Polyglycidol as a scaffold for multifunctional polyethers
Transcript of Polyglycidol as a scaffold for multifunctional polyethers
Polyglycidol as a scaffold for multifunctional
polyethers
Von der Fakultät für Mathematik, Informatik und
Naturwissenschaften der RWTH Aachen University zur
Erlangung des akademischen Grades eines Doktors der
Naturwissenschaften genehmigte Dissertation
vorgelegt von
M. Sc. RWTH
Fabian Marquardt
aus Rüdersdorf
Berichter: Universitätsprofessor Dr. Martin Möller
Universitätsprofessor Dr. Andrij Pich
Tag der mündlichen Prüfung: 23. Oktober 2018
Diese Dissertation ist auf den Internetseiten der
Universitätsbibliothek verfügbar.
I hereby declare that I have created this work completely
on my own and used no other sources or tools than the ones
listed, and that I have marked any citations accordingly.
Hiermit versichere ich, dass ich die vorliegende Arbeit
selbstständig verfasst und keine anderen als die
angegebenen Quellen und Hilfsmittel benutzt, sowie Zitate
kenntlich gemacht habe.
Aachen, October 2018
Fabian Marquardt
Contents
i
Contents
Abstract ......................................................................................................... v
Überblick ................................................................................................... vii
Acknowledgements ................................................................................. ix
Publications ............................................................................................... xi
Chapter 1
Introduction & Motivation ..................................................................... 1
1.1 Motivation ....................................................................................... 3
1.2 Scope of the thesis ......................................................................... 4
1.3 References ....................................................................................... 5
Chapter 2
From Glycidol to Functional Polyethers ............................................ 9
2.1 Glycidol – Synthesis & Usage ..................................................... 9
2.2 Polymerization of Glycidol ....................................................... 10
2.3 Functionalization of Polyglycidol ............................................ 15
2.4 References .................................................................................... 21
Chapter 3
Straightforward Synthesis of Phosphate Functionalized Linear
Polyglycidol ............................................................................................... 33
3.1 Introduction ..................................................................................... 33
Contents
ii
3.2 Experimental Section ................................................................. 34
3.3 Results and Discussion .............................................................. 38
3.4 Conclusions ................................................................................. 46
3.5 References .................................................................................... 46
Chapter 4
Novel Antibacterial Polyglycidols: Relationship between
Structure and Properties ........................................................................ 51
4.1 Introduction................................................................................. 51
4.2 Experimental Section ................................................................. 54
4.3 Results and Discussion .............................................................. 64
4.4 Conclusions ................................................................................. 76
4.5 References .................................................................................... 77
Chapter 5
Homoserine Lactone as a Structural Key Element for
Multifunctional Polyglycidols ............................................................. 83
5.1 Introduction................................................................................. 83
5.2 Experimental Section ................................................................. 85
5.3 Results and Discussion .............................................................. 88
5.4 Conclusions ................................................................................. 92
5.5 References .................................................................................... 93
Chapter 6
Light-induced Cross-linking and Post-cross-linking
Modification of Polyglycidol ............................................................... 97
6.1 Introduction................................................................................. 97
6.2 Experimental Section ................................................................. 99
6.3 Results and Discussion ............................................................ 104
6.4 Conclusions ............................................................................... 112
6.5 References .................................................................................. 113
Contents
iii
Chapter 7
Summary ................................................................................................... 119
Additional Information ....................................................................... 121
A.1 Phosphate Functionalized Polyglycidols ......................... 121
A.2 Antibacterial Polyglycidols ................................................. 126
A.3 Homoserine Lactone Functionalized Polyglycidol ........ 140
A.4 Post-cross-linking Modification ........................................ 145
List of Abbreviations ............................................................................. 151
List of Figures ......................................................................................... 153
List of Schemes ....................................................................................... 159
List of Tables ........................................................................................... 163
Curriculum Vitae .................................................................................... 165
Abstract
v
Abstract
In this thesis, various multifunctional polyglycidols are synthesized via
post-polymerization modification protocols. Every functionalized
polyglycidol is meticulously characterized by appropriate analytical
methods in regard to its degree of functionalization, molecular weight,
molecular weight distribution and purity. All syntheses are optimized
to give maximum control on the degree of functionalization, high
yields and pure products.
The introduction of pendant diethyl phosphate groups into poly-
glycidol is achieved by straightforward reaction of the hydroxymethyl
side groups with diethyl chlorophosphate. The degree of function-
alization is controlled by the ratio of hydroxymethyl groups attached
to the polyether backbone to the organophosphorus reagent. Removal
of one and both ethyl groups is accomplished by dealkylation with
sodium iodide or bromotrimethylsilane, respectively.
The synthesis of cationic/hydrophobic polyglycidols with various
structures is presented. Functional polyethers are examined in regard
to their antimicrobial properties against E. coli and S. aureus. Poly-
glycidol with statistically distributed cationic and hydrophobic groups
(cationic to hydrophobic balance 1:1) is compared to (a) polyglycidol
with a hydrophilic modification at the cationic functionality, (b)
polyglycidol with cationic as well as hydrophobic groups at every
repeating unit, and (c) polyglycidol with a cationic to hydrophobic
balance of 1:2. Structure-property relationships are presented.
The usage of bio-based building blocks for polymer synthesis is
investigated by functionalization of polyglycidol with homoserine
lactone. The resulting polyethers with lactone groups in the side chains
Abstract
vi
are converted to cationic/hydrophilic polymers by ring-opening
reaction with 3-(dimethylamino)-1-propylamine, followed by quarter-
nization with methyl iodide.
The light-induced cross-linking of functional polyglycidol and its post-
cross-linking modification are presented. Linear polyglycidol is first
functionalized with a tertiary amine in a two-step reaction. The
dimethylaminopropyl functional polyglycidol is cross-linked in an UV-
light-induced reaction, using camphorquinone as a Type II photo-
initiator. The cross-linked polyglycidol is further functionalized by
quaternization with various organoiodine compounds. Aqueous
dispersions of the cross-linked polymers are investigated in regard to
their size and zeta potential. Dried polymer films are evaluated
concerning the thermal transitions and chemical transformations.
Überblick
vii
Überblick
In dieser Arbeit werden diverse multifunktionelle Polyglycidole an-
hand polymeranaloger Reaktionsprotokolle synthetisiert. Alle funktio-
nalisierten Polyglycidole werden durch geeignete analytische Metho-
den sorgfältig in Hinblick auf ihren Grad der Funktionalisierung, ihr
Molekulargewicht, der Molekulargewichtsverteilung und ihrer Rein-
heit charakterisiert. Alle Syntheseprotokolle werden optimiert, so dass
sie maximale Kontrolle über den Grad der Funktionalisierung, hohe
Ausbeuten und reine Produkte geben.
Die Einführung von Diethylphosphatgruppen an die Polyglycidol-
hauptkette erfolgt durch Reaktion der Hydroxymethyl-Seitengruppen
des Polyglycidols mit Diethylchlorphosphat. Der Grad der Funktio-
nalisierung wird über das Verhältnis der Hydroxymethylgruppen zum
Organophosphat kontrolliert. Entfernen von einer und beiden
Ethylgruppen wird durch Dealkylierung mit Natriumiodid, respektive
Bromtrimethylsilan erreicht.
Die Synthese kationisch/hydrophob funktionalisierter Polyglycidole
mit diversen Strukturen wird präsentiert. Die funktionellen Polyether
werden hinsichtlich ihrer antimikrobiellen Eigenschaften gegen E. coli
und S. aureus untersucht. Ein Polyglycidol mit statistisch verteilten
kationischen und hydrophoben Gruppen (Verhältnis kationisch:hy-
drophob von 1:1) wird mit (a) einem Polyglycidol mit einer hydro-
philen Modifikation an der kationischen Funktionalität, (b) einem
Polyglycidol mit kationischen und hydrophoben Gruppen an jeder
Wiederholungseinheit und (c) einem Polyglycidol mit kationischen
und hydrophoben Gruppen im Verhältnis von 1:2 verglichen. Der
Einfluss der Struktur auf die Eigenschaften wird gezeigt.
Überblick
viii
Die Verwendung biobasierter Bausteine in der Polymersynthese wird
durch Funktionalisierung von Polyglycidol mit Homoserin-Lacton
untersucht. Der Polyether mit Lactongruppen in den Seitenketten wird
durch eine ringöffnende Reaktion mit 3-Amiopropyldimethylamin
und anschließender Quaternisierung mit Methyliodid in ein katio-
nisch/hydrophiles Polymer umgewandelt.
Die lichtinduzierte Vernetzung und anschließende chemische Modifi-
kation von funktionalisiertem Polyglycidol wird präsentiert. Lineares
Polyglycidol wird zuerst in einer Zweistufenreaktion mit einem tertiä-
ren Amin funktionalisiert. Das 3-Dimethylaminopropyl funktionelle
Polyglycidol wird unter Verwendung von Campherchinon als Typ-II-
Photoiniator in einer UV-lichtinduzierten Reaktion vernetzt. Das
vernetzte Polyglycidol wird durch Quaternisierung mit verschiedenen
Organoiod-Verbindungen weiter funktionalisiert. Wässrige Dispersio-
nen der vernetzten Polymere werden hinsichtlich Größe und Zeta-
potential untersucht. Getrocknete Polymerfilme werden in Bezug auf
ihre thermischen Übergange, sowie ihrer chemischen Umwandlung
evaluiert.
Acknowledgements
ix
Acknowledgements
The present work was accomplished at the Institute for Technical and
Macromolecular Chemistry and the DWI - Leibniz Institute for Inter-
active Materials from January 2014 to February 2018 under the
supervision of Prof. Dr. Martin Möller. I want to thank Prof. Dr.
Martin Möller for the opportunity to be a part of his research group
and the possibility to work on an interesting research topic. Great
thanks go to my subgroup leader Dr. Helmut Keul, who taught me a
lot about polymer chemistry, beginning from when he first supervised
me during my Master thesis. Though our work approaches differ, I
enjoyed working with him and having him as a companion on the
journey to a successful PhD thesis. Next, I want to thank Dr. Jens
Köhler, my lab partner for sparking my interest in polymer chemistry
during one of the research works I did for him during my studies and
all the fruitful discussions and fun that followed. I also thank my other
fellow colleagues for making my stay at the institute a pleasant one.
Special thanks go to Rainer Haas, the gear that keeps the chroma-
tography running, for all the measurements he did.
I also want to thank all co-authors that contributed to my publications.
Thanks to Cornelia Stöcker and Justin Lange for supporting me with
their manpower during their research works. Thank you to Dr.
Elisabeth Heine and Rita Gartzen for the performance and evaluation
of antimicrobial measurements and the fruitful discussions that
followed. Thanks to Dr. Michael Bruns for the performance and
evaluation of XPS measurements. Thanks to Dr. Walter Tillmann for
the IR spectroscopy measurements. Special thanks to Prof. Yusuf
Acknowledgements
x
Yagci for the inspiration to develop the synthetic protocol presented
in chapter 6.
