, J = 7.69 Hz, J = 4.27 Hz, 1H total
for the signals at 4.88 and 4.83), 3.52 (m, 4H), 3.40 (t, 2H, J = 6.66 Hz), 3.34 (s,
3H), 1821 (br m, 2H), 1.4-1.6 (br m, 4H), 124-14 (br m, 4H). ”C NMR 6
98
166.87, 165.66, 76.24, 75.41, 71.87, 71.20, 71.15, 69.89, 58.93, 31.75, 29.87,
29.27, 28.74, 28.60, 25.65, 24.38, 24.18. Anal. Calcd. for C22H4008: C, 61.11; H,
9.26 Found: C, 60.80; H, 8.87. MS (m/z) 433.3 (M+1).
3,6-Bis-{6-[2-(2-methoxy-ethoxy)-ethoxy]-hexyI}-[1,4]dioxane-2,5-dione (5b).
The colorless oil was distilled (190 °C I 3 mTorr) to give 7.8 g of 5b (28%). 1H
NMR 5 4.88 (dd, J = 8.30 Hz, J = 4.88 Hz), 5 4.83 (dd, J = 7.69 Hz, J = 4.27 Hz,
1H total for the signals at 4.88 and 4.83), 3.62 (m, 4H), 3.57 (m, 4H), 3.40 (t, 2H,
J = 6.66 Hz), 3.34 (s, 3H), 1.9-2.2 (br m, 2H), 1.47-1.7 (br m, 4H), 1.3-1.47 (br m,
4H). 13C NMR 5 166.87, 165.69, 76.28, 75.46, 71.88, 71.18, 71.12, 70.57, 70.45,
70.01, 58.94, 31.80, 29.93, 29.33, 28.79, 28.65, 25.70, 24.43, 24.22. Anal. Calcd.
for C26H430102 C, 60.00; H, 9.23 Found: C, 60.10; H, 9.60. MS (m/z) 521.1 (M+1).
3,6-Bis-(6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)-[1 ,4]dioxane-2,5-
dione (5c). The colorless oil was distilled ( 210 °C / 3 mTorr) to give 6.9 g of 5c
(21%). 1H NMR 5 4.88 (dd, J = 8.30 Hz, J = 4.88 Hz), 5 4.83 (dd, J = 7.69 Hz, J =
4.27 Hz, 1H total for the signals at 4.88 and 4.83), 3.62 (m, 8H), 3.57 (m, 4H),
3.40 (t, 2H, J = 6.66 Hz), 3.34 (s, 3H), 1922 (br m, 2H), 1.47-1.7 (br m, 4H),
1.3-1.47 (br m, 4H). 13’0 NMR 5 166.84, 165.48, 76.05, 75.21, 71.64, 70.93,
70.88, 70.32, 70.29, 70.21, 69.80, 58.70, 31.54, 29.66, 29.15, 29.13, 28.61,
28.44, 25.51, 25.49, 24.21, 24.00. Anal. Calcd. for CgoH55012: C, 59.21; H, 9.21
Found: C, 59.34; H, 9.60. MS (m/z) 609.4 (M+1).
3,6-Bis-[6-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-hexyl]-
[1 ,4]dioxane-2,5-dione (5d). The light brown oil was distilled (238 °C / 3 mTorr)
to give 5.2 g of 5d (15%) as colorless oil. 1H NMR 5 4.88 (dd, J = 8.30 Hz, J =
99
4.88 Hz), 5 4.83 (dd, J = 7.69 Hz, J = 4.27 Hz, 1H total for the signals at 4.88 and
4.83), 3.62 (m, 12H), 3.57 (m, 4H), 3.40 (t, 2H, J = 6.66 Hz), 3.34 (s, 3H), 1922
(br m, 2H), 1.47-1.7 (br m, 4H), 1.3-1.47 (br m, 4H). 13C NMR 5 166.90, 165.71,
76.31, 75.49, 71.88, 71.21, 71.16, 70.55, 70.52, 70.46, 70.03, 58.97, 31.84,
29.94, 29.38, 28.82, 28.69, 25.74, 24.46, 24.26. Anal. Calcd. for C34H54014: C,
58.62; H, 9.19 Found: c, 58.30; H, 9.25. MS (m/z) 697.4 (M+1).
Bulk Polymerization of PEO Functionalized Substituted Giycolides
Solvent free polymerizations were run in sealed tubes prepared from 3/8 in.
diameter glass tubing. A representative polymerization is described. The desired
amount of freshly distilled monomer and a small magnetic stir bar were added to
the tube. The monomer was stirred and the tube was evacuated under vacuum
(3 mTorr) for 12 hours at the desired temperature. After cooling to room
temperature and back-filling with argon, a syringe was used to add toluene
solutions of the catalyst (Sn(2-ethyihexanoate)2, 0.2 mol%) and initiator (tert-
butylbenzyl alcohol, ~0.01 M). After careful removal of the toluene under vacuum,
the tube was sealed under vacuum and immersed into an oil bath at 130 °C and
stirred magnetically for the desired polymerization time. At the end of the
polymerization, the tube was cooled in ice water and opened. A portion of the
polymer was analyzed by NMR for conversion, and the remaining polymer was
purified by dialysis (MWCO = 12-14,000) in acetone to give PEO-grafted
polylactides.
100
Poly(5a). Monomer (2.24 g) was dried at 105 °C and polymerized for 4 h. The
monomer conversion was 94%. After dialysis and removal of solvent by rotary
evaporation, the residue was dried under vacuum (4 mTorr) at 70 °C overnight to
give 1.86 g of Poly(5a) as a colorless viscous liquid (83%). 1H NMR 5 5.01-5.23
(br, 1H), 3.53-3.64 (br, 4H), 3.44-3.52 (br. m, 2H), 3.39-3.43 (s, 3H), 1.82-2.03
(br, 2H), 1.55-1.70 (br, 2H), 1.28-1.53 (br, 6H). Anal. Calcd. for (C22H4003)n: C,
61.11; H, 9.26 Found: C, 61.18; H, 9.33.
Poly(5b). The monomer (2.22 g) was dried at 115 °C and polymerized for 11 h.
The monomer conversion was 95%. After dialysis and removal of solvent by
rotary evaporation, the residue was dried overnight under vacuum (4 mTorr) at
70 °C to give Poly(5b) (1.72 g) as a colorless viscous liquid (77%). 1H NMR 5
501-523 (br, 1H), 3.64-3.72 (br. m, 4H), 3.54-3.64 (br, 4H), 3.43-3.52 (br. m,
2H), 3.37-3.43 (s, 3H), 1.83-2.05 (br, 2H), 1.54-1.69 (br, 2H), 1.25-1.52 (br, 6H).
Anal. Calcd. for (CzeH4301o)n: C, 60.00; H, 9.23 Found: C, 59.83; H, 9.11.
Poly(Sc). The monomer (1.90 g) was dried at 120 °C and polymerized for 15 h.
The monomer conversion was 87%. After dialysis and removal of solvent by
rotary evaporation, the residue was dried under vacuum (4 mTorr) at 70 °C
overnight to give 1.40 g of Poly(5c) as a colorless viscous liquid (73%). 1H NMR
5 501-524 (br, 1H), 3.63-3.74 (br. m, 8H), 3.54-3.63 (br, 4H), 3.42-3.51 (br. m,
2H), 3.38-3.42 (s, 3H), 1.79-2.05 (br, 2H), 1.53-1.69 (br, 2H), 1.25-1.53 (br, 6H).
Anal. Calcd. for (C30H55012)n: C, 59.21; H, 9.21 Found: C, 59.13; H, 9.06.
Poly(5d). The monomer (1.3 g) was dried at 130 °C and polymerized for 20 hrs.
The monomer conversion was 74%. After dialysis and removal of solvent by
101
rotary evaporation, the residue was stirred under vacuum (4 mTorr) overnight to
give 0.68 g of Poly(5d) as light yellow liquid (52%). 1H NMR 5 5.01523 (br, 1H),
3.64-3.71 (br. m, 12H), 3.55-3.63 (br, 4H), 3.43-3.50 (br. m, 2H), 3.38-3.42 (s,
3H), 1.80-2.05 (br, 2H), 1.54-1.69 (br, 2H), 1.25-1.52 (br, 6H). Anal. Calcd. for
(C34H54014)n: C, 58.62; H, 9.19 Found: C, 58.64; H, 9.08.
102
Chapter 4 Functionalization of Polylactides by “Click” Chemistry
Introduction
Aliphatic polyesters derived from lactide, glycolide and e-caprolactone have
been extensively studied for biomedical applications due to their biodegradability
and biocompatibility. However, their range of applications is limited by their
hydrophobic nature and the lack of chemical functionality along the polymer
backbone to support further modification. Polyesters with pendant
I 210,212,213 I 214 150.151.210.211 I 215,216
I 1 I
hydroxy carboxy poly(ethylene oxide), ally and
acetylene150 functionalities have been synthesized using a variety of strategies
including polymerization of functional monomers, post-polymerization
modifications of polymers, or a combination of these two approaches. However,
the functional monomer approach typically involves complex and tedious
synthetic procedures, while careful control of conditions is required in the case of
post-polymerization modification to avoid backbone degradation. In most cases,
the chemical modifications are limited to a single class of functional groups.
Having a single procedure that allows the introduction of a family of pendant
functional groups onto a single polyester substrate polymer is highly desirable.
Because of its high selectivity, reliability, and tolerance to broad range of
functional groups and reaction conditions, “click” chemistry, specifically the
copper(l)-mediated 1,3-dipolar cycloaddition of azides and alkynes, is an
excellent strategy for elaborating polymer architectures. “Click” chemistry has
141,217
been used for the preparation of block copolymers, cross-linked
103
1354384554 and for the introduction of pendant and
adhesives,155 dendrimers,
terminal functional groups into various polymers including polyestersm'
‘“"50'151'157 The Emrick group first described the use of aqueous “click” chemistry
to graft azide-terminated PEO and peptides onto polyesters containing pendant
acetylene groups.150 Later, Jéréme and coworkers found Emrick’s conditions
caused significant backbone degradation during functionalization,151 and using
less severe conditions (THF as the solvent), they were able to introduce PEO,
tertiary amines and ammonium salts onto caprolactone-based polyesters having
pendant azides. However, in Jér5me’s case, it is necessary to end-cap the
terminal hydroxyl group of the polymer backbone to avoid significant backbone
degradation when using lactide copolymers as substrates, and click reactions
using Cul, the catalyst used by Jér5me, are known to cause more side reactions
than in situ generated Cu(l).‘3’4 It would be useful to have a simpler and more
reliable protocol for click functionalization of polyesters, and especially polyesters
wholly based on lactide monomers.
We are interested in tailoring the properties of polylactides through the
synthesis and polymerization of substituted lactides. Over the years, this
approach has lead to the successful preparation of poly(phenyllactide),‘77
178 176 216
polymandelide, alkyl substituted polylactides, allyl substituted polylactide,
PEO substituted polylactides, and alkyl/PEO substituted amphiphilic
polylactides.218 Stimulated by the versatility of post-polymerization modification of
polyesters by click chemistry and the usefulness of having wholly lactide-based
functional polymers, we synthesized and polymerized the acetylene-
104
functionalized glycolide monomer, 3,6-dipropargyl-1,4-dioxane-2,5-dione (3). The
subsequent polymerization of glycolide 3 provided the homopolymer of 3 as well
as random and block copolymers with lactide that have pendant acetylene
groups available for the attachment of functionality using click chemistry. The
drawbacks encountered in Emrick’s and Jér5me’s conditions for click
functionalization of polyesters were overcome by carrying out the reaction in
DMF at room temperature in the presence of CuSO4 and sodium ascorbate. The
effectiveness of this protocol was demonstrated by the preparation of alkyl and
PEO grafted polylactides
Results and Discussion
Monomer synthesis.
Scheme 13 shows the synthetic route to propargyl glycolide, an acetylene-
functionalized monomer, and its polymers. The Refon'natsky-type reaction of
propargyl bromide with freshly distilled ethyl glyoxylate in the presence of
activated zinc generated ethyl 2-hydroxy-3-butynoate in 51% yield.219 The
byproducts, most likely oligomers, were removed by eluting the crude product
through silica gel using a 70:30 mixture of hexane/ethyl acetate. Hydrolysis of
the ester in refluxing water yielded 2-hydroxy-3-butynoic acid in 84% yield.
Hydrolysis under basic conditions resulted in lower yields due to side reactions.
Dimerization of 2-hydroxy-3-butynoic acid in refluxing toluene using p-
toluenesulfonic acid as a catalyst yielded a mixture of the mesa and racemic
105
0
ll
_ HCCOOCsz _ 0 H20 O
__ +7 _ = :
Br Zn T O/\ reflux \(LKOH
THF/Ether OH OH
0 °c 1 2
PTSA
// toluene reflux
NO
// / °M
4 O
3
Sn(Oct)2/BBA
// o
O O
O
‘to O .. ojfirOW/u‘h, fl
0 O
// 5 0
Scheme 13. Synthetic route to propargyl glycolide and its polymers
diastereomers in 34% yield. The byproducts primarily consisted of linear
oligomers which could in principle be recycled or thermally cracked to yield
additional monomer. The 300 MHz 1H NMR spectrum of propargyl glycolide is
shown in Figure 56. The methine protons of the propargyl glycolide ring appear
as a triplet at 5.29 ppm and a doublet of doublets at 5.05 ppm; integration
confirms the 1:1 ratio of the mesa (R,S) to rac (RR/SS) diastereomers expected
for the statistical coupling of a racemic mixture of hydroxy acids. After
recrystallization, the diastereomeric ratio was 2:3, favoring rec-propargyl
glycolide.
106
I 0.1
r"'11'1—r'1111’1—r'1"1TT1’l""1'Ti"TFT1’1'1lT1111 111111 ‘T 1T1 11r1Tr11111111T11T
.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 10 0.5
o o o
oJ'fié\\c
l O I I
111111111T'A‘r’11—TT—1—1‘ T111" 1' 111—1111111111
.o 7.5 7.0 6'5 6'0 55 5.0 4'5 4.0 3'5 3.0 2'5 2'0 1'0 0.5
ppm
Figure 56. 300 MHz 1H NMR spectra of propargyl glycolide and poly(propargyl
glycolide)
Polymerization
Bulk polymerizations of propargyl glycolide at 130 °C catalyzed by Sn(2-
ethylhexanoate)2 using t-butylbenzyl alcohol as the initiator yielded polymer 4.
The catalyst to initiator ratio was 1:1 for all the polymerizations, and the
monomer:initiator ratio ranged from 50:1 to 300:1. The increase in polymer
molecular weight as a function of degree of polymerization (X) was monitored by
gel permeation chromatography (GPC) in THF and calculated relative to
polystyrene standards. The theoretical for each reaction, corrected for
conversion, was calculated by 1H NMR analyses of samples removed from the
reaction mixture. We note that 1H NMR provides a convenient method for
107
monitoring the polymerization reaction since as shown in Figure 56, the methine
peaks at 5.05 and 5.29 ppm evolve into a broad peak at ~5.38 ppm during
Table 5. Bulk polymerization results for propargyl glycolide
[Ml/[l] Time (min) Conversion (%)al X..." M,6 (glmol) PDIc
50 1 0 85 43 9100 1 .1 3
100 15 89 89 18500 1.21
150 25 91 136 28600 1.30
200 30 73 146 30500 ‘131
250 55 78 195 38300 1.37
300 60 90 270 54600 1 .38
300 75 94 280 56500 1 .49
(a) Measured by 1H NMR. (b) Corrected for conversion. (0) Measured by GPC in
THF and calibrated using polystyrene standards.
60000
50000 4
40000 —
30000 a
Mn (QIMOII
20000 —
10000 —
0 50 100 150 200 250 300
Xn
Figure 57. Relationship between Mn and Xn the degree of polymerization for the
bulk polymerization of propargyl glycolide.
108
polymerization. Typical results for the bulk polymerization of propargyl glycolide
are listed in Table 5. The molecular weights measured by GPC range from 9-60
kglmol and are in good agreement with the theoretical values. The evolution of
the molecular weight (measured by GPC) is plotted in Figure 57 as a function of
the expected number average degree of polymerization, X,,, corrected for
conversion. The linear relationship and polydispersities of 1.2-1.5 are consistent
with a reasonably controlled homopolymerization of propargyl glycolide.
Control over the number of pendant acetylene groups in a polymer can be
achieved through copolymerization of propargyl glycolide and lactide. in a model
copolymerization, we polymerized a mixture of rec-lactide and 8 mol% propargyl
glycolide with the monomer to initiator ratio set to target an Xn of 300. The
polymerization was run under the same conditions used for homopolymerization
of propargyl glycolide. The incorporation of propargyl glycolide in the copolymer
was 7.9%, calculated from integration of the 1H NMR signals at 5 2.85
(methylene protons in pendant acetylene group) and the signal at 5 5.20
(methine proton in polymer backbone). The 13C NMR spectrum of the copolymer
is consistent with the propargyl glycolide being distributed throughout the
polymer chains. Shown in Figure 58 are spectra for the copolymer as well as
polylactide and propargyl glycolide homopolymers. A comparison between the
carbonyl regions showed the appearance of an additional peak at 168.92 ppm
from the lactide repeat units and an ~0.2 ppm shift of the propargyl glycolide
repeat units, suggesting that the propargyl glycolide units are not concentrated in
“blocky” segments, but instead are distributed along the polymer backbone.
109
M polylactide
poly(propargyl glycolide)
poly(propargyl glycolide-block-lactide), 27.8 mol % propargyl
l poly(propargyl glycolide-co-Iactide), 7.9 mol % propargyl
WWW
_I_T T'" —T T' T’_T-r T T_T_ l T‘ ‘T—I ‘T' _T_‘ r—“r I T'_Y I‘I 7"! "IT. INT—WY" ‘7"—
169.5 169.0 165.5 1650 1675255 167.0 165.5 166.0 165.5 165.0 164.5
ppm
Figure 58. 75 MHz 13C NMR carbonyl region of propargyl glycolide
homopolymer, copolymers, and polylactide
Poly(propargyl gchoiide)(PPGL)-bIock-polylactide was prepared by using
scrupulously purified propargyl glycolide homopolymer as a macroinitiator (Xn =
150) and Sn(2-ethylhexanoate)2 as the catalyst for lactide polymerization
([l]/[Cat] = 1). The polymerization was carried out in THF at 70 °C to minimize
transesterification. GPC traces show a shift of the peak molecular weight to
shorter retention times, with slight broadening and a increase in the PDI, (Figure
59), both suggesting the formation of blocky architecture. The carbonyl regions in
110
the 13C NMR spectrum of this copolymer directly correlate to the two
homopolymers (Figure 58), which further confirms the blocky nature of this
copolymer.