Besonderer Dank gilt meiner Familie, die mich immer unterstützt hat
und mir die Freiheit gegeben hat, alles in meinem Leben so zu
gestalten, wie ich es für richtig halte.
Publications
xi
Publications
Parts of this thesis are published and have been presented at
conferences.
Publications
1. Marquardt, F.; Keul, H.; Möller, M. Straightforward synthesis
of phosphate functionalized linear polyglycidol, Eur. Polym. J.
2015, 69, 319–327. (see Chapter 3)
2. Marquardt, F.; Stöcker, C.; Gartzen, R.; Heine, E.; Keul, H.;
Möller M. Novel Antibacterial Polyglycidols: Relationship
between Structure and Properties, Polymers 2018, 10, 96. (see
Chapter 4)
3. Marquardt, F.; Mommer, S.; Lange, J.; Jeschenko, P. M.;
Keul, H., Möller, M. Homoserine Lactone as a Structural Key
Element for the Synthesis of Multifunctional Polymers,
Polymers 2017, 9, 130. (see Chapter 5)
4. Marquardt, F.; Bruns, M.; Keul, H.; Yagci, Y.; Möller, M.
Light-induced cross-linking and post-cross-linking
modification of polyglycidol, Chem. Commun. 2018, 54, 1647.
(see Chapter 6)
Publications
xii
Poster Presentations
1. Ring-Opening of D,L-Homocysteine Thiolactone Functionalized
Polyglycidols: Adjustment of Antimicrobial Properties, Marquardt,
F.; Stöcker, C.; Keul, H.; Heine, E.; Möller M., Warwick
Polymer Conference 2016, Warwick (United Kingdom).
2. Homoserine lactone: A structural key element for multifunctional
polymers, Marquardt, F.; Keul, H.; Möller M., Brightlands
Rolduc Polymer Conference 2017, Kerkrade (Netherlands).
Chapter 1
1
Chapter 1
Introduction & Motivation
In 1600 B.C. ancient Mesoamericans were producing natural rubber
by harvesting latex from the Panama rubber tree (Castilla elastica) and
processing it with liquid extracted from the tropical white morning-
glory (Ipomoea alba).1 3500 years later Baekeland presented the first fully
synthetic resin (Bakelite, a phenol formaldehyde resin) by poly-
condensation of phenol with formaldehyde under acidic conditions.2
This milestone and Staudinger’s groundbreaking work on the theory
of polymerization3 paved the way for the large-scale industrial
production of polymers in the 1950s. Today, life without synthetic
polymers and the respective products seems unthinkable, emphasized
by an increase in polymer production from 1.5 Mt in 1950 to ~322 Mt
in 2015.4 The most commonly produced polymers are polyethylene
(PE) and polypropylene (PP).4 The field of application of PE is
dependent on its degree of crystallinity.5 Low-density PE is used in,
e.g. reusable bags, trays and containers and food packaging, while high-
density PE is used as a material for toys, housewares, shampoo bottles,
or pipes. PP is used as a material for food packaging, pipes and
automotive parts.6 Other polymers, such as polyvinyl chloride (PVC)7
are used in construction, polyethylene terephthalate (PET) is used as a
material for bottles8, and polystyrene (PS) is processed to plastic cups,
egg trays and other packaging material.9 These commodity polymers
account for ~90% of the global demand on plastics (Table 1.1).10
Chapter 1
2
Table 1.1: Industrially processed polymers, their abbreviation and fields of
application.
Polymer Field of application
Polyethylene
(PE)
Low density PE: reusable bags, trays and containers;
agricultural films; food packaging films; cable
sheathing
High density PE: toys; shampoo bottles; milk
bottles; housewares; pipes
Polypropylene
(PP)
Food packaging; snack wrappers; living hinges;
pipes; ropes; centrifuge tubes; automotive parts
Polyvinyl chloride
(PVC)
Window profiles; pipes; flooring; roof sheeting;
cable insulation; pleather; slip-proof surfaces
Polyethylene
terephthalate
(PET)
Bottles for carbonated drinks, juices, cleaners, etc.;
textile fibers; carrier foils; vascular implants
Polystyrene
(PS)
Plastic cups; egg trays; packaging material;
disposable cutlery; insulation; model making
Monomers used in the synthesis of these polymers are derived from
fossil hydrocarbons and the resulting materials lack specialization, due
to the absence of functional groups and/or the difficulty of post-
polymerization functionalization.11 In contrast to synthetic polymers,
natural polymers, such as polysaccharides, nucleic acids and peptides,
are multifunctional and exhibit highly specialized properties.12
Polysaccharides are derived from monosaccharides by enzyme
catalyzed polymerization, resulting in polydisperse polymers with
various potential complex structures based on the functionality of the
monomer.13,14 Peptides and nucleic acids are sequentially polymerized,
yielding monodisperse linear polymers with specific monomer
sequences.15-19 The similarity between all these biopolymers is the
possibility to create a vast amount of structures with very specific
applications from a limited number of building blocks.20 In the case of
peptides, the polymer is derived from the sequence-controlled
polymerization of amino acids, under the formation of peptide bonds.
The properties of the formed polyamide are dependent on the
functionality of each amino acid incorporated.21 In nature peptides are
Chapter 1
3
part of diverse, complex structures, such as enzymes, hormones,
antibodies, toxins, collagen, keratin, spider silk, etc.
As nature has always been an inspiration for scientists in the
development of systems in polymer and materials science, mimicking
of biopolymers has been the objective of extensive research.22,23
Poly(meth-)acrylates are an interesting scaffold for the synthesis of
functional polymers and thus, a promising candidate as a platform for
biomimetic polymers.24 Polymethacrylates have been functionalized
with catechol moieties to mimic the adhesion mechanism of mussels.25
The incorporation of di- and monohydroxyl catechols resulted in a
simple coatability of the biomimetic polymer on various surfaces and
excellent antifouling properties. Imitation of antimicrobial peptides
was achieved by functionalization of poly(meth-)acrylates with cat-
ionic and hydrophobic moieties.26,27 The prepared polymers exhibited
excellent antimicrobial behavior against bacterial and fungal biofilms.
Nature has demonstrated, how different functionalities and substi-
tution patterns in α-polyamides lead to a variety of complex, special-
ized properties. Based on this concept synthetic chemists have shown
that the properties of poly(meth-)acrylates can be tailored by intro-
duction of functional groups in the side chains. As an alternative to
these polymers, this thesis wants to evaluate the influence of a flexible,
hydrophilic polyether main chain on the properties of the functional
polymer.
1.1 Motivation
In recent years, the field of functional polymers has received an
increased interest due to the enhanced demands of modern
technology.28 Polymer scaffolds that allow the introduction of multiple
functionalities to the same polymer backbone are promising
candidates for the preparation of complex, specialized materials. The
motivation for this thesis is the presentation of polyglycidol as a
suitable, future-oriented alternative to poly(meth-)acrylates. Poly-
glycidol is a highly functionalized polyether with a hydroxyl func-
tionality in every repeating unit, allowing various post-polymerization
modifications.29 It is soluble in aqueous media, non-toxic towards cells
and licensed by the Food & Drug Administration (FDA).30,31 Addi-
Chapter 1
4
tionally, the glycidol monomer can be synthesized from renewable
resources.32 Enhancement of the polyglycidol library may prove as an
important stepping stone towards more complex, specialized
polymers.
1.2 Scope of the thesis
In chapter 2 a literature review of polyglycidol is presented. The
synthesis and various polymerization techniques of the glycidol
monomer, as well as the various post-polymerization functionalization
protocols of polyglycidol are discussed.
Phosphorus-containing compounds are of great interest for the
preparation and functionalization of polymers, as they show attractive
properties for the biomedical field. In chapter 3 polyglycidol is
functionalized with pendant diethyl phosphate groups in a controlled
manner. Removal of one and both ethyl groups is presented to prepare
phosphate diester and phosphate monoester functionalities,
respectively.
Polymers with pendant cationic and hydrophobic functionalities
exhibit antimicrobial properties and are an attractive alternative to low
molecular weight biocides, due to an enhanced chemical stability.
Chapter 4 shows the introduction of cationic and hydrophobic groups
into polyglycidol by various post-polymerization functionalization
protocols. Specific microstructures are prepared and compared in
regard to their antibacterial activity against the Gram-negative E. coli
and the Gram-positive S. aureus.
The utilization of bio-based materials in polymers is a huge milestone
on the way to a greener chemistry. In chapter 5 homoserine lactone
is established as a bio-based building block for the preparation of
multifunctional polyglycidols. The homoserine lactone ring is first
attached to the side chain, opened by a primary amine, and sub-
sequently quaternized to prepare cationic/hydrophilic polyethers.
Chapter 1
5
Chapter 6 introduces the concept of post-cross-linking modification.
Polyglycidol is first functionalized with a 3-(dimethylamino)-1-propyl-
amine in a two-step reaction. The functional polyether is then cross-
linked in a light-induced reaction, using camphorquinone as a Type II
photoinitiator. Further functionalization of the cross-linked poly-
glycidol with various organoiodine compounds yields cationic/hydro-
phobic, cationic/hydrophilic and cationic/superhydrophobic poly-
ether particles.
1.3 References
1. Hosler, D.; Burkett, S.L.; Tarkanian, M.J. Prehistoric
polymers: Rubber processing in ancient mesoamerica. Science
1999, 284, 1988.
2. Baekeland, L.H. The synthesis, constitution, and uses of
bakelite. J. Ind. Eng. Chem. 1909, 1, 149.
3. Staudinger, H. Über Polymerisation. Berichte d. D. Chem.
Gesellschaft 1920, 53, 1073.
4. PlasticsEurope. Plastic - the facts 2016: An analysis of
european plastics production, demand and waste data. 2016.
5. Vasile, C.; Pascu, M. Practical guide to polyethylene. Rapra
Technology Limited: Shawbury, Shrewsbury, Shropshire,
UK, 2005.
6. Maddah, H.A. Polypropylene as a promising plastic: A
review. American Journal of Polymer Science 2016, 6, 1.
7. Patrick, S.G. Practical guide to polyvinyl chloride. Rapra
Technology Limited: Shawbury, Shrewsbury, Shropshire,
UK, 2005.
8. ILSI Europe Report on packaging materials: 1. Polyethylene
terephthalate (PET) for food packaging applications.
Brussels, Belgium, 2000.
9. Gurman, J.L.; Baier, L.; Levin, B.C. Polystyrenes: A review
of the literature on the products of thermal decomposition
and toxicity. Fire and Materials 1987, 11, 109.
10. Andrady, A.L.; Neal, M.A. Applications and societal benefits
of plastics. Philos. Trans. R. Soc. B 2009, 364, 1977.
Chapter 1
6
11. Geyer, R.; Jambeck, J.R.; Law, K.L. Production, use, and fate
of all plastics ever made. Sci. Adv. 2017, 3, e1700782.