I l I I
12 13 14 15 16 17
elution time (min)
Figure 59. GPC traces of the PPGL macroinitiator, and PPGL-block-polylactide.
(black line: PPGL; pink line: PPGL-block-polylactide)
“Click” functionalization
Alkyl-grafted polylactides prepared by click chemistry. Emrick et al.
reported the click functionalization of pendant acetylenes incorporated into
polycaprolactone. While the conditions for the reaction are somewhat
aggressive, an aqueous solution of CuSO4 and sodium ascorbate at 80 °C or
even higher temperatures for 10-12 hours,‘5° they successfully modified
111
polycaprolactone without significant degradation. However, when poly(propargyl
glycolide) (PPGL) (Mn,Gpc = 56 500, PDI = 1.49) was stirred in an acetone/water
mixture at 50 °C for eight hours, GPC traces showed a significant reduction in
M... This result was not surprising since the polylactide backbone is known to be
more sensitive to degradation than polycaprolactone. Recently, Jér5me et al.
reported the click functionalization of a copolymer prepared from an azide-
functionalized caprolactone and lactide using milder conditions, Cul in THF at 35
°C.151 However, esterification of the terminal hydroxyl group was necessary to
suppress backbone degradation, which complicated the synthetic procedure. In
addition, the direct use of copper (l) salts in click reactions can reduce selectivity
and lead to formation of undesired by-products.134
We solved these problems by carrying out the “click” reaction in the presence
of CuSO4 and sodium ascorbate in DMF at room temperature. The low solubility
of sodium ascorbate in DMF had no discernable effect on the reaction. The
efficiency of the Huisgen 1,3-dipoiar cycloaddition was demonstrated by grafting
1-azidodecane, synthesized by nucleophilic substitution of 1-bromodecane using
sodium azide, onto PPGL. Thus, a propargyl glycolide polymer (Mmcpc = 35,500,
PDI = 1.44) was reacted with three equivalents of 1-azidodecane in the presence
of 12 mol% sodium ascorbate and 5 mol% 00804 (with respect to acetylene). 1H
NMR spectra taken after 2 hours showed that resonances at 2.85 ppm (-CH2-
CCH) and 2.05 ppm (-CH2-CCH) had disappeared completely and a new peak
appeared at 7.6 ppm (H of the triazole ring) indicating the quantitative formation
of the triazole.
112
12 13 14 15 16 17
elution time (min)
Figure 60. GPC traces of PPGL and C10-grafted PPGL. (pink line: PPGL; black
line: C10-grafted PPGL)
The GPC results (Figure 60) of the resulting alkyl-grafted polymer (Mmepc =
49,400, PDI = 1.41) confirmed an increase in molecular weight, with the
symmetry of the polymer peak and its molecular weight distribution unchanged.
These experimental results confirm that no significant backbone degradation
occurred during the “click” reaction of PPGL. To further confirm the stability of the
backbone under these conditions, we treated PPGL (Mmepc = 32,600, PDI =
1.45) using the same experimental protocol (DMF, RT, 0.12 eq. sodium
ascorbate, 0.05 eq. CuSO4, 2 h) but in the absence of 1-azidodecane. The GPC
trace showed a slight decrease in molecular weight with the PDI unchanged
(ManPC = 32 100, PDI = 1.44) (Figure 61). Thus, “click” functionalization of PPGL
113
can be effected quantitatively in DMF at room temperature without significant
backbone degradation by generating Cu(l) in situ. The formation of undesired by-
products was minimized by the lower lower reaction temperature, and protection
of the terminal hydroxyl group at the chain and was not necessary.
I I I I
12 13 14 15 16 17
elutlon time (min)
Figure 61 . GPC traces from a control reaction where PPGL was exposed to click
conditions, but without added azide. (black line: PPGL before the reaction; pink
line: PPGL after the reaction)
PEG-grafted polylactide prepared by “click” chemistry. “Click” chemistry
provides a simple route to analogs of the PEO-substituted polylactides described
in Chapter 3. We selected a PEG-550 monomethyl ether as the pendant group
because of its ready availability from commercial suppliers, and transformed it
into the corresponding a,w-PEG-550 monomethyl ether azide by tosylation of
114
PEG-550 monomethyl ether, followed by nucleophilic substitution using sodium
azide. The azide group is easily identified by its IR absorption at 2105 cm‘1 and
by resonances for the methylene or to the azide at 3.38 ppm (-OCH2CH2N3) in the
1H NMR spectrum and at 50.5 ppm in the 13C NMR spectrum. The “click”
PEGylation of PPGL was performed under conditions identical to those described
for grafting alkyl groups to PPGL (DMF, RT, 0.12 eq. sodium ascorbate, 0.05 eq.
CuSO4, 3 eq. of azide, 2 h). Completion of the reaction was again confirmed by
the disappearance of the 1H NMR resonances at 2.85 ppm (-CH2-CCH) and 2.05
ppm (CHZCCH) and the appearance of a new resonance at 7.6 ppm (H of
triazole). The crude product was purified by dialysis in acetone/water (1:1)
mixture, and drying under vacuum gave the PEG-grafted polyglycolide as a
water-soluble, viscous liquid tinted light green due to contamination by Cu(li).
Direct GPC analysis of this PEG-grafted polylactide proved to be problematic.
When THF was used as solvent, we did not detect the polymer eluting from the
column and we speculated that either the polymer and THF were iso-refractive,
or that the polymer had adsorbed onto the column. We ran several control
experiments to rule out backbone degradation during “click” PEGylation. We first
subjected PPGL (Mn,ng = 32, 600, PDI = 1.45) to the same experimental
conditions (DMF, RT, 0.12 eq. sodium ascorbate, 3 eq. of PEG azide, 2 h) but in
the absence of CuSO4. GPC results for the recovered PPGL (Mmcpc = 32,200,
PDI = 1.44) showed no sign of backbone degradation. In a related experiment, a
115
I T I I
12 13 14 15 16 17
elutlon time (min)
Figure 62. GPC traces of a polylactide sample exposed to “click” conditions.
(black line: polylactide before the click reaction; pink line: polylactide after
reaction)
1 T T 1 1'
12 13 14 15 16 17
elutlon time (min)
Figure 63. GPC traces for the poly(propargyl glycolide-co-lactide) click
PEGylation. The concentration of propargyl glycolide in the copolymer was 7.9
moi %. (black line: copolymer before the click reaction; pink line: copolymer after
click reaction)
116
mixture of PPGL (Mmepc = 32,600, PDI = 1.45) and polylactide (Mmcpc = 18,600,
PDI = 1.26) was subjected to the click PEGylation conditions. GPC results for the
treated polylactide (Mmcpc = 18, 300, PDI = 1.26) (
Figure 62) again showed no loss in molecular weight.
The random copolymer of lactide with 7.9 mol% propargyl glycolide (Mn,ng =
63,600, PDI = 1.66) was PEGylated under the identical experimental conditions.
GPC analysis of this PEG-grafted copolymer shows a shift of the peak molecular
weight to longer retention time than the starting copolymer (Figure 63), indicating
a lower relative molecular weight (Mmspc = 16,800, PDI = 1.43). This result
seems at odds with the results of previous control experiments that showed no
change in molecular weight for polymers under click conditions, and we
suspected the apparent decrease in molecular weight could be related to a
decrease in the hydrodynamic radius of the polymer after PEGylation. Using
light scattering, we characterized the starting copolymer (MmLs = 83,200, PDI =
1.20) and PEG-grafted copolymer (MmLs = 156,000, PDI = 1.21) which confirmed
the stability of the polymer during “click” PEGylation. Thus, the combined results
from these control experiments ruled out backbone degradation during the “click”
PEGylation of propargyl glycolide homopolymer and copolymers, and also point
to interesting solvent-induced changes in the size of the PEGylated polymer.
DiEG-grafted and DiEGlalkyl mixed—grafted polylactides and their
thermoresponsive properties. 1-(2-Azidoethoxy)-2-(2-methoxyethoxy)ethane
(DiEG-azide) was synthesized by the same procedure described for the
synthesis of 0,00-PEG550 monomethyl ether azide. Recent reports demonstrate
117
that anchoring pendant oligo(ethylene gylcol) groups onto hydrophobic polymer
backbones can lead to water-soluble polymers that have lower critical solution
temperatures (LCSTs) in an easily accessible temperature range, and that the
LCST can be tuned by changing the PEG segment length.99'"5'122 As described
in Chapter 3, we found that the same design rule holds for polylactides. However,
the synthesis of the thermoresponsive polylactides was rather difficult. Having
devised a simple route to PPGL, click PEGylation of PPGL should provide easy
access to thermoresponsive polylactides. From preliminary experiments using
several oligo(ethylene glycol) azides, we found that the PEG-grafted polymer is
water soluble (no cloud point) over the entire 0 to 100 °C range when there are
three or more ethylene oxide units in the side chain. We did observe a cloud
point for the DiEG-grafted polymer at ~ 80 °C, which is too high for biomedical
applications.