12. Hardy, J.G.; Römer, L.M.; Scheibel, T.R. Polymeric materials
based on silk proteins. Polymer 2008, 49, 4309.
13. Woods, R.J. Three-dimensional structures of oligo-
saccharides. Curr. Opin. Struct. Biol. 1995, 5, 591.
14. Aravamudhan, A.; Ramos, D.M.; Nada, A.A.; Kumbar, S.G.
Natural polymers. In Natural and synthetic biomedical polymers,
2014; pp 67.
15. Saxena, T.; Karumbaiah, L.; Valmikinathan, C.M. Proteins
and poly(amino acids). In Natural and synthetic biomedical
polymers, 2014; pp 43.
16. Weber, A.L.; Miller, S.L. Reasons for the occurrence of the
twenty coded protein amino acids. J. Mol. Evol. 1981, 17, 273.
17. Dickerson, R.; Drew, H.; Conner, B.; Wing, R.; Fratini, A.;
Kopka, M. The anatomy of a-, b-, and z-DNA. Science 1982,
216, 475.
18. Brautigam, C.A.; Steitz, T.A. Structural and functional
insights provided by crystal structures of DNA polymerases
and their substrate complexes. Curr. Opin. Struct. Biol. 1998, 8,
54.
19. McCulloch, S.D.; Kunkel, T.A. The fidelity of DNA
synthesis by eukaryotic replicative and translesion synthesis
polymerases. Cell Res. 2008, 18, 148.
20. Lutz, J.F.; Ouchi, M.; Liu, D.R.; Sawamoto, M. Sequence-
controlled polymers. Science 2013, 341, 1238149.
21. Berg, J.M.; Tymoczko, J.L.; Stryer, L. Chapter 3. Protein
structure and function. In Biochemistry, W. H. Freeman: New
York, 2002.
22. Hwang, J.; Jeong, Y.; Park, J.M.; Lee, K.H.; Hong, J.W.; Choi,
J. Biomimetics: Forecasting the future of science,
engineering, and medicine. Int. J. Nanomedicine 2015, 10, 5701.
23. Carlini, A.S.; Adamiak, L.; Gianneschi, N.C. Biosynthetic po-
lymers as functional materials. Macromolecules 2016, 49, 4379.
24. Coessens, V.; Pintauer, T.; Matyjaszewski, K. Functional
polymers by atom transfer radical polymerization. Prog. Polym.
Sci. 2001, 26, 337.
Chapter 1
7
25. Duan, J.; Wu, W.; Wei, Z.; Zhu, D.; Tu, H.; Zhang, A.
Synthesis of functional catechols as monomers of mussel-
inspired biomimetic polymers. Green Chem. 2018.
26. Qu, Y.; Locock, K.; Verma-Gaur, J.; Hay, I.D.; Meagher, L.;
Traven, A. Searching for new strategies against polymicrobial
biofilm infections: Guanylated polymethacrylates kill mixed
fungal/bacterial biofilms. J. Antimicrob. Chemother. 2016, 71,
413.
27. Kurtz, C.; Neenan, T.X. Antimicrobial compositions and
methods. US 6482402 B1, 2002.
28. Braun, D.; Cherdron, H.; Rehahn, M.; Ritter, H.; Voit, B.
Functional polymers. In Polymer synthesis: Theory and practice,
2013; pp 375.
29. Thomas, A.; Müller, S.S.; Frey, H. Beyond poly(ethylene
glycol): Linear polyglycerol as a multifunctional polyether for
biomedical and pharmaceutical applications. Biomacromolecules
2014, 15, 1935.
30. Frey, H.; Haag, R. Dendritic polyglycerol: A new versatile
biocompatible material. Rev. Mol. Biotechnol. 2002, 90, 257.
31. Kainthan, R.K.; Janzen, J.; Levin, E.; Devine, D.V.; Brooks,
D.E. Biocompatibility testing of branched and linear
polyglycidol. Biomacromolecules 2006, 7, 703.
32. Sutter, M.; Silva, E.D.; Duguet, N.; Raoul, Y.; Metay, E.;
Lemaire, M. Glycerol ether synthesis: A bench test for green
chemistry concepts and technologies. Chem. Rev. 2015, 115,
8609.
8
Chapter 2
9
Chapter 2
From Glycidol to Functional
Polyethers
Polyglycidol was first mentioned by Richter in 1877 as an unwanted
product in the synthesis of glycidol from epichlorohydrin.1 Since then,
many protocols for the controlled polymerization of glycidol have
been reported to receive polyglycidol in various topologies and molar
masses.2 This chapter gives a brief overview on the synthesis and
different polymerization techniques of glycidol, and the diverse
possibilities to functionalize polyglycidol.
2.1 Glycidol – Synthesis & Usage
Glycidol or 2,3-epoxypropan-1-ol is an organic compound that is used
in the syntheses of functional epoxides, glycidyl ethers, esters and
amines.3 It is also used as a demulsifier and as a stabilizer for natural
oils and vinyl polymers.4,5 Glycidol contains both an epoxide and a
hydroxyl functional group and can be synthesized via various
protocols. Industrial production is based on the hydrolysis of
epichlorohydrin under alkaline conditions6 (Scheme 2.1a) or the
epoxidation of allyl alcohol with hydrogen peroxide and a
homogenous or heterogeneous catalyst based on titanium7, tungsten8
or vanadium9 (Scheme 2.1b). Non-racemic glycidols (optically pure
(R)- and (S)-glycidols) can be prepared by asymmetric epoxidation
Chapter 2
10
using titanium(IV) isopropoxide, diisopropyl tartrate and cumene
peroxide.10,11 However, the endeavor of a “greener” chemistry, and
thus, metal-free and environmentally friendly processes has led to a
new approach in the synthesis of glycidol by decarboxylation of
glycerol carbonate (glycerol carbonate prepared from glycerol and
carbon dioxide) in the presence of ionic liquids (Scheme 2.1c).12-14
Scheme 2.1: Synthesis of glycidol by (a) hydrolysis of epichlorohydrin,
(b) epoxidation of allyl alcohol, and (c) decarboxylation of glycerol
carbonate.
2.2 Polymerization of Glycidol
Glycidol is used as monomer in the preparation of polyglycidol (PG),
a highly functionalized polyether with a hydroxyl group in every
repeating unit.15 The polymer is soluble in aqueous media, non-toxic,
biocompatible and licensed by the Food and Drug Administration
(FDA).16,17 Synthesis of polyglycidol is possible by means of anionic,
cationic, enzymatic, and coordination type polymerization, yielding
linear, star-shaped, and branched polyethers in various molecular
masses.
2.2.1 Anionic polymerization
The anionic ring-opening polymerization of epoxides is based on the
initiation step by formation of an alkoxide species from the corres-
ponding alcohol and the following propagation step by nucleophilic
attack on the epoxide.18 In case of glycidol the initiation step is
composed of the deprotonation of a mono- or polyfunctional alcohol
by an alkali metal alkoxide. The reactivity of the formed initiator
mainly depends on the nature of the counter-ion. The initiator acts as
a nucleophile and attacks the epoxide ring of the glycidol, cleaving the
Chapter 2
11
CH2―O bond, and generating a secondary alkoxide unit which can
propagate the chain growth to form polyglycidol. However, the pri-
mary hydroxyl group facilitates an intramolecular transfer reaction
with the secondary alkoxide, leading to two possible propagation sites,
and thus, the formation of branched polyglycidols.19,20
Scheme 2.2: Mechanism of the anionic ring-opening polymerization of
glycidol.
Nevertheless, the intramolecular transfer does not occur on every
hydroxyl functionality so that primary as well as secondary hydroxyl
groups are found in the polymer chains of the branched polyether
(Scheme 2.3). Branched polyglycidols have been successfully syn-
thesized with molecular weights of Mn ≤ 6000 g mol–1 and narrow
molecular weight distributions.21 To control the molecular weight and
polydispersity of the branched polyglycidol Sunder et al. used a partially
deprotonated trifunctional initiator and the slow monomer addition
technique.22,23 The use of a low molecular weight polyglycidol as
macroinitiator allowed the preparation of branched polyglycidols with
Mn ≤ 24,000 g mol–1 under controlled conditions, due to a higher
concentration of active reaction sides.24
Non-branched polyglycidols are received by inhibition of the intra-
molecular transfer reaction. Therefore, the hydroxyl group of the
glycidol is functionalized with a suitable protecting group prior to poly-
merization. Common protected monomers include ethoxyethyl glyci-
dyl ether (EEGE), tert-butyl glycidyl ether (tBuGE) and allyl glycidyl
ether (AGE) (Scheme 2.4a).25 EEGE is prepared by reaction of gly-
cidol with ethyl vinyl ether, using p-toluenesulfonic acid as a catalyst.26
Chapter 2
12
Scheme 2.3: Synthesis of branched polyglycidol with primary (blue) and
secondary (red) hydroxyl groups along the polymer chain.
Though, tBuGE and AGE are commercially available, EEGE is
predominantly used in the synthesis of linear polyglycidol, because the
acetal group can be easily removed after polymerization under mild
acidic conditions (Scheme 2.4b). Recently, tetrahydropyranyl glycidyl
ether (TGE) has been discussed as an alternative to EEGE
(Scheme 2.4a).27 The first successful polymerization of EEGE was
reported by Taton et al.28 Under usage of cesium hydroxide as initiator
in bulk they received poly(ethoxyethyl glycidyl ether) (P(EEGE)) with
molecular weights of Mn = ~30,000 g mol–1 and a broad molecular
weight distribution (Ð = ~1.5). The implementation of different
initiator systems, such as cesium and potassium alkoxides29,30 or sec-
BuLi/phosphazene base t-BuP431, allowed the synthesis of poly-
glycidols with narrow molecular weight distributions. However, higher
molecular weight polyglycidols could not be prepared by usage of alkali
metal based initiators. The basicity of the propagating alkoxide at the
chain end causes proton abstraction from the monomer, leading to the
formation of allylic end groups and limiting the molecular weight.32
Gervais et al. presented the anionic polymerization of EEGE in the
presence of a binary initiating system, containing tetraoctylammonium
bromide as initiator and an excess of triisobutylaluminum (iBu3-Al).33
The reaction mechanism comprises (i) complexation of the initiator by
iBu3-Al, and (ii) nucleophilic activation of the oxirane by complexation
with iBu3-Al.34 The reaction protocol allows the polymerization of
EEGE at low temperatures, yielding PG with a molecular weight of
Mn ≤ 85,000 g mol–1 with a narrow molecular weight distribution
(Ð ≥ 1.03).
Chapter 2
13
Scheme 2.4: a) Protected glycidol monomers used in the polymerization of
polyglycidol. b) Synthesis of linear polyglycidol from EEGE using potassium
alkoxide as initiator.
The controlled polymerization of EEGE is not limited to the pre-
paration of linear polyglycidol. Changing the initiator system from a
monofunctional to a multifunctional alkoxide allows the synthesis of
star-shaped polyglycidols. Hans et al. prepared 4-arm-star shaped poly-
glycidol with Mn = ~2300 g mol–1, using the tetrafunctional di-
(trimethylolpropane) and potassium methanolate as initiator system.35
This concept was transferred by Schmitz et al. to synthesize 3-arm- and
6-arm-star shaped polyglycidols from trifunctional (trimethylol-
propane) and hexafunctional (dipentaerythritol) initiators.36
2.2.2 Cationic polymerization
The first synthesis of branched polyglycidol copolymers by cationic
copolymerization with 1,3-dioxolane was reported by Goethals et al.37
In general, the cationic polymerization of glycidol is carried out by
initiation with Lewis acids (SnCl4, BF3 · Et2O) or Brønsted acids (triflic
acid, trifluoroacetic acid). Dependent on the initiator the polyether is
either formed by an activated monomer, or active chain-end mecha-
nism (Scheme 2.5).38 Brønsted acids facilitate the active chain-end
mechanism. The protonation of the monomer leads to a positive
partial charge in the methylene and methine groups of the glycidol.
Chapter 2
14
Reaction with a second monomer causes scission in the first oxirane
unit and the formation of primary hydroxyl groups in the resulting
polyglycidol.39 Lewis acids promote the activated monomer mecha-
nism, causing the addition of protonated monomer to the hydroxyl
group of the glycidol. This addition does not only form primary, but
also secondary hydroxyl groups in the polyglycidol side chains. Since
the activated monomer can add to any hydroxyl group in the polyether,
branching is unavoidable.
As an approach towards a “greener” chemistry Mohammadifar et al.
presented the cationic polymerization of glycidol with citric acid.
Starting from citric acid as a trifunctional core, branched polyglycidols
with narrow molecular weight distributions were prepared at ambient
conditions.40 Recently, Dadkhah et al. have described the use of
ascorbic acid as an activator for the cationic polymerization of glycidol
to prepare low molecular weight, hyperbranched polyglycidols.41
Scheme 2.5: Cationic polymerization of glycidol by active chain-end
mechanism (top) and activated monomer mechanism (bottom).
2.2.3 Coordination polymerization
Anionic ring-opening polymerization is the most commonly used
protocol for the synthesis of polyglycidol. Though, the control during
this process is high, the degree of polymerization and the resulting
molecular weight are limited. Coordination polymerization with
organometallic catalysts allows the synthesis of high molecular weight
Chapter 2
15
linear polyglycidol by polymerization of EEGE.42 Haout et al.
introduced diethylzinc/water as an initiating system which has since
then successfully been used in the preparation of polyglycidols with
molecular weights of up to Mn = 1,450,000 g mol–1.43,44 However, the
coordination polymerization of EEGE is not well-controlled, leading
to high molecular weight distributions (Ð = 1.8).45
2.2.4 Enzymatic polymerization
Studies on the enzymatic polymerization of glycidol were reported by
Soeda et al.46,47 Using various lipase enzymes as biocatalysts, poly-
glycidols with molecular weights of Mn = 900 g mol–1 were prepared.
Nevertheless, the low reaction rates and the occurrence of macrocycle
formation demand further work to make this protocol a viable type of
polymerization for the formation of polyethers from glycidol.
2.3 Functionalization of Polyglycidol
The introduction of functional groups into polyglycidol is possible
before or after the polymerization. Pre-polymerization protocols
include the usage of functional glycidyl ether monomers25,48-55, or the
-end-functionalization by utilization of suitable initiator systems.33,56-
64 Post-polymerization functionalization comprises the -end-
functionalization, and the backbone functionalization by reaction with
the pendant hydroxyl groups in every repeating unit of the
polyglycidol. Due to the focus of this work, only post-polymerization
functionalization techniques will be described. Further information on
pre-polymerization functionalization protocols can be found in the
respective references.
-End-functionalization of polyglycidol
-End-functionalization of polyglycidol comprises the reaction of end
hydroxyl group(s) with an appropriate reactant. In hyperbranched
polyglycidols multiple hydroxyl groups are present at the surface which
can be targeted by post-polymerization functionalization protocols
(Scheme 2.6). The synthesis of -end-functionalized linear
polyglycidol is realized by reaction of the end hydroxyl group of
Chapter 2
16
P(EEGE) after polymerization, followed by removal of the acetal
groups under acidic conditions. Various protocols for successful end-
capping have been presented.
End-functionalization of hyperbranched polyglycidol with tertiary
amine groups was presented by Salazar et al.65 The hydroxyl groups
were reacted with tosyl chloride under alkaline conditions, followed by
reaction with diethylamine or di-n-pentylamine, respectively, to
prepare tertiary amine-terminated polyglycidols (Scheme 2.6, A). The
synthesized polyethers were successfully used as ligands in the copper-
catalyzed oxidative coupling of terminal acetylenes. Schubert et al.
reported the functionalization with methyl and trimethylsilyl moities.66
Methyl groups were introduced by methylation of the hydroxyl func-
tionalities with methyl iodide (Scheme 2.6, B).67,68 Silylation was per-
formed using hexamethyldisilazane and catalyzed with iodine (Scheme
2.6, C).69 Both functionalization techniques were used to study the
effect of hydrogen bonding in hyperbranched polyglycidols in a broad
molecular weight range on the melt rheology. Türk et al. described the
preparation of polyanionic polyglycidols as new heparin analogues.70
Sulfate and carboxylate moieties were introduced by reaction with a
sulfur trioxide pyridine complex (Scheme 2.6, D), or sodium chloro-
acetate (Scheme 2.6, E), respectively. Hyperbranched polyglycidols,
carrying anionic functionalities were also reported by Weinhart et al.71
The functionalization was performed by 1,3-dipolar cycloaddition of
azide-terminated polyglycidol with anionic sulfonate, carboxylate,
phosphonate, and bisphosphonate alkynes (Scheme 2.6, I).72 Additio-
nally, phosphate functionalization was achieved by reaction with
chloro diethylphosphite, followed by in situ oxidation and ethyl ester
hydrolysis (Scheme 2.6, F). All polyanions were examined in regard to
their L-selectin inhibition. Yu et al. used the 1,3-dipolar cycloaddition
to react choline phosphate and phosphatidyl choline alkynes with azide
functionalized polyglycidol. The prepared zwitterionic polyethers were
used as biomembrane adhesives.73 The first synthesis of azide-
terminated PG was reported by Roller et al.74 The synthetic protocol
comprised the functionalization of polyglycidol with mesyl chloride,
followed by nucleophilic substitution with sodium azide (Scheme 2.6,
G). The azide moieties could further be reacted to the corresponding
amine by reaction with triphenylphosphane (Scheme 2.6, H).
Chapter 2
17
Scheme 2.6: -End-functionalization of hyperbranched polyglycidol.
Chapter 2
18
Amine-terminated PG was functionalized with catechol groups by
Krysiak et al. to study their adsorption mechanism on titan dioxide
surfaces.75 Therefore, the catechol functionalities were introduced by
amide coupling with 3,4-dihydroxyhydrocinnamic acid in various
degrees of functionalization (Scheme 2.6, J). Branched polyglycidol
functionalized with viologen chromophores to study the photo- and
electrochromic performance were reported by Cao et al.76 Esteri-
fication with chloroacetyl chloride, followed by quaternization of 4,4’-
bipyridyl lead to polyglycidols which could repeatedly be colorized by
UV-light and bleached with oxygen (Scheme 2.6, K). Additionally, the
polyether responded with reversible color changes to pulsed electrical
stimuli. Stiriba et al. used esterification with palmitoyl chloride to
functionalize linear and hyperbranched polyglycidols.77 The amphi-
philic PGs were compared in regard to their nanocapsule formation
capabilities. Linear and star-shaped polyglycidols were functionalized
with vinyl sulfonate groups by Haamann et al.78-80 Vinyl sulfonate
groups were introduced by reaction with 2-chloro-ethanesulfonyl
chloride. Various model reactions with primary amines confirmed the
successful functionalization.
The -end-functionalization of linear polyglycidol has been used in
the preparation of various copolymers. Mendrek et al. reported a
protocol to end-cap P(EEGE) with 2-chloropropionyl and 2-
bromopropionyl units.81 The functionalized polyethers were used as
macroinitiators for the atom transfer radical polymerization (ATRP)
of N-isopropylacrylamide. Removal of the acetal groups gave
polyglycidol-block-poly(N-isopropylacrylamide) copolymers with
controlled composition and narrow molecular weight distribution. The
end-functionalization of linear P(EEGE) with methacrylic acid
anhydride was presented by Thomas et al.82 The methacrylate
functionalized macromonomers were polymerized by ATRP and
deprotected under acidic conditions to receive poly(methacrylate)-
graft-polyglycidol copolymers. Another approach to receive meth-
acrylate containing macromonomers involves the end-capping of
linear polyglycidol with propargyl bromide, followed by 1,3-cyclo-
additon with azido hexyl methacrylate.83 Graft-copolymers were pre-
pared by radical polymerization with AIBN as initiator. Meyer et al.
used the end-capping of linear polyglycidol to introduce L-alanine as
Chapter 2
19
an endgroup.84 Therefore, P(EEGE) was first ω-end-functionalized by
anionic ring-opening reaction with glycidyl phthalimide. The
phthalimide was converted to the amine via hydrazinolysis and
subsequently reacted with L-alanine N-carboxyanhydride.
2.3.2 Backbone functionalization of polyglycidol
The backbone functionalization of polyglycidol comprises the reaction
of hydroxyl groups along the main chain with an appropriate reactant.
Various protocols have been reported to target these functional groups
randomly, or in a controlled manner.85,86
Hydroxyl groups can be esterified by reaction with a carboxylic acid.