Several strategies can be used to lower the LCST, including the introduction
of additional methylene spacers between the azide group and the PEG segment,
changing the w-methyl group to a higher alkyl group, using shorter PEG
segments, or by grafting a mixture of alkyl and DiEG groups to PPGL. To
minimize the synthetic complexity, we adopted the mixture of DiEG/alkyl group
strategy and carried out click chemistry using a 2:1 mixture of DiEG-azide and 1-
azidodecane. By comparing the integration from 5 4.36-4.56 with 5 4.12-4.36 in
the 1H NMR spectrum of the grafted polymer, we concluded that ~48 % of the
grafts were DiEG, which suggests that the click chemistry reaction rate for 1-
118
azidodecane is higher than for DiEG-azide. The resulting DiEG/alkyl mixed-
grafted polylactide is still water-soluble at room temperature.
30 °C
28 °C
25 °C
5 °C k
0.1 1' 1'0 100 1000 10000
Rh ("1'")
Figure 64. DLS of DiEG/alkyl-grafted PPGL (5 mg/mL in water)
To determine the cloud point, a 5 mg/mL solution of DiEG/alkyl grafted
polylactide in water was prepared and filtered through a 0.2 pm PTFE syringe
filter. The solution was transparent when the temperature was below 28 °C and
turned into cloudy when heated to 31 °C. The thermoresponsive behavior of the
polymer solution was also monitored by variable temperature dynamic light
scattering measurements. Shown in Figure 64 are the DLS results for a solution
(5 mglmL) of DiEG/alkyl grafted polylactide at different temperatures. When the
solution was heated from 5 °C to 25 °C, the average hydrodynamic radius of
119
particles in the solution remained constant at ~55 nm. Upon further heating to 28
°C, the average hydrodynamic radius slightly increased to ~8 nm, and then
dramatically increased to hundreds of nanometers at 30 °C. The magnitude of
the hydrodynamic radius at >30 °C suggests a transition from a hydrated state to
an agglomerated insoluble state.
45
40*
351
30—
25*
20“
Mass %
O I I I I
01 1 10 100 1000 10000
Rh (nm)
Figure 65. DLS of PEGylated PPGL-block-polyiactide in water
This approach to PEGylated polymers is easily extended to block copolymers.
PPGL-block-PLA (Mmepc = 38 000, PDI = 1.44, 72 mol% lactide) was PEGylated
using PEG-550 azide under the same experimental conditions as described
before. The PEG-grafted PPGL-block-PLA was isolated as a green-tinted viscous
liquid. The addition of an acetone solution of PEG-grafted PPGL-block-PLA to
120
magnetically stirred water followed by evaporation of acetone under reduced
pressure resulted in a milky microemulsion. DLS measurement taken at room
temperature for a 20 mg/mL solution (Figure 65) indicates the formation of
polymeric micelles with an average hydrodynamic radius of 23 nm.
Conclusions
The synthesis of a propargyl glycolide 3 provides a convenient entry to “click"
chemistry modification of polyglycolides. This functional monomer was
homopolymerized in a controlled fashion to yield polyglycolide with pendant
acetylene groups, and the preparation of random and block copolymers of 3 with
lactide also was successful. Click reactions using these acetylene-containing
polylactides with PEG550 azide provided PEG-grafted water soluble polylactides,
PEG-grafted random copolymers, and new amphiphilic block copolymers.
Grafting DiEG and DiEG/alkyl azide mixtures to poly(propargyl glycolide) (48%
DiEG incorporated) provides water-soluble polymers which show lower critical
solution temperatures. The approximate cloud points of DiEG and DiEG/alkyl
grafted poly(propargyl glycolide) in aqueous solutions were 80 °C and 30 °C
respectively, which were confirmed by variable temperature DLS measurements.
The use of mild click reaction conditions avoided backbone degradation and
eliminated the need to end-cap polylactides. Considering polylactide’s sensitivity
to backbone degradation, this protocol should also be applicable to the click
functionalization of other polyesters such as poly(caprolactone).
121
Experimental Section
Materials. Ethyl glyoxylate (Alfa Aesar, 50 wt % in toluene) was distilled
before use. THF was dried by passage through a column of activated alumina.
DMF was dried over activated 4A molecular sieves. Zinc (Spectrum, 20 mesh)
was treated with 2M HCI, and then washed sequentially with distilled water and
absolute ethanol and dried under vacuum at 60 °C. Propargyi bromide (Alfa
Aesar, 80 wt % in toluene), and all solvents were ACS reagent grade and used
as received from commercial suppliers.
Characterization. Polymer molecular weight were determined by gel
permeation chromatography (GPC) at 35 °C using two PLgel 10p mixed-B
columns in series, and THF as the eluting solvent at a flow rate of 1 mUmin. A
Waters 2410 differential refractometer was used as the detector, and
monodisperse polystyrene standards were used to calibrate the molecular
weights. The concentration of polymer solutions used for GPC was 1mg/ mL. 1H
NMR (300 or 500 MHz) and 13C NMR (75 or 125 MHz) spectra were acquired in
‘CDCI3 using either a Varian Gemini 300 spectrometer or a Varian UnityPlus-500
spectrometer with the residual proton signals from the solvent used as the
chemical shift standard. Mass spectral analyses were carried out on a VG Trio-1
Benchtop GC-MS. Dynamic light scattering (DLS) data were obtained using a
temperature-controlled Protein Solutions Dyna Pro-MS/X system. All samples
were filtered through a 0.2 pm Whatman PTFE syringe filter and allowed to
equilibrate in the instrument for 15 min at 25 °C before measurements were
taken that resulted in calculation of the hydrodynamic radius (R1,). The uniformity
122
of the particle sizes was determined by a monomodal curve fit, which assumes a
single particle size with a Gaussian distribution.
Synthesis of 2-hydroxy-4-pentynoic acid ethyl ester (1). Propargyi
bromide (~10 g) was added under a blanket of N2 to a 3 L round bottom flask
containing 350 mL anhydrous THF and Zn (230 g, 3.5 mol). The mixture was
stirred at room temperature for 30 min and then cooled in an ice bath. A toluene
solution of ethyl glyoxylate (51 wt %, determined by NMR, 473 g, 2.36 mol) and a
toluene solution of propargyl bromide (80 wt %, 352 g, 2.36 mol) were combined
with a mixture of 500 mL dry THF and 700 mL dry ether and added dropwise to
the strirred slurry. After the addition was complete, the mixture was stirred at 0 °C
overnight. The reaction mixture was then poured into a 4 L Erlenmeyer flask
containing 1 L of ice-cold 3M HCI. After separation of organic layer, the aqueous
layer was extracted with ether (3 x 300 mL) and the combined organic layers
were dried over MgSO4. Filtration and removal of the solvents by rotary
evaporation gave a dark blue oil, which was purified by column chromatohraphy
using silica gel with EtOAc/hexanes (30l70) as the eluent. Vacuum distillation
(50-55 °Cl100 mTorr) gave 170 g of 1 as a colorless oil (51%). 1H NMR 5 4.25
(m, 3H), 3.11 (cl, 1H, J = 6.35 Hz), 2.65 (m, 2H), 2.03 (t, 1H, J = 2.68 Hz), 1.28 (t,
3H, J = 7.20 Hz). 13C NMR 5 172.99, 78.53, 71.25, 68.64, 62.11, 24.81, 14.13.
Synthesis of 2-hydroxy-4-pentynoic acid (2). Ester 1 (170 g) was added to
800 mL distilled water and heated to reflux for three days. After cooling to room
temperature, the solution was acidified by the addition of 100 mL of concentrated
123
HCI and continuously extracted with ether for two days. The ether solution was
diluted to 1.5 L with additional ether and dried over MgSO4 for two hours. After
filtration, the solution was concentrated by rotary evaporation and dried under
vacuum to give a light brown solid, which was purified by recrystallization from
CH2CI2 at 0 °C, followed by sublimation at 58 °C and a second recrystallization
from CH2CI2 at 0 °C to give 115 g of 2 as white crystals (84%). 1H NMR 5 4.42 (t,
1H, J: 5.00 Hz), 2.75 (m, 2H), 2.10 (t, 1H, J: 2.56 Hz). 13C NMR 6 177.28,
77.97, 71.96, 68.51, 24.66. MS (m/z) 115.3 (M+1), mp 61-63 °C.
Synthesis of 3,6-di-2-propynyl-1,4-dioxane-2,5-dione (3). 2-Hydroxy-4-
pentynoic acid (2) (18 g) and p-toluenesulfonic acid monohydrate (1.5 g) were
added to a 2 L round bottom flask charged with 1.8 L of toluene. The flask was
heated to reflux for 3 days, and the water was removed azeotropically using a
Barrett trap. After cooling to room temperature, the toluene was removed by
rotary evaporation, and the residue was dissolved in 500 mL CHZCIZ, washed
with saturated NaHCO;; (3 x 150 mL) and dried over M9804. Filtration and
removal of the CH2CI2 gave the product as a light brown solid which was washed
with diethyl ether (3 x 50 mL), sublimed at 75 °C and recrystallized from toluene
to give 6.1 g 3 as white crystals (34%). 1H NMR 5 5.29 (t, J = 4.64 Hz), 5.05 (dd,
J = 7.08 Hz, J = 4.39 Hz), (1H total for the signals at 5.29 and 5.05 ppm), 2.95
(m, 2H), 2.17 (t, J = 2.56 Hz), 2.11 (t, J = 2.69 Hz), (1H total for the signals at
2.17 and 2.11 ppm). 130 NMR 6 164.26, 163.44, 76.77, 76.67, 74.82, 74.15,
73.34, 72.02, 23.94, 21.24. Anal. Calcd. for C10H804: C, 62.50; H, 4.17 Found: C,
62.80; H, 4.01. MS (m/z) 193.2 (M+1), mp 103-106 °C.