Dworak et al. presented a method to randomly functionalize linear
polyglycidol with acetate moieties by reaction with acetic anhydride
(Scheme 2.7, A).87 The ester was introduced to hydrophobically
modify the polyglycidol and control its lower critical solution
temperature. Groll et al. used the esterification to introduce thiol
groups to the polyglycidol backbone.88 The polyglycidol was reacted
with 3,3’-dithiodipropionic acid, using DCC/DMAP as a catalyst
system, followed by reduction of the disulfide with TCEP (Scheme
2.7, B). The received thiol functionalized polyethers were used in the
preparation of nanogels to study the degradation behavior of these
gels. A protocol to convert the hydroxyl groups of the polyglycidol to
thiol groups was presented by Southan et al. (Scheme 2.7, C).89
Therefore, the polyglycidol was first esterified by reaction with tosyl
chloride. The tosylated polyether was reacted with triphenyl-
methanethiol, and deprotected under acidic conditions. Poly(ethylene
oxide)-co-polyglycidylthiol copolymers were successfully used in inkjet
printing. Erberich et al. functionalized polyglycidol with alkyne moieties
by nucleophilic substitution with propargyl bromide.25 The alkyne
functionalities were further reacted with azido sugar in a 1,3-dipolar
cycloaddition (Scheme 2.7, D). The introduction of urethane groups
to polyglycidol block-copolymers was presented by Dimitrov et al.90
The hydroxyl groups were reacted with ethyl isocyanate, using
dibutyltin dilaurate as catalyst (Scheme 2.7, E). The poly(ethyl glycidyl
carbamate) was used in a cross-linking reaction with a diacyl chloride
reagent by Utrata-Wesolek et al. to study the thermoresponsive behavior
of the received hydrogels.91 Backes et al. used the same protocol to
Chapter 2
20
synthesize amphiphilic block copolymers based on polyglycidol by
functionalization with various C12–C16 alkyl isocyanates (Scheme 2.7,
F).92 The copolymers were investigated in regard to their thermal
behavior, exhibiting three reversible thermal transitions. A different
protocol to introduce carbamates to polyglycidol was presented by
Theiler et al.93 Hydroxyl groups are reacted with phenyl chloroformate
under alkaline conditions to generate phenyl carbonates (Scheme 2.7,
G). The phenyl carbonate moieties can then act as active esters in the
nucleophilic substitution with primary amines, yielding carbamate
groups. Hydrophilic, hydrophobic and cationic amines were
introduced in the polyglycidol and examined in regard to their
antimicrobial activity. The same method was used by Ozdemir et al. in
the synthesis of polyglycidol based double-comb copolymers.94 Beezer
et al. presented a protocol for the amino-oxy functionalization of
polyglycidol (Scheme 2.7, H).95 The polyether was reacted with N-
oxyphthalimide in a Mitsonubu reaction, followed by hydrazinolysis of
the oxyphthalimide groups. The reaction protocol allowed the
introduction of the amino-oxy species in a defined ratio. Kaluzynski et
al. presented three different types of post-polymerization modifica-
tion.96 Functionalization with phosphoric acid was carried out by
reaction with phosphorus oxychloride in triethyl phosphate and
subsequent hydrolysis of the phosphorus dichloride (Scheme 2.7, I).
However, the reaction is not controllable, leading to the formation of
diesters and thus, to intra- and intermolecular cross-linking.97
Carboxylic acid groups were introduced by reaction of polyglycidol
with ethyl bromoacetate and hydrolysis under alkaline conditions
(Scheme 2.7, J). Additionally, polyglycidol was reacted with 1,3-
propane sultone to yield sulfonic acid functionalized polyethers
(Scheme 2.7, K). The functionalization of linear polyglycidol with
sulfate groups was performed by Malineni et al.98 The hydroxyl side
groups were reacted with a sulfur trioxide triethylamine complex and
the resulting poly(glycidyl sulfate) was used as part of a heparin-
mimetic copolymer (Scheme 2.7, L). Penczek et al. presented the
functionalization of polyglycidol with 2-diethyl-phosphonoethyl
acrylate.99 Dealkylation of the phosphonic ester groups gave the
corresponding phosphonic acid, while hydrolysis of the carboxylic
ester gave the carboxylic acid, allowing the simultaneous introduction
Chapter 2
21
of two functionalities (Scheme 2.7, M). The controlled addition of
phosphonic acid groups to the polyglycidol backbone was presented
by Köhler et al.100 The hydroxyl groups were reacted with diethyl vinyl
phosphonate in a base catalyzed Michael addition and subsequently
dealkylated (Scheme 2.7, N). The phosphonate functionalized
polyglycidols were used as macroinitiators in the graft-copolymeri-
zation of ε-caprolactone, leading to an enhancement of the hydrolytic
degradability of the poly(caprolactone).101-104 Additionally, phosphonic
acid and acrylate functionalized polyglycidols were prepared and
examined as UV-active adhesion promoters for a hydrogel coating on
stainless steel wires.105
Scheme 2.7: Backbone functionalization of polyglycidol.
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Chapter 2
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Chapter 2
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Chapter 2
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Chapter 2
32
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Chapter 3
33
Chapter 3
Straightforward Synthesis of
Phosphate Functionalized
Linear Polyglycidol
3.1 Introduction
Phosphorus containing compounds are of great interest for the
preparation and functionalization of polymeric materials. Thus, a
variety of polymers was synthesized by either (co-)polymerization of
monomers carrying the phosphorus atom or by post-polymerization
modification of polymers with phosphorus based reagents.1,2
Polyphosphates and polyphosphonates show attractive properties for
the biomedical field, due to their biodegradability, blood compatibility,
and strong interactions with dentin, enamel and bone.3-6 Hence, the
synthesis of phosphate and phosphonate functionalized polymers, e.g.
poly(acrylates), poly(vinylalcohols), and poly(acrylamides) has been
achieved by polymerization of the respective monomers or by polymer
analogous reactions.7-10 Introduction of the phosphonate moiety
allows the preparation of precursors for the corresponding
phosphonic acid.11,12 Phosphonic acids are known to show strong
interactions with metal oxides, leading to various applications, such as
adhesion promotion or corrosion inhibition.13-16
Chapter 3
34
Köhler et al. presented the post-polymerization functionalization of
polyglycidol with diethyl vinylphosphonate and subsequent
dealkylation of the pendant phosphonate groups.17 This method
allowed the tailoring of the amount of phosphonate/phosphonic acid
groups introduced into the polyglycidol backbone. The phosphonate
functionalized polyglycidols were used as macroinitiators in the graft-
copolymerization of ε-caprolactone, enhancing the hydrolytic degrada-
bility of the poly(caprolactone) formed.18,19 Additionally, multifunc-
tional polyglycidols carrying phosphonic acid and acrylate groups were
prepared and examined as UV-active adhesion promoters for a
hydrogel coating on stainless steel wires.20
Introduction of phosphate groups into polyglycidol follows two
different approaches. Babu et al. prepared phosphate functionalized
monomers based on glycidol, which were polymerized by anionic ring-
opening polymerization using a Zn(II) catalyst and tetrabutylammo-
nium bromide as initiator yielding polymers with fairly high molecular
weights.21 Weinhart et al. synthesized dendritic polyglycidol phosphate
by functionalization with chloro diethylphosphite followed by in situ
oxidation.22 However, this approach uses an excess of the phosphor-
ylation agent and allows no control of the degree functionalization.
Herein, a straightforward approach for the introduction of pendant
phosphate groups into linear polyglycidol is presented. The synthetic
pathway involves the partial phosphorylation of polyglycidol with
diethyl chlorophosphate and subsequent dealkylation of the pendant
phosphate groups. Additional functionalities can be introduced into
the remaining hydroxy groups to prepare tailor-made polymers,
carrying diethylphosphate, ethylphosphate or phosphoric acid groups.
3.2 Experimental Section
3.2.1 Materials
Potassium tert-butoxide (1 M solution in THF, Aldrich), diethyl
chlorophosphate (>97%, Aldrich), pyridine (99.5%, dry over
molecular sieve, Acros), 4-dimethylaminopyridine (>98%, Fluka),
sodium iodide (99.9+%, anhydrous, Chempur), 2-hexanone (98%,
Chapter 3
35
Aldrich), bromotrimethylsilane (≥97%, Aldrich), and dichloro-
methane (≥99.8%, anhydrous, Aldrich) were used as received.
Diglyme was distilled over sodium before use. 3-Phenyl-1-propanol
(99%, Aldrich) was stirred with calcium hydride for 24 h and distilled.
Ethoxyethyl glycidyl ether (EEGE) was synthesized from 2,3-
epoxypropan-1-ol (glycidol) and ethyl vinyl ether according to Fitton et
al.23, purified by distillation, and stored under a nitrogen atmosphere
over molecular sieve (3 Å).
All reactions were carried out in a nitrogen atmosphere. Nitrogen
(Linde 5.0) was passed over molecular sieve (4 Å) and finely distributed
potassium on aluminum oxide.
3.2.2 Measurements
1H NMR, 13C NMR, and proton decoupled 31P NMR spectra were
recorded on a Bruker DPX-400 FT-NMR spectrometer at 400, 101,
and 162 MHz, respectively. Dimethyl sulfoxide (DMSO-d6) and
deuterium oxide (D2O) were used as solvents. The residual solvent
signal was used as internal standard. 31P {1H} NMR spectra were
referenced against 85% H3PO4 as external standard. Coupling
constants Jxy are given in Hz.
FTIR spectra were recorded on a Thermo Nicolet Nexus 470 FTIR
spectrometer at 25 °C. The samples were prepared as KBr pellets and
scanned over a range of 400–4000 cm–1.
DSC measurements were performed on a Netzsch DSC 204
differential scanning calorimeter under a nitrogen atmosphere.
Samples were prepared in perforated closed aluminum pans using
5 mg of the sample. The sample was heated and cooled with a rate of
10 °C min–1 in a range of 25–250 °C. The heat flow was measured as
a function of the temperature. Transitions were reported during the
second heating cycle and first cooling cycle.
Autotitration was performed with a Metrohm Titrando 905 connected
to a conductivity module. 0.1 N HCl and 0.1 N NaOH were used as
acid and base, respectively. The concentration of the sample was
5 mg mL–1 in water and the titrant was added with a drop rate of
14 µL min–1.
Molecular weights (Mn,SEC) and molecular weight distributions (Đ)
were determined by size exclusion chromatography (SEC). SEC
Chapter 3
36
analyses were carried out with DMF or water as eluent. SEC with DMF
(HPLC grade, VWR) as eluent was performed using an Agilent 1100
system equipped with a dual RI-/Visco detector (ETA-2020, WGE).
The eluent contained 1 g L–1 LiBr (≥99%, Aldrich). The sample
solvent contained traces of distilled water as internal standard. One
pre-column (8x50 mm) and four GRAM gel columns (8x300 mm,
Polymer Standards Service) were applied at a flow rate of
1.0 mL min–1 at 40 °C. The diameter of the gel particles measured
10 µm, the nominal pore widths were 30, 100, 1000 and 3000 Å.
Calibration was achieved using narrowly distributed poly(methyl
methacrylate) standards (Polymer Standards Service). Results were
evaluated using the PSS WinGPC UniChrom software (Version 8.1.1).
Preparative SEC with THF (HPLC grade, Merck) as eluent was
performed using two HPLC pumps (PU-2087plus, Jasco) equipped
with a refractive index detector (RI-2031plus, Jasco). The sample
solvent contained toluene (15 drops per 100 mL THF, p.a., Aldrich)
as internal standard. One pre-column (50x20 mm) and two SDplus gel
columns (300x20 mm, SDplus, MZ Analysentechnik) were applied at
a flow rate of 3.0 mL min–1 at 20 °C. The diameter of the gel particles
measured 10 µm, the nominal pore widths were 500 and 104 Å.
Dialysis was performed in methanol using Biotech CE Tubing
(MWCO: 100–500 D, 3.1 mL cm–1, Spectrumlabs). The membrane
was washed for 15 min in water before use to remove the sodium azide
solution.
3.2.3 Syntheses
Synthesis of poly(glycidol diethylphosphate-co-glycidol) (P(GDEP-co-G)) (3a–d)
Polyglycidol (PG24) (2) (1.488 g, 20.09 mmol OH) was dissolved in
pyridine (13.94 mL) and 4-dimethylaminopyridine (4-DMAP) (0.247 g,
2.01 mmol) and diethyl chlorophosphate (DECP) (2.600 g,
15.07 mmol) were added. The reaction mixture was stirred for 20 h at
room temperature. The solvent was removed under reduced pressure,
the residue redissolved in dichloromethane and precipitated in
pentane/diethyl ether (1:1 v/v). The product was purified by dialysis
in methanol. A yellowish viscous liquid was obtained. P(GDEP22-co-G8)
3c: yield 38%. Functionalized polyglycidols 3a, 3b, and 3d were
Chapter 3
37
synthesized following the same protocol. The reagent ratios and
reaction conditions are summarized in Table A.1.1 of appendix A.1. 1H NMR (400 MHz, DMSO-d6) (3c): = 1.25 (t, 3JHH
= 7.0 Hz,
POCH2CH3), 1.73–1.83 (m, ArCH2CH2), 2.57–2.65 (m, ArCH2CH2),
3.32–3.69 (m, ArCH2CH2CH2, OCH2CH(CH2OH)O, OCH2CH-
(CH2OP)O), 3.88–4.15 (m, POCH2CH3, OCH2CH(CH2OP)O), 4.55
(br. s, CHCH2OH groups), 7.12–7.31 (m, ArCH2CH2) ppm. 13C NMR
(101 MHz, DMSO-d6) (3c): = 15.9 (d, 3JCP =6.2 Hz, POCH2CH3),
30.9 (ArCH2CH2), 31.6 (ArCH2CH2), 60.8 (OCH2CH(CH2OH)O),
63.3 (d, 2JCP = 5.3 Hz, POCH2CH3), 66.0 (OCH2CH(CH2OP)O), 68.1–
69.5 (ArCH2CH2CH2, OCH2CH(CH2OH)O, OCH2CH(CH2OP)O),
77.5 (OCH2CH(CH2OP)O), 80.0 (OCH2CH(CH2OH)O), 125.8 (Ar),
128.3 (Ar), 141.7 (Ar) ppm. 31P {1H} NMR (162 MHz, DMSO-d6)
(3c): = -0.97 ppm. IR (KBr) (3c): υmax = 3412 (w), 2984 (m), 2910
(m), 1446 (w), 1394 (w), 1369 (w), 1266 (s), 1032 (vs), 979 (s), 871 (w),
819 (w), 752 (w), 526 (w) cm–1.
Synthesis of poly(glycidol ethylphosphate-co-glycidol) (P(GEP-co-G)) (4a–d)
P(GDEP22-co-G8) (3c) (0.196 g, 0.83 mmol DEP) was dissolved in 2-
hexanone (20 mL) and sodium iodide (0.149 g, 0.99 mmol) was added.
The reaction mixture was stirred under reflux for 48 h. The solvent
was removed and the product dried under reduced pressure. A
brownish solid was obtained. P(GEP22-co-G8) 4c: yield 97%. 4a, 4b, and
4d were synthesized following the same protocol. The reagent ratios
and reaction conditions are summarized in Table A.1.2 of appendix
A.1. 1H NMR (400 MHz, D2O) (4c): = 1.21–1.32 (m, POCH2CH3),
1.85–1.95 (m, ArCH2CH2), 2.66–2.75 (m, ArCH2CH2), 3.52–3.83 (m,
ArCH2CH2CH2, OCH2CH(CH2OH)O, OCH2CH(CH2OP)O), 3.84–
4.07 (m, POCH2CH3, OCH2CH(CH2OP)O), 7.24–7.40 (m, ArCH2-
CH2) ppm. 13C NMR (101 MHz, D2O) (4c): = 15.8 (POCH2CH3),
30.4 (ArCH2CH2), 31.5 (ArCH2CH2), 60.8 (OCH2CH(CH2OH)O),
62.3 (POCH2CH3), 64.4 (OCH2CH(CH2OP)O), 67.2–69.0 (ArCH2-
CH2CH2, OCH2CH(CH2OH)O, OCH2CH(CH2OP)O), 78.4 (OCH2-
CH(CH2OP)O), 79.8 (OCH2CH(CH2OH)O), 126.0 (Ar), 128.7 (Ar)
ppm. 31P {1H} NMR (162 MHz, D2O) (4c): = 0.60 ppm. IR (KBr)
(4c): υmax = 3436 (s), 2979 (m), 2940 (m), 1642 (w), 1467 (w), 1394 (w),
1237 (s), 1059 (vs), 951 (s), 830 (m), 772 (w), 553 (m) cm–1.
Chapter 3
38
Synthesis of poly(glycidol phosphate-co-glycidol) (P(GP-co-G)) (5a–d)
P(GDEP22-co-G8) (3c) (0.409 g, 1.73 mmol DEP) was dissolved in dry
dichloromethane (35 mL) and bromotrimethylsilane (0.91 mL,
6.92 mmol) was added over 1 h at 0 °C using a syringe pump. The
reaction was allowed to warm to room temperature and stirred for a
further 17 h. Water (20 mL) was added and the reaction mixture was
vigorously stirred for 2 h. The mixture was repeatedly washed with
dichloromethane (3 x 20 ml), the aqueous phase was separated and the
solvent removed. The product was dried under reduced pressure at
50 °C. A brownish viscous liquid was obtained. P(GP22-co-G8) 5c: yield
91%. 5a, 5b, and 5d were synthesized following the same protocol.
The reagent ratios and reaction conditions are summarized in Table
A.1.3 of appendix A.1. 1H NMR (400 MHz, D2O) (5c): = 1.85–1.93
(m, ArCH2CH2), 2.66–2.72 (m, ArCH2CH2), 3.49–3.88 m, ArCH2CH2-
CH2, OCH2CH(CH2OH)O, OCH2CH(CH2OP)O), 3.90–4.17 (m,
OCH2CH(CH2OP)O), 7.23–7.41 (m, ArCH2CH2) ppm. 13C NMR
(101 MHz, D2O) (5c): = 30.0 (ArCH2CH2), 31.1 (ArCH2CH2), 60.5
(OCH2CH(CH2OH)O), 64.7 (OCH2CH(CH2OP)O), 68.4–70.3
(ArCH2CH2CH2, OCH2CH(CH2OH)O, OCH2CH(CH2OP)O), 77.7
(OCH2CH(CH2OP)O), 79.6 (OCH2CH(CH2OH)O), 125.8 (Ar),
128.4 (Ar), 141.8 (Ar) ppm. 31P {1H} NMR (162 MHz, D2O) (5c): =
-0.12 ppm. IR (KBr) (5c): υmax = 2944 (m), 2889 (m), 2318 (w), 1666
(w), 1464 (w), 1349 (w), 1044 (vs), 873 (w), 484 (m) cm–1.
3.3 Results and Discussion
In this chapter, an easy and straightforward protocol for the controlled
functionalization of linear polyglycidol with pendant phosphate
groups is presented. The synthetic pathway involves the phospho-
rylation of linear polyglycidol (PG) with diethyl chlorophosphate
(DECP) under alkaline conditions in the presence of a nucleophilic
catalyst. The phosphate groups are subsequently dealkylated using
either sodium iodide for removal of one ethyl group or bromo-
trimethylsilane for removal of both ethyl groups, respectively.
Chapter 3
39
3.3.1 Functionalization of polyglycidol (2) with diethyl chlorophosphate
Linear polyglycidol (2) was prepared by anionic ring-opening
polymerization of ethoxyethyl glycidyl ether using 3-phenyl-1-
propanol as initiator followed by removal of the acetal protecting
groups under acidic conditions. A polyalcohol with 24 repeating units
(PG24) and Mn,SEC = 2700 g mol–1 was obtained with a narrow
molecular weight distribution (Ð = 1.17). The NMR and SEC analyses
of PG24 (2) can be found in appendix A.1 (Fig. A.1.1–A.1.3).
PG24 was reacted with various amounts of DECP and catalytic
amounts of 4-dimethylaminopyridine (4-DMAP) in pyridine at room
temperature with ratios of DECP to hydroxy groups of 0.25, 0.50,
0.75, and 1.0 (Scheme 3.1). The synthesized poly(glycidyl diethyl
phosphate-co-glycidol)s (P(GDEP-co-G)) (3a–d) were purified by
dialysis in methanol and characterized by 1H, 13C, 31P {1H} NMR
spectroscopy, FTIR spectroscopy and SEC analysis.
Scheme 3.1: Functionalization of linear polyglycidol with diethyl
chlorophosphate.
1H and 13C NMR spectra of P(GDEP-co-G) in DMSO-d6 show
characteristic signals of the ethyl groups adjacent to the phosphorus
atom, proving the successful phosphorylation of PG24. In the 1H NMR
spectrum the signals appear as a triplet at δ = 1.25 ppm (Signal 11) and
as a multiplet at δ = 3.88–4.15 ppm (Signal 10) (Fig. 3.1a). This
multiplet also contains the methylene group of the glycidol repeating
unit adjacent to the phosphate group. In the 13C NMR spectrum the
characteristic signals appear as doublets at δ = 15.9 ppm and δ =
63.3 ppm, respectively (Fig. 3.1b). The phosphorus NMR spectrum
shows a distinctive signal at δ = -0.97 ppm, which was assigned to the
diethyl phosphate side group of P(GDEP-co-G) (Fig. 3.1c).
The number of diethyl phosphate groups attached to PG24 (2) was
calculated by comparing the signal intensity of the phenyl group of the
Chapter 3
40
3-phenyl-1-propanol (Signal 1–3), which was used as initiator in the
synthesis of 2, with signal 11. The degree of functionalization (FDEP)
and absolute molecular weights (Mn,NMR) were calculated likewise using
the 3-phenyl-1-propyl end group as an internal reference. The 1H
NMR spectra of all phosphate functionalized polyglycidols are similar,
differing only in the relative intensity of the signals.
Figure 3.1: 1H NMR (a), 13C NMR (b) and 31P {1H} NMR (c) spectra of
P(GDEP22-co-G8) (3c) measured in DMSO-d6.
FTIR spectra of P(GDEP-co-G) exhibit characteristic absorption bands
of the diethyl phosphate groups.25 The asymmetric stretching vibration
of P―O―C groups gives a very strong broad band at 1032 cm–1.
Additionally a strong band at 979 cm–1 is found, which is distinctive
for ethyl phosphates. The stretching vibration of the P═O group
shows a band at 1266 cm–1 (Fig. A.1.10, appendix A.1). The signals are
Chapter 3
41
consistent with literature and verify the successful functionalization of
PG24 with DECP.