124
General procedure for bulk polymerizations. Monomer and a small
magnetic stir bar were added to a bulb prepared from 3/8 in. diameter glass
tubing. The tube was then held under vacuum (3 mTorr) for 12 hours at a room
temperature and then filled with nitrogen. A syringe was used to add catalyst
(Sn(2-ethylhexanoate)2) and initiator (BBA) solutions (~0.03 M in toluene) to the
bulb, and after careful removal of the toluene under vacuum, the bulb was sealed
under vacuum. Bulbs were immersed into an oil bath at 130 °C for the desired
period of time, with the contents stirred magnetically. At the end of the
polymerization, the bulb was removed from the bath, cooled in ice water and
opened. A portion of the polymer was analyzed by NMR for conversion. The
remaining polymer was dissolved in 011ch2, precipitated from cold methanol five
times and dried under vacuum (4 mTorr) at 40 °C for 24 hours.
Polymerization of propargyl glycolide. Propargyi glycolide (2.49 g) was
polymerized for 25 min of a [M]/[l] = 150. The conversion of monomer to polymer
calculated from 1H NMR was 90.6%. Precipitation and drying under vacuum gave
2.16 g poly(propargyl glycolide) as a light brown solid (86.7%). 1H NMR: 5 5.31-
5.46 (br, 1H), 2.79-3.03 (br m, 2H), 2.01-2.18 (br, 1H). GPC (THF): Mn = 28, 600
glmol, PDI = 1.30.
Copolymerization of propargyl glycolide and rec-lactide. A mixture of
propargyl glycolide (0.384 g, 2 mmol) and rec-lactide (3.394 g, 23.6 mmol) was
polymerized for 50 min of a [M]/[l] = 300. Precipitation and drying under vacuum
gave 3.59 g of the random copolymer as a white solid (95%). 1H NMR: 5 5.03-
5.39 (br m, 12.7H), 2.75-2.96 (br m, 2H), 1.97-2.11 (br, 1H), 1.43-1.65 (br m,
125
38.8H). GPC (THF, light scattering and refractive index detectors): Mn = 8.32 x
104 glmol, PDI = 1.20. '
Preparation of PPGL-block-polylactide. PPGL (1.0 g, Mngpc = 28,500, PDI
= 1.30) and lactide (5.0 g) were placed into a 25 mL Schlenk flask. The Schlenk
flask was then sealed with a rubber septum and held under vacuum overnight to
remove any residual water. The flask was then filled with nitrogen. After using a
syringe to add 1.21 mL of a 0.0288 M solution of Sn(2-ethylhexanoate)z in
toluene and 8 mL of anhydrous THF, the flask was placed into an oil bath at 70
°C for 10 hours and the solution was stirred magnetically. At the end of the
polymerization, the polymer was isolated by precipitation into cold methanol five
times and dried under vacuum at 45 °C overnight to give 2.8 g of the block
copolymer as a white solid. 1H NMR: 5 5.31-5.44 (br, 1H), 5.06-5.25 (br m, 2.6H),
2.80-3.02 (br m, 2H), 2.05-2.14 (br, 1H), 1.48-1.62 (br m, 8.1H). GPC (THF): Mn
= 38,000 glmol, PDI = 1.44.
General procedure for “click” functionalization. The desired amount of
acetylene functionalized polymer and three equivalents of azide (with respect to
acetylene groups) were dissolved in DMF in a Schlenk flask, and the solution
was deoxygenated by three freeze-pump-thaw cycles. After the contents were
refrozen, 5 mol % of CuSO4-5H20 crystals and 12 mol% of sodium ascorbate
powder (with respect to acetylene group) were added to the frozen mixture under
a nitrogen purge, and the flask was evacuated and backfilled with nitrogen. The
mixture was then deoxygenated by three additional freeze-pump-thaw cycles,
and then stirred at room temperature under nitrogen for 2 hours. At the end of the
126
reaction, the solids in the reaction mixture were removed by filtration and the
polymer was isolated by dialysis (MWCO = 12-14,000) in acetone/water (1:1)
mixture overnight and then dried under vacuum.
1-Azidodecane-grafted PPGL. PPGL (54 mg, Mmcpc = 35,500 glmol, PDI =
1.44) and 300 mg of 1-azidodecane were dissolved in 5 mL DMF for the click
reaction. The decane-grafted PPGL was isolated as a light green solid (133 mg,
87%). GPC (THF): Mmspc = 49,400, PDI = 1.41.
PEGS50-grafted PPGL. PPGL (100 mg) (Mmspc = 35,500 g/mol, PDI = 1.44)
and PEG-550 azide (1.72 g) were dissolved in 10 mL DMF for the click reaction.
PEG550-grafted PPGL was isolated as a light green viscous liquid (514 mg,
77%).
Poly(propargyl glycolide-co-Iactide) grafted with PEGSSO. The copolymer
(550 mg) and PEG-550 azide (990 mg) were dissolved in 20 mL DMF for the
click reaction. The product was isolated as a light green rubbery solid (650 mg,
74 %). GPC (THF, light scattering): Mn = 1.56 x 105 glmol, PDI = 1.21.
DiEG-grafted PPGL PPGL (250 mg) (Mmgpc = 35,500 glmol, PDI = 1.44) and 1-
(2-azidoethoxy)-2-(2-methoxyethoxy) ethane (1480 mg) were dissolved in 20 mL
DMF for the click reaction. The DiEG-grafted PPGL was isolated as a light green
elastomer (590 mg, 79%).
AIkyIIDiEG-grafted PPGL PPGL (122 mg) (Mmgpc = 35,500 glmol, PDI = 1.44),
1-(2-azidoethoxy)-2-(2-methoxyethoxy) ethane (480 mg, 2.6 mmol), and 1-
azidodecane (240 mg, 1.3 mmol) were dissolved in 10 mL of DMF for the click
reaction. The product was isolated as a light green elastomer (320 mg, 88%). 1H
127
NMR: 5 7.36-7.78 (br, 1H), 5.22-5.56 (br, 1H), 4.36-4.56 (br, 1H), 4.12-4.36 (br,
1.1H), 3.73-3.91(br, 1H), 0.70-0.94 (br, 1.7H).
PEGS50-grafted PPGL-block-polylactide. The block copolymer (300 mg) and
PEG-550 azide (1.78 g, 3.2 mmol) were dissolved in 20 mL DMF for the reaction.
The product was isolated as a light green viscous liquid (690 mg, 78 %).
128
Chapter 5 PEG/Alkyl-Grafted Comb Polylactides
Introduction
Aliphatic polyesters such as polylactide (PLA), polyglycolide (PGA), and
polycaprolactone (PCL) are of interest for medical and pharmaceutical
applications due to their biodegradability and biocompatibility.220 Poly(ethylene
glycol) (PEG) functionalized polyesters are of particular interest, because these
polymers are amphiphilic and resistant to protein adsorption?”222 PEG and
polyester block copolymers such as PEG-PLA and PEG-PLA-PEG are being
extensively investigated for drug delivery applications,""0‘3'22'0'2’23'224 however, the
degradation profiles of these block copolymers are dependent on their
compositional parameters and are typically irreproducible.223 Additionally, the
structural heterogeneity of these block copolymers can also lead to increasing
PLA/PEG ratios during degradation?“226 which can change the protein resistant
characteristics of particles and complicate drug release kinetics.
Trying to solve these problems, several groups have reported PEG-grafted-
polyesters and argued that their inherent structural homogeneity should lead to
predictable degradation behavior.21°'2”'227 However, these polymers often suffer
from ill-defined chemical structures, low grafting densities, backbone degradation
or high polydispersities. In some of these copolymers, the chemical nature of the
linker between PEG grafts and polymer backbone can potentially cause
compositional changes during degradation.
129
Structurally well-defined graft copolymers with hydrophilic PEG groups and
hydrophobic alkyl groups on the same polymer backbone are a new family of
amphiphilic polymers. Their structure suggests interesting possibilities for self-
assembly. For example, ultrathin films of PEG/aIkyl-grafted-polythiophene were
manipulated and processed on the nano— and micrometer scales using a self-
assembly approach,123 PEG/alkyl-grafted-poly(p-phenylene) self-organized into
fibrous aggregates in micellar surfactant solutions.1"'5'126
To avoid the problems encountered in exisiting PEG-grafled-polyesters and
develop new amphiphilic biodegradable polymers, we synthesized asymmetric
lactide monomers containing a PEG chain and linear alkyl group. Subsequent
polymerizations of these monomers provided structurally homogeneous
PEG/alkyl-grafted amphiphilic polyesters with high molecular weights. Similar to
other PEG/alkyl grafted polymers, these new polyesters should have useful
properties arising from self-assembly. Furthermore, the introduction of protected
hydroxyl groups into the PEG grafts provides opportunities for further chemical
modification after deprotection.
130
Results and Discussion
Scheme 14 shows the synthetic route to the two monomers described in this
chapter. The reaction of tri(ethyiene glycol) monomethyl ether or tri(ethyiene
glycol) monobenzyl ether with 1,6-dibromohexane generated the corresponding
PEG functionalized hexyl bromide. The competing elimination reaction was
minimized by conducting the reaction at approximately -25 °C. The reaction of
Grignard reagents generated from these PEG functionalized hexyl bromides with
diethyl oxalate at -78 °C provided the corresponding a-keto esters, with no
detectable contamination from second addition of the Grignard reagent to the
substrate. Catalytic hydrogenation of the crude keto esters at 1500 psig using Pt
on carbon yielded the a—hydroxy esters, but since purification of the esters
proved difficult, the crude o-hydroxy esters were hydrolyzed and isolated as the
o-hydroxy acids. Crystallization of the acids from ether at low temperatures gave
colorless to light brown oils in an overall yield of ~65 % from diethyl oxalate. The
1H NMR spectra of both a-hydroxy acids are shown in Figure 66, with the most
important spectral features being the methine protons, appearing as a doublet of
doublets at 4.20 ppm, and the benzylic protons of compound 2b at 4.51 ppm. To
the best of our knowledge, neither o-hydroxy acid has been previously reported.
The reaction of o-hydroxy acids with 2-bromooctadecanoyl chloride‘ml (3) in
the presence of base yielded linear dimers. But since their purification proved
difficult, the crude linear dimers were directly cyclized in refluxing acetone in the
presence of N33, yielding exclusively the rec diastereomer in low yield. The
byproducts primarily consisted of linear oligomers, which in principle, could be
131
recycled. 1H NMR spectra of both monomers are shown in Figure 67. The
doublet of doublets at 4.83 ppm from the methine protons of the 3,6-disubstituted
glycolide ring can be integrated to measure the conversion of polymerizations.
Also prominent are the benzylic protons of compound 4b at 4.51 ppm.
0
Mg/THFA
REOV‘IO/WV Br diethyl oxalat'e ,(«OVZOW/lkgov
1aR=Me 1,H2,5%Ptl
2. H20
1" R = 3" NaHC03
EtOH
Br OH
/\/\/\/\/\/\/\)\n/C' ,. RIOflOA/WOH
3 0
2a R = Me
1. Et3N 2. Et3N 2b R = 8n
ether acetone
4aR=Me
4bR=Bn
Sn(2-ethylhexanoate)2
tart-butylbenzyl alcohol
I 130°C
’7K
poly(4a) R = Me
poly(4b) R = Bn
Scheme 14. Synthesis of amphiphilic glycolide monomers
132
ITWIITTIII’
I I I I I I I I I I I I 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 66. 300 MHz 1H NMR spectra of PEG containing a-hydroxy acids
These new monomers were bulk polymerized at 130 °C using Sn(2-
ethylhexanoate)2 as the catalyst and 4-tert-butyl benzyl alcohol as the initiator,
yielding poly(4a) and poly(4b) (Scheme 14). The molar ratio of monomer,
catalyst and initiator was 250:1:1. Since the data from chapter 2 show that
substituted lactides generally polymerize slower than lactide, we used a 2 h
reaction time and achieved over 90 % conversion of monomer to polymer. The
1H NMR spectrum of poly(4a) (Figure 68) shows the expected peaks associated
with alkyl and PEG side chains plus the methine protons of the polymer
133
backbone. The spectrum of poly(4b) (Figure 68) is similar, except that the
resonance at 3.35 ppm from the terminal methoxy group in the PEG side chains
was replaced by resonances at 4.54 ppm and 7.3 ppm for the benzyl group.
11 1I JILL AMI/II
7 TT f
11111111111111111111111111111” 1111111111111'1111'11111'1'1'11111111'111'11
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 0.5
PM“
Figure 67. 500 MHz 1H NMR spectra of amphiphilic glycolide monomers
134
(CH2)6(OCH2CH2)3OCH3
O
(’0 o n
0
(0121150113
l 2,. 11.- 2,211 l
(CH2)6(OCH2CH2)3OBII
O
to o n
O
(CH2115CH3
I 51 25161.2.
IIIrTIj—II II
n .. .. e. .. .I..rq....1..
8'0' 7'5 7.0 6.5 60' '5'5' 5'0 4'5' 4'0 3'5 '3'() 2.5 2.0 1.5 1.0 0.5
IfITITIT—IIITII—IIT
ppm
Figure 68. 500 MHz 1H NMR spectra of amphiphilic polyglycolides
The GPC traces show that the molecular weight distributions of both polymers
are somewhat bimodal (Figure 69). The origins of the high molecular weight
shoulders seen in the GPC traces are not clear, but we note that the GPC traces
of the PEG-containing polymers described in Chapter 3 also showed signs of
bimodality. The molecular weight (M) of poly(4a) as measured by GPC (vs.
polystyrene standards) was 132,000 glmol which was in good agreement with
the theoretical value (136,200 glmol). The molecular weight of poly(4b) (Mn =
146,000 glmol) was also in good agreement with the theoretical value (152,300
glmol.
135
12 13 14 15 16
elution time (min)
Figure 69. GPC traces of amphiphilic polyglycolides (pink line: poly(4a); black
line: poly(4b)
0.5 w/g
DOB/(48)
poly(4b)
temperature (°C)
Figure 70. DSC heating traces of amphiphilic polylactides (second heating scan,
10 °Clmin in N2)
136
The DSC traces of both polymers showed a melt transition at ~17 °C, and a
glass transition temperature (T9) at ~ -60 °C (Figure 70). Based on our results
with alkyl-substituted polyglycolides, the melt transition can be associated with
side chain crystallization. We also found that when the side chains are longer
than 10 carbon atoms, they crystallize and the Tg from the backbone is not
detectable using DSC. Thus we assign the glass transition temperature at ~ -60
°C to the PEG segment in the side chain rather than from main chain, which was
confirmed by comparing the DSC traces of the polymer and the corresponding
monomer (not shown).
70
60~
50-
Mass %
l
l
40— .
301 l
20~
10-
1 10 100 1000
Rh (nm)
Figure 71. DLS of polymeric micelles and azobenzene loaded polymeric micelles
(5 mg/mL in water, pink line: polymer only; black line: polymer + azobenzene)
137
Using the solvent displacement method, polymeric micelles encapsulating
azobenzene can be prepared from polymer (4a) in aqueous media. Polymer (4a)
and azobenzene were dissolved in acetone and the acetone solution was added
drop-wise to stirred ice-cold water. Acetone was removed under vacuum to yield
a stable homogenous microemulsion (polymer + dye) after filtration. Shown in
Flgure 71 are the DLS results for the polymeric micelles, and azobenzene-
loaded polymeric micelles. In both systems, there are two peaks corresponding
to average hydrodynamic radii of ~20 nm and ~60 nm, respectively. The reason
for the bimodal distribution in particle size is unclear, but it may be related to the
bimodal molecular weight distribution seen in the GPC data.
1 __._
0.9 ~
0.8 -
0.7 — '
0.6 ~
0.5 ~
0.4 ~
0.3 ~
0.2 A
0.1 ~
0 I I I I
200 250 300 350 400 450
Absorbance
Wavelength (nm)
Flgure 72. UV-vis spectra of polymeric micelles, azobenzene loaded polymeric
micelles, and azobenzene in water. (black line: azobenzene; pink line: poly(4a);
blue line: poly(4a) + azobenzene)
138
Shown in Figure 72 are UV-Vis spectra of polymeric micelles, azobenzene
loaded polymeric micelles, and azobenzene in water. The “azobenzene”
spectrum shows only a small absorption peak at ~265 nm due to residual
acetone and no absorption from azobenzene, which is completely insoluble in
water. The spectrum of the polymeric micelles shows a weak absorption at ~ 260
nm from the ester group. In contrast, neither the peak from residual acetone nor
the peak from the polyester backbone is visible in the spectrum of azobenzene
loaded polymeric micelles. Instead, the spectrum is dominated by the
characteristic absorption peaks of azobenzene at ~ 230 nm and ~320 nm. This
simple experiment demonstrates the solubilization of otherwise water-insoluble
azobenzene by poly(4a), thus suggesting the potential of related polymers as
delivery vehicles for hydrophobic compounds.
Conclusions
PEG/alkyl substituted amphiphilic lactide monomers were synthesized by
condensing a PEG-containing a-hydroxy acid with an alkyl-containing o-bromo
acid chloride. The resulting AB substituted glycolide was isolated exclusively as
the rec isomer. Subsequent ring-opening polymerization of the monomers using
tert-butyl benzyl alcohol as initiator and Sn(2-ethylhexanoate)2 as catalyst yielded
novel amphiphilic polylactides capable of side chain crystallization due to their
long linear alkyl side chain. The potential application of these new amphiphilic
polylactides as drug delivery vehicles was demonstrated by encapsulation of
azobenzene in the polymeric micelles using the solvent displacement method.
139
Experimental Section
Materials THF was dried by passing the solvent through a column of
activated alumina. Compounds 1a and 2a were synthesized according to
procedure described in Chapter 3. All other chemicals were used as received.