SEC analysis using DMF as eluent confirms the synthesis of P(GDEP-
co-G) with molecular weight distributions of 1.23 ≤ Đ ≤ 1.44.
However, purification by dialysis in methanol led to fractionation of
the functionalized polymers. The high and low molecular weight
fractions were separated by preparative SEC with THF as eluent. 1H
NMR spectroscopy of those fractions showed that phosphate
functionalized polyglycidol was obtained in both cases. The SEC
analysis of P(GDEP22-co-G8) (3c) and of fractions separated by
preparative SEC can be found in Figure 3.2.
Figure 3.2: DMF-SEC traces of P(GDEP22-co-G8) (3c) (black line) and
fractions separated by preparative SEC with THF as eluent (red and blue
dotted lines).
At this point some observations during purification of P(GDEP-co-G)
(3a–d) should be mentioned. As shown in table 3.1 the degrees of
functionalization obtained for 3a–c were in excellent agreement with
the ratios adjusted in the feed. However, the functionalization of all
hydroxy groups of 2 was not possible, reaching a maximum degree of
functionalization of 87%. P(GDEP-co-G) purified by dialysis in
methanol (3a–d) shows slight deviations from the theoretical degree
Chapter 3
42
of functionalization since the dialysis leads to fractionation of the
polymers due to diffusion of lower molecular weight fractions through
the dialysis membrane. The starting degree of polymerization of
polyglycidol (2) was Pn = 24, however the samples of 3a–d show a
degree of polymerization of Pn = 38 for 3a, Pn = 34 for 3b and Pn =
30 for 3c and 3d.
To prove this assumption a higher molecular weight polyglycidol
(Mn,SEC = 7100 g mol–1, Đ = 1.30) was functionalized with DECP with
a ratio of DECP to hydroxy groups of 0.50. The degree of
functionalization in the product was in perfect agreement with the
ratio adjusted in the feed. The purification by dialysis in methanol did
not lead to a fractionation of the polymer.
The SEC traces of higher molecular weight polyglycidol and its
phosphate functionalized equivalent can be found in appendix A.1
(Fig. A.1.6, appendix A.1).
Table 3.1: Ratio of diethyl chlorophosphate (DECP) to hydroxyl groups,
degree of functionalization (FDEP) and molecular weight (Mn,NMR) calculated
from 1H NMR and SEC data of linear P(GDEP9-co-G29) (3a), P(GDEP
16-co-G18)
(3b), P(GDEP22-co-G8) (3c), P(GDEP
26-co-G4) (3d).
Polymer ratio
[DECP]
/[OH]
FDEP a
[%]
Mn,NMR a
[g mol–1]
Mn,SEC b
[g mol–1]
Đ b Yield c
[%]
3a 0.25 24 4176 5000 1.30 23
3b 0.50 47 4832 5200 1.29 41
3c 0.75 73 5352 5000 1.29 38
3d 1.00 87 5897 5200 1.44 27
a Degree of functionalization of hydroxyl groups with DECP (FDEP) and molecular weight (Mn,NMR) calculated from 1H NMR with an accuracy of integration of ± 5%. b Number average molecular weight (Mn,SEC) and molecular weight distribution (Đ) determined by size exclusion chromatography (SEC) using narrowly distributed P(MMA) standards in DMF. c Yield of P(GDEP
x-co-Gy) obtained after dialysis in MeOH for two days.
3.3.2 Monodealkylation of P(GDEP-co-G) (3a–d)
Monophosphoric acids can be easily prepared by a highly selective
method using sodium iodide or lithium bromide as a dealkylating
reagent.26,27 According to this synthetic protocol P(GDEP-co-G) (3a–d)
Chapter 3
43
were reacted with sodium iodide in 2-hexanone under reflux (Scheme
3.2). The synthesized poly(glycidyl ethyl phosphate-co-glycidol)
(P(GEP-co-G)) (4a–d) were characterized by 1H, 13C, 31P {1H} NMR
spectroscopy and DSC analysis (Table 3.2).
Scheme 3.2: Synthesis of poly(glycidyl ethyl phosphate-co-glycidol) (4a–d).
1H and 13C NMR spectra of P(GEP-co-G) (4a–d) in D2O present
characteristic signals of the ethyl group adjacent to the phosphorus
atom of P(GEP-co-G). In the 1H NMR spectrum the signals appear as
a multiplet at δ = 1.21–1.31 ppm (Signal 11) and as a multiplet at δ =
3.84–4.07 ppm (Signal 10) (Fig. 3.3a). The second multiplet also
contains the methylene group of the glycidol repeating unit adjacent
to the phosphate. In 13C NMR spectrum the characteristic signals
appear at δ = 15.8 ppm and δ = 62.3 ppm, respectively (Fig. A.1.4,
appendix A.1). The phosphorus NMR spectrum shows a distinctive
signal at δ = 0.60 ppm, which was assigned to P(GEP-co-G). (Fig. A.1.5,
appendix A.1)
The number of ethyl phosphate groups attached to PG24 (2) was
calculated as described previously. In comparison with the 1H NMR
spectra of P(GDEP-co-G) (3a–d) the relative intensity of signals of the
ethyl groups adjacent to the phosphorus atom is halved.
FTIR spectra of P(GEP-co-G) (4a–d) exhibit characteristic absorption
bands of the ethyl phosphate groups.25 The stretching vibration bands
of the P═O, P―O―C, and P―O―Et groups are found at 1237 cm–1,
1059 cm–1, and 951 cm–1, respectively, and are in good agreement with
the absorption bands of P(GDEP-co-G) (Fig. A.1.10, appendix A.1).
Additionally, a broad band at 1642 cm–1 is observed, which is
distinctive for the P―OH group, and confirms the successful
monodealkylation of P(GDEP-co-G) (3a–d).
Chapter 3
44
Table 3.2: Degree of functionalization (FEP) and molecular weight (Mn,NMR)
calculated from 1H NMR of linear P(GEP9-co-G29) (4a), P(GEP
16-co-G18) (4b),
P(GEP22-co-G8) (4c) and P(GEP
26-co-G4) (4d).
Polymer FEP a
[%]
Mn,NMR a
[g mol–1]
4a 24 3778
4b 47 4231
4c 73 4577
4d 87 5005
a Degree of functionalization of hydroxyl groups with ethyl phosphate groups (FEP) and molecular weight (Mn,NMR) calculated from 1H NMR with an accuracy of integration of ± 5%.
Figure 3.3: 1H NMR spectra of P(GEP22-co-G8) (4c) (top) and P(GP
22-co-G8)
(5c) (bottom) measured in D2O.
In all experiments 100 % conversion of diethyl phosphate groups is
reached after 48 h according to 31P analysis (Fig. A.1.5, appendix A.1).
Chapter 3
45
3.3.3 Dealkylation of P(GDEP-co-G) (3a–d)
The synthesis of poly(glycidyl phosphate-co-glycidol) (P(GP-co-G) (5a–
d) was achieved by conversion of P(GDEP-co-G) (3a–d) with
bromotrimethylsilane in dichloromethane as solvent (Scheme 3.3).
After stirring at room temperature for 17 h, the silalyted intermediates
were hydrolyzed with water. Washing with dichloromethane gave
P(GP-co-G) (5a–d) in yields of 81–94%. The P(GP-co-G)s (5a–d) were
characterized by 1H, 13C, 31P {1H} NMR spectroscopy (Table 3.3).
Scheme 3.3: Synthesis of poly(glycidyl phosphate-co-glycidol) (5a–d) by
dealkylation of P(GDEP-co-G) (3a–d).
The successful dealkylation of P(GDEP-co-G) was proven by the
absence of the characteristic diethyl phosphate signals at δ = 1.21–
1.31 ppm and δ = 3.84–4.07 ppm in the 1H NMR spectra (Fig. 3.3b)
and the signals at δ = 15.8 ppm and δ = 62.3 ppm in the 13C NMR
spectra (Fig. A.1.8, appendix A.1). In the 31P {1H} NMR spectrum a
signal appears at δ = -0.12 ppm, which was assigned to P(GP-co-G)
(5a–d) (Fig. A.1.9, appendix A.1).
FTIR spectra of P(GP-co-G) confirm the successful dealkylation by
absence of the distinctive ethyl phosphate absorption band at 940–
985 cm–1. Additionally, two broad bands at 2318 cm–1 and 1666 cm–1
are found, which are characteristic for phosphoric acid groups (Fig.
A.1.10, appendix A.1).
The titration curve of P(GP22-co-G8) (5c) was recorded in a pH range
of 2.0 to 11 using 0.1 N hydrochloric acid and 0.1 N sodium hydroxide
solution, respectively (Fig. A.1.7, appendix A.1). The graph shows two
equivalent points at pH = 5.13 and pH = 9.53, distinctive for the
deprotonation of the diprotic phosphate group. The phosphate group
shows acid dissociation constants of pKa,1 = 2.33 and pKa,2 = 7.80,
which are in good agreement with the pKa values of phosphoric acid.28
Chapter 3
46
Table 3.3: Degree of functionalization (FP) and molecular weight (Mn,NMR)
calculated from 1H NMR of P(GP9-co-G29) (5a), P(GP
16-co-G18) (5b), P(GP22-
co-G8) (5c) and P(GP26-co-G4) (5d).
Polymer FP a
[%]
Mn,NMR a
[g mol–1]
5a 24 3320
5b 47 3416
5c 73 3456
5d 87 3681
a Degree of functionalization of hydroxyl groups with dihydrogen phosphate groups (FP) and molecular weight (Mn,NMR) calculated from 1H-NMR with an accuracy of integration of ± 5%.
In all experiments conversions of diethyl phosphate groups of 100%
were reached after 17 h according to 31P analysis (Fig. A.1.9, appendix
A.1).
3.4 Conclusions
In this chapter, a synthetic strategy for the preparation of polyglycidols
with pendant phosphate groups has been developed. The successful
synthesis was confirmed by 1H, 13C, 31P {1H} NMR spectroscopy,
FTIR spectroscopy, and SEC analysis. Diethyl phosphate groups were
subsequently (mono-)dealkylated. This method allows tailoring of the
concentration of pendant phosphate/phosphoric acid groups intro-
duced into polyglycidol.
3.5 References
1. Monge, S.; Canniccioni, B.; Graillot, A.; Robin, J.J.
Phosphorus-containing polymers: A great opportunity for
the biomedical field. Biomacromolecules 2011, 12, 1973.
2. Wang, Y.C.; Yuan, Y.Y.; Du, J.Z.; Yang, X.Z.; Wang, J.
Recent progress in polyphosphoesters: From controlled
synthesis to biomedical applications. Macromol. Biosci. 2009, 9,
1154.
Chapter 3
47
3. Renier, M.L.; Kohn, D.H. Development and characterization
of a biodegradable polyphosphate. J. Biomed. Mater. Res. 1997,
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4. Huang, S.W.; Wang, J.; Zhang, P.C.; Mao, H.Q.; Zhuo, R.X.;
Leong, K.W. Water-soluble and nonionic polyphosphoester:
Synthesis, degradation, biocompatibility and enhancement of
gene expression in mouse muscle. Biomacromolecules 2004, 5,
306.