Characterization. The molecular weights of polymers were determined by
gel permeation chromatography (GPC) at 35 °C using two PLgel 10p mixed-B
columns in series with THF as the eluting solvent at a flow rate of 1 mUmin. A
Waters 2410 differential refractometer was used as the detector, and
monodisperse polystyrene standards were used to calibrate the molecular
weights. The concentration of polymer solutions used for GPC was 1 mg/ mL. 1H
NMR (300 or 500 MHz) and 13C NMR (75 or 125 MHz) spectra were acquired in
CDCI3 using either a Varian Gemini 300 spectrometer or a Varian UnityPlus-500
spectrometer with the residual proton signals or carbon signals from the solvent
used as the chemical shift standard. Mass spectral analyses were carried out on
a VG Trio-1 Benchtop GC-MS. Dynamic light scattering (DLS) measurements
were performed with a temperature-controlled Protein Solutions Dyna Pro-MS/X
system. Samples were filtered through a 0.2 pm Whatman PTFE syringe filter
and allowed to equilibrate in the instrument for 15 min at 25 °C before taking
measurements that resulted in calculation of the hydrodynamic radius (Rh).
2-Bromooctadecanoyl chloride (3). Stearic acid (142 g, 0.5 mol, recrystallized
from ethanol) and SOCI2 (140 mL, 1.9 mol) were placed into a 500 mL round
bottom flask. The mixture was refluxed for 2 hours under nitrogen, and then
140
bromine (40 mL, 0.77 mol) was added dropwise to the solution. The mixture was
refluxed under nitrogen overnight, and then the excess reagents were removed
under vacuum at room temperature to give 187 g of 3 as a brown oil (98%). The
product was used without further purification. 1H NMR 0 4.44-4.52 (dd, 1H, J =
7.61 Hz, J = 6.59 Hz), 2.07-2.22 (m, 1H), 1.94-2.07 (m, 1H), 1.38-1.55 (br, 2H),
1.20-1.36 (br, 26H), 0.81-0.91 (t, 3H, J = 6.73 Hz). 130 NMR 5 170.11, 54.14,
34.84, 31.93, 29.69, 29.66, 29.62, 29.54, 29.40, 29.36, 29.20, 28.72, 26.84,
22.68, 14.09.
2-Hydroxy-8-{2-[2-(2-methoxyl ethoxy)-ethoxyl]-ethoxyl}-octanoic acid (2a).
Compound 1a (164 g, 0.50 mol) was dissolved in dry THF (600 mL) and stirred
with magnesium turnings (24 g, 1.0 mol) until the solution stopped boiling. The
Grignard reagent was then added dropwise under nitrogen to a 2 L round bottom
flask containing a stirred solution of diethyl oxalate (56 g, 0.38 mol) in dry THF
(300 mL) at -80 °C. After the addition was complete, the mixture was stirred for
an additional hour at -80 °C, and then quenched with 300 mL of 2M HCI. The
water layer was extracted with ether (5 x 200 mL) and the combined organic
layers were dried over MgSO4. Filtration and removal of the solvents by rotary
evaporation gave the a-keto ester as a light brown oil. After dissolving the oil in
ethanol (500 mL) and adding 1 g of 5% PVC and 15 g NaHCOa, the o-keto ester
was hydrogenated at ~1500 psig H2. When 1H NMR showed that the o-keto
ester had been consumed (the disappearance of the triplet at 2.80 ppm), the
solids were removed by filtration and the ethanol solution was concentrated by
rotary evaporation to give a colorless oil. The oil was then dissolved in ether (500
141
mL) and continuously extracted with water for a week. Removal of water by
rotary evaporation gave a light yellow oil, which was dissolved in diethyl ether
(1000 mL) and dried over M9804. Filtration, recrystallization from diethyl ether
(once at -80 °C and twice at -45 °C), and removal of residual solvent under
vacuum (20mTorr) at room temperature for 24 hours gave 76 g of compound 2a
as a colorless oil (61%). 1H NMR 5 4.20 (dd, 1H), 3.62 (m, 8H), 3.56 (m, 4H),
3.43 (t, 2H), 3.35 (s, 3H), 1.78 (m, 1H), 1.66 (m, 1H), 1.55 (p, 2H), 1.24-1.48 (br
m, 6H). 13C NMR 8 177.69, 71.77, 71.21, 70.44, 70.26, 69.97, 69.88, 33.83,
29.19, 28.78, 25.65, 24.47.
2-[2-(2-benzyloxyn ethoxy)-ethoxy]-ethanol. Benzyl chloride (165 g, 1.3 mol)
was added to a 2 L round bottom flask that had been charged with tri(ethyiene
glycol) (975 g, 6.5 mol), NaOH (80 g, 2.0 mol) and water (80 mL). The mixture
was heated at 110 °C for 36 hours, cooled to room temperature, and poured into
600 mL water. The water layer was continuously extracted with diethyl ether for
24 hours, and then the ether layer was dried over M9804 and the solvent
evaporated in vacuo. The residue was fractionally distilled under vacuum (122-
126 °Cl30 mTorr) to give 265 g of the benzyl-protected tri(ethyiene glycol) as a
colorless liquid (85%). 1H NMR: 6 7.22-7.36 (m, 5H), 4.52-4.57 (s, 2H), 3.55-3.74
(m, 12H), 2.37-2.44 (s, 1H).
1-Bromo-6-{2-[2-(2-benzyloxy-ethoxy)-ethoxy]-ethoxy}-hexane (1 b). A 3 L
round bottom flask containing dry THF (1200 mL), NaH (42 g 1.75 mol), and 1,6-
dibromohexane (900 g, 3.69 mol) was cooled to ~ -30 °C under a blanket of N2.
Tri(ethylene glycol) monobenzyl ether (210 g 0.87 mol) was dissolved in 600 mL
142
dry THF and added dropwise to the strirred slurry. After the addition was
complete, the mixture was stirred at ~ -15 °C for 24 hours and at 0 °C for 2 days.
The solids were removed by filtration, and the solvent was removed by rotary
evaporation to give a light yellow oil, which was re—dissolved in 1000 mL hexane
and washed with water (3 x 350 mL). The hexane layer was then dried over
M9804 and evaporated in vacuo. Removal of water and excess 1,6-
dibromohexane under vacuum in a 120 °C oil bath gave 340 g of the product as
a light brown oil (97%), which was used without further purification.
2-Hydroxy-8-{2-[2-(2-benzyloxy ethoxy)-ethoxy]-ethoxy}-octanoic acid (2b).
Compound 1b (333 g, 0.83 mol) was dissolved in dry THF (1200 mL) and stirred
with magnesium turnings (36 g, 2.0 mol) until the solution stopped boiling. The
Grignard reagent was then added dropwise under nitrogen to a 2 L round bottom
flask containing a stirred solution of diethyl oxalate (83 g, 0.57 mol) in dry THF
(200 mL) at -80 °C. After the addition was complete, the mixture was stirred for
an additional hour at -80 °C, and then was quenched with 300 mL of 3M HCI.
The water layer was extracted with ether (2 x 200 mL) and the combined organic
layers were dried over M9804. Filtration and removal of the solvents by rotary
evaporation gave the a-keto ester as a light brown oil. After dissolving the oil in
ethanol (1000 mL) and adding 2 g of 5% PVC and 15 g NaHCO3, the o-keto ester
was hydrogenated at ~1500 psi. When 1H NMR showed that the a-keto ester had
been consumed (disappearance of the triplet at 2.80 ppm), the solids were
removed by filtration and the ethanol solution was concentrated by rotary
evaporation to give a colorless oil. The oil was then mixed with 1 L of 2M
143
aqueous NaOH solution. The mixture was heated at reflux for four days, cooled
to room temperature, extracted with diethyl ether (3 x 200 mL, discarded), and
acidified to pH = 1 using concentrated HCI. The acidic solution was then
extracted with ether (4 x 300 mL), and the combined ether layers were dried over
M9804. Filtration, recrystallization from diethyl ether (twice at -80 °C and twice at
-45 °C) and removal of residual solvent under vacuum (20 mTorr) at room
temperature for 24 hours gave 152 g of 2b as a light yellow oil (67%). 1H NMR 8
7.21-7.33 (m, 5H), 4.52-4.56 (s, 2H), 4.13-4.20 (dd, 1H), 3.58-3.68 (m, 10H),
3.51-3.58 (m, 2H), 3.38-3.46 (t, 2H), 1.70-1.86 (m, 1H), 1.59-1.70 (m, 1H), 1.48-
1.59 (br m, 2H), 1.22-1.47 (br, 6H). 13C NMR 8 177.61, 137.92, 128.29, 127.73,
127.59, 73.12, 71.24, 70.47, 70.44, 70.40, 69.98, 69.88, 69.23, 33.80, 29.18,
28.75, 25.63, 24.41.
3-(6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)-6-Hexadecyl-
[1,4]dioxane-2,5-dione (4a). NEt3 (16.6 mL, 120 mmol) was added dropwise
under nitrogen to a 0 °C solution of 2a (10 g, 31 mmol) and 3 (19 g, 50 mmol) in
diethyl ether (250 mL). After stirring at 0 °C for 5 hours, the mixture was washed
with 2M HCI (2 x 100 mL) and dried over MgSO4. After filtration and removal of
solvent, the residual brown oil and NEta (13.8 mL, 100 mmol) were dissolved in
acetone (2500 mL) and refluxed for 16 hours. After removing the solvent by
rotary evaporation, the residue was re-dissolved in diethyl ether (500 mL),
washed with 0.5M HCI (3 x 200 mL), saturated NaHCOa (3 x 200 mL) and then
dried over MgSO4. Filtration and evaporation of the ether gave a brown oil, which
was purified by column chromatography (silica gel, 3/1 hexanes/EtOAc),
144
recrystalized five times from hexanes at 5 °C, and dried under vacuum (15
mTorr) at room temperature overnight to give 2.2 g of 4a as white crystals (12%).
1H NMR 8 4.83 (dd, 2H, J = 7.69 Hz, J = 4.27 Hz), 3.62 (m, 8H), 3.53 (m, 4H),
3.42 (t, 2H, J= 6.71 Hz), 3.35 (s, 3H), 2.07 (m, 2H), 1.92 (m, 2H), 1.60-1.40 (br,
6H), 1.40-1.20 (br, 30H), 0.85 (t, 3H). 13C NMR 8 166.92, 75.61, 75.53, 71.92,
71.23, 70.61, 70.56, 70.50, 70.05, 59.00, 31.89, 30.10, 30.01, 29.66, 29.56,
29.46, 29.41, 29.33, 29.27, 29.07, 28.85, 25.77, 24.36, 24.29, 22.66, 14.09. Anal.
Calcd. for 033H5208: C, 67.58; H, 10.58 Found: C, 67.98; H, 10.55. MS-El (m/z)
587.3 (M+1), mp 51-55 °C.
3~(6-{2-[2-(2-benzyloxy-ethoxy)-ethoxy]-ethoxy}-hexyl)-6-Hexadecyl-
[1,4]dioxane-2,5-dione (4b). N83 (20 mL, 145 mmol) was added dropwise
under nitrogen to a 0 °C solution of 2b (20 g, 50 mmol) and 3 (30 g, 79 mmol) in
diethyl ether (400 mL). After stirring at 0 °C for 5 hours, the mixture was washed
with 2M HCI (2 x 200 mL) and water (2 x 200 mL) and dried over M9804. After
filtration and removal of solvent, the residual brown oil and N33 (15 mL, 110
mmol) were dissolved in acetone (4000 mL) and refluxed for 16 hours. After
removing the solvent by rotary evaporation, the residue was re-dissolved in
diethyl ether (600 mL), washed with 0.5M HCI (3 x 200 mL) and saturated
NaHC03 (3 x 200 mL) and dried over M9804. After filtration and removal of the
ether, the brown oil was purified by column chromatography (silica gel, 4/1
hexanes/EtOAc), recrystalized five times from hexanes at 5 °C, and dried under
vacuum (15 mTorr) at room temperature overnight to give 3.2 g of 4b as white
crystals (9.7%). 1H NMR 5 7.25-7.34 (m, 5H), 4.79-4.84 (dd, 2H, J = 7.81Hz, J =
145
4.39 Hz), 4.53-4.56 (s, 2H), 3.59-3.68 (m, 10H), 3.53-3.57 (m, 2H), 3.40-3.44 (t,
2H, J = 6.71 Hz), 2.03-2.12 (m, 2H), 1.87-1.97 (m, 2H), 1.41-1.59 (br, 6H), 1.20-
1.40 (br, 30H), 0.82-0.88 (t, 3H). 13C NMR 5 166.92, 138.27, 128.34, 127.72,
127.56, 75.61, 75.52, 73.21, 71.24, 70.65, 70.64, 70.63, 70.61, 70.08, 69.42,
31.90, 30.09, 30.00, 29.67, 29.65, 29.63, 29.62, 29.58, 29.47, 29.42, 29.34,
29.28, 29.07, 28.86, 25.78, 24.36, 24.29, 22.67, 14.11. Anal. Calcd. for CagHssOaI
C, 70.69; H, 9.97 Found: C, 70.97; H, 9.90. MS-El (m/z) 663.5 (M+1), mp 51-53
°C.
General procedure for bulk polymerizations. The desired amount of
monomer was loaded into a polymerization bulb prepared from 3/8 in. diameter
glass tubing along with a magnetic stir bar. The bulb was connected to a
vacuum line and the monomer was dried under vacuum (5 mTorr) at 105 °C for
18 hours. After cooling to room temperature, a syringe was used to add toluene
solutions of catalyst (Sn(2-ethylhexanoate)2) and initiator (4-tert-butylbenzyl
alcohol) (monomerzcatalyst:initiator ratio = 2502121). The solvent was removed
under vacuum, and the bulb was flame-sealed under vacuum and immersed in
an oil bath at 130 °C for 2 hours. At the end of the polymerization, the tube was
cooled in water, opened, and portions of the sample were removed for NMR and
GPC analyses.
Poly(4a). Monomer 4a was polymerized on a 704 mg scale. The monomer
conversion determined by 1H NMR was 93%, and the molecular weight (M) from
GPC was 132,000 glmol with a PDI of 1.30. The crude product was purified by
146
precipitation into cold methanol from CHzClz five times and dried under vacuum
at 50 °C overnight to give 430 mg of poly(4a) as a viscous liquid in 61% yield.
NMR shows ~2% residual monomer in poly(4a) after precipitation. 1H NMR 8
4.96-5.18 (br, 2H), 3.58-3.70 (br m, 8H), 3.49-3.58 (br m, 4H), 3.37-3.46 (br t,
2H), 3.33-3.37 (s, 3H), 1.72-2.04 (br, 4H), 1.48-1.62 (br, 2H), 1.14-1.48 (br, 34H),
0.80-0.92 (t, 3H).
Poly(4b). Monomer 4b was polymerized on a 1.0 9 scale. The monomer
conversion determined by 1H NMR was 92%, and the molecular weight (M) from
GPC was 146,000 glmol with a PDI of 1.31. The crude product was purified by
precipitation into cold methanol from CHZClz three times and dried under vacuum
at 50 °C overnight to give 0.80 g of poly(4b) as a viscous liquid in 80% yield. 1H
NMR 8 7.21-7.34 (m, 5H), 4.94-5.18 (br, 2H), 4.50-4.58 (s, 2H), 3.63-3.70 (br m,
6H), 3.58-3.63 (br m, 4H), 3.50-3.57 (br, 2H), 3.36-3.44 (br, 2H), 1.70-2.01 (br,
4H), 1.49-1.62 (br, 2H), 1.09-1.49 (br, 34H), O.78-0.91 (t, 3H).
Preparation of polymeric micelles. Polymer (5 mg) and azobenzene (5
mg) were dissolved in 1mL acetone, and then the acetone solution was added
drop-wise over two minutes to 5 mL of ice-cold water (magnetically stirred) in a
25 mL Schlenk flask. The flask was then placed under a partial vacuum to
remove the acetone. Floating particles were removed by filtration, giving a stable
homogenous microemulsion (polymer + dye). For controls, the same procedure
was used to prepare micelles free of azobenzene (polymer only) and
azobenzene solutions free of polymer (dye only).
147
Appendicies
148
Appendix A. NMR Spectra
149
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Appendix A 1. 1” NMR spectrum of CG-o-hydroxy acid
150
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152
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153
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156
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157
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162
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164
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169
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Appendix A 21. 1” NMR spectrum of C16 d-hydroxy acid
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Appendix A 22. 13° NMR spectrum of C16 d-hydroxy acid
171
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Appendix A 24. 13° NMR spectrum of C16 dimer
173
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Appendix A 25. 1” NMR spectrum of polyCG
174
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175
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Appendix A 27.1” NMR spectrum of polyC10
176
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Appendix A 28. 1" NMR spectrum of polyC12
177
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Appendix A 30. 1” NMR spectrum of polyC16
179
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Appendix A 31. 1” NMR spectrum of MonoEG-CS bromide
180
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Appendix A 32. 13° NMR spectrum of MonoEG-CS bromide
181
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Appendix A 35. 1“ NMR spectrum of MonoEG-C6 dimer
184
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188
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Appendix A 40. 13° NMR spectrum of DiEG-C6-a-hydroxy acid
189
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190
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Appendix A 43. 1” NMR spectrum of TriEG-CG bromide
192
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193
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Appendix A 45. 1” NMR spectrum of TriEG-CS-a-hydroxy acid
194
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Appendix A 46. 13C NMR spectrum of TriEG-CB-a-hydroxy acid
195
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Appendix A 47. 1” NMR spectrum of TriEG-CG dimer
196
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Appendix A 48. ‘30 NMR spectrum of TriEG-CS dimer
197
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198
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199
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202
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Appendix A 54. 1” NMR spectrum of poly(MonoEG-C6)
203
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Appendix A 57. 1“ NMR spectrum of poly(TetraEG-CG)
206
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207
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209
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210
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211
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212
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213
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214
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215
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216
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217
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218
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219
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220
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Appendix A 73. 1“ NMR spectrum of TriEG-CG-C16 dimer
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231
Appendix B. FT-IR Spectra
232
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233
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234
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236
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Appendix B 5. FT-IR spectrum of C14 dimer
237
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Appendix B 6. FT-IR spectrum of C16 dimer
238
1500
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Appendix B 7. FT-IR spectrum of MonoEG-C6 dimer
239
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240
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241
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242
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243
500
1000
1500
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4000
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244
1500
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