5. Wang, S.; Wan, A.C.; Xu, X.; Gao, S.; Mao, H.Q.; Leong,
K.W.; Yu, H. A new nerve guide conduit material composed
of a biodegradable poly(phosphoester). Biomaterials 2001, 22,
1157.
6. Mou, L.; Singh, G.; Nicholson, J.W. Synthesis of a
hydrophilic phosphonic acid monomer for dental materials.
Chem. Commun. 2000, 345.
7. Moszner, N.; Salz, U.; Zimmermann, J. Chemical aspects of
self-etching enamel-dentin adhesives: A systematic review.
Dent. Mater. 2005, 21, 895.
8. Macarie, L.; Ilia, G. Poly(vinylphosphonic acid) and its
derivatives. Prog. Polym. Sci. 2010, 35, 1078.
9. Schott, H.; Bretzger, W. Funktionalisierung heterogen-
vernetzter Polyvinylalkohol-Gele. Makromol. Chem. 1988, 189,
2847.
10. Moszner, N.; Zeuner, F.; Pfeiffer, S.; Schurte, I.;
Rheinberger, V.; Drache, M. Monomers for adhesive
polymers, 3. Synthesis, radical polymerization and adhesive
properties of hydrolytically stable phosphonic acid
monomers. Macromol. Mater. Eng. 2001, 286, 225.
11. Wagner, T.; Manhart, A.; Deniz, N.; Kaltbeitzel, A.; Wagner,
M.; Brunklaus, G.; Meyer, W.H. Vinylphosphonic acid
homo- and block copolymers. Macromol. Chem. Phys. 2009,
210, 1903.
12. Ingratta, M.; Elomaa, M.; Jannasch, P. Grafting
poly(phenylene oxide) with poly(vinylphosphonic acid) for
fuel cell membranes. Polym. Chem. 2010, 1.
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13. Guerrero, G.; Mutin, P.H.; Vioux, A. Anchoring of
phosphonate and phosphinate coupling molecules on titania
particles. Chem. Mater. 2001, 13, 4367.
14. Pellerite, M.J.; Dunbar, T.D.; Boardman, L.D.; Wood, E.J.
Effects of fluorination on self-assembled monolayer forma-
tion from alkanephosphonic acids on aluminum: Kinetics
and structure. J. Phys. Chem. B 2003, 107, 11726.
15. Demadis, K.D.; Papadaki, M.; Raptis, R.G.; Zhao, H.
Corrugated, sheet-like architectures in layered alkaline-earth
metal R,S-hydroxyphosphonoacetate frameworks: Applica-
tions for anticorrosion protection of metal surfaces. Chem.
Mater. 2008, 20, 4835.
16. Gawalt, E.S.; Avaltroni, M.J.; Danahy, M.P.; Silverman, B.M.;
Hanson, E.L.; Midwood, K.S.; Schwarzbauer, J.E.; Schwartz,
J. Bonding organics to ti alloys: Facilitating human osteoblast
attachment and spreading on surgical implant materials.
Langmuir 2003, 19, 200.
17. Koehler, J.; Keul, H.; Möller, M. Post-polymerization
functionalization of linear polyglycidol with diethyl
vinylphosphonate. Chem. Commun. 2011, 47, 8148.
18. Koehler, J.; Marquardt, F.; Keul, H.; Moeller, M.
Phosphonoethylated polyglycidols: A platform for tunable
enzymatic grafting density. Macromolecules 2013, 46, 3708.
19. Koehler, J.; Marquardt, F.; Teske, M.; Keul, H.; Sternberg,
K.; Moeller, M. Enhanced hydrolytic degradation of
heterografted polyglycidols: Phosphonoethylated monoester
and polycaprolactone grafts. Biomacromolecules 2013, 14, 3985.
20. Koehler, J.; Kuehne, A.J.C.; Piermattei, A.; Qiu, J.; Keul,
H.A.; Dirks, T.; Keul, H.; Moeller, M. Polyglycidol-based
metal adhesion promoters. J. Mater. Chem. B 2015, 3, 804.
21. Babu, H.V.; Muralidharan, K. Polyethers with phosphate
pendant groups by monomer activated anionic ring opening
polymerization: Syntheses, characterization and their
lithium-ion conductivities. Polymer 2014, 55, 83.
22. Weinhart, M.; Groger, D.; Enders, S.; Dernedde, J.; Haag, R.
Synthesis of dendritic polyglycerol anions and their efficiency
toward L-selectin inhibition. Biomacromolecules 2011, 12, 2502.
Chapter 3
49
23. Fitton, A.O.; Hill, J.; Jane, D.E.; Millar, R. Synthesis of simple
oxetanes carrying reactive 2-substituents. Synthesis 1987,
1140.
24. Hans, M.; Gasteier, P.; Keul, H.; Moeller, M. Ring-opening
polymerization of ε-caprolactone by means of mono- and
multifunctional initiators: Comparison of chemical and enzy-
matic catalysis. Macromolecules 2006, 39, 3184.
25. Socrates, G. Infrared characteristic group frequencies. John Wiley &
Sons: Chichester, New York, Brisbane, Toronto, 1980.
26. Kluger, R.; Taylor, S.D. Mechanisms of carbonyl
participation in phosphate ester hydrolysis and their
relationship to mechanisms for the carboxylation of biotin. J.
Am. Chem. Soc. 1991, 113, 996.
27. Krawczyk, H. A convenient route for monodealkylation of
diethyl phosphonates. Synth. Commun. 1997, 27, 3151.
28. Riedel, E.; Janiak, C. Anorganische Chemie. 7th Edition ed.;
Walter de Gruyter: Berlin, New York, 2007.
Chapter 4
51
Chapter 4
Novel Antibacterial
Polyglycidols: Relationship
between Structure and
Properties
4.1 Introduction
Contamination by microorganisms such as bacteria, fungi and algae is
a key issue in medicine1, pharmaceutical production2, water purifica-
tion systems3, food packaging4 and various other fields.5,6 Artificial
materials lack defense against microbial growth, allowing microbes to
attach to the surface and form a biofilm.7 One way to prevent the
biofilm formation is the usage of disinfectants to keep the surface
sterile. Common disinfectants include low molecular weight sub-
stances such as alcohols, aldehydes, quaternary ammonium com-
pounds, silver compounds, peroxygens and bisphenols.8 However,
these classes of antimicrobial substances need to be applied regularly,
leading to the development of resistance in the microbial strains.9
Another way to prevent microbial growth is the coating of surfaces
with antimicrobial substances that either kill microorganisms on
contact or repel the attachment of microbes.10 Nevertheless, the
leaching of biocides from those coatings causes the same previously
mentioned problems. An attractive alternative to low molecular weight
Chapter 4
52
biocides are antimicrobial polymers, because they are non-volatile,
chemically stable and can be used as non-releasing additives.11 These
polymers are prepared either by (co-)polymerization of functionalized
monomers or by post-polymerization functionalization.12 Though, the
antimicrobial properties are derived from a variety of functionalities
such as biguanides13,14, benzoate esters and benzaldehydes15 or poly-
(acrylic acid)16, the most common active moieties are based on a
combination of quaternary ammonium, pyridinium or phosphonium
groups and hydrophobic functionalities.17-19 The proposed and com-
monly accepted mechanism for these types of polymers features the
electrostatic interaction between the cationic moieties and the nega-
tively charged bacterial cell membrane and the disruption of the cell
membrane by the hydrophobic groups, leading to leakage and subse-
quently cell death20,21. However, due to the heterogeneity and bacterial
strain specificity of the cell wall composition the efficacy of antimicro-
bial polymers is species dependent. The outer part of the cell wall of
Gram-positive bacteria is composed of about 90% peptidoglycan. In
Gram-negative bacteria the peptidoglycan layer accounts for approxi-
mately 20% of the cell envelope, being located between outer mem-
brane and inner cell membrane. Before reaching the inner cell mem-
brane polymers interact with the negatively charged components of
the outer part of the bacterial cell envelope, e.g. teichoic acids in the
thick peptidoglycan layers of Gram-positive bacteria, and phospho-
lipids and lipopolysaccharides in the outer membrane of Gram-
negative bacteria.22,23 The effectiveness of the antimicrobial cationic/
hydrophobic polymers is dependent on various factors.24 One factor
is the molecular weight of the polymer. Ikeda et al. synthesized poly-
methacrylates with pendant biguanide units and various molecular
weights and tested the antimicrobial activity against Staphylococcus
aureus, reaching an optimal activity at molecular weights between 50–
100 kDa.25 Kanazawa et al. showed an increase in biocidal activity of
poly[tributyl(4-vinylbenzyl)phosphonium chloride] against S. aureus
with increasing molecular weight.26 Based on the described mechanism
they assume that a higher molecular weight and a consequential higher
charge density enhance the adsorption of the polymers to the cell
membrane. A stronger adsorption leads to a stronger disruption of the
cell membrane and thus, to a higher activity of the polymer. However,
Chapter 4
53
Lienkamp et al. found that when the molecular weight reaches a
threshold value, the efficacy of the polymers decreases.27 Additionally,
Locock et al. reported the reverse effect on guanylated polymeth-
acrylates.28 The presented polymers showed higher antimicrobial acti-
vity at lower molecular weights, proving that the efficacy of antimicro-
bial polymers does not exclusively depend on their molecular weight.
A second factor for the antimicrobial behavior is the alkyl chain length
of the hydrophobic moiety. However, the optimal alkyl chain length is
different for different types of polymers. Pasquier et al. prepared
branched poly(ethylene imine)s with pendant ammonium and alkyl
functionalities, ranging from C6 to C16. An increase in the alkyl chain
length lead to an increase in the antimicrobial activity against E. coli.29
The activity was further enhanced by He et al., attaching the hydro-
phobic chain directly to the ammonium group.30 The opposite influ-
ence of aliphatic side chains was reported by Xu et al. on comb-like
ionenes.31 Here, a decrease in the alkyl chain length lead to an increase
in the antimicrobial activity against E. coli. On the other hand Chen et
al. prepared poly(propylene imine) dendrimers with alkyl chains rang-
ing from C8 to C16, showing a parabolic dependence between the bio-
cidal effect and the alkyl chain length, with the highest activity at C10.32
In this chapter, the preparation of various antimicrobial polymers
based on polyglycidol with quaternary trimethylammonium groups as
the cationic moiety and dodecyl chains as the hydrophobic part is
presented. Polyglycidol is a highly functional polymer with a hydroxy
group in every repeating unit, allowing various further modifica-
tions.33,34 It is non-toxic, soluble in aqueous media, and licensed by the
Food and Drug Administration (FDA).35,36 The cationic and hydro-
phobic side chain functionalities were distributed statistically along the
polymer backbone (cationic to hydrophobic ratio of 1:1). This func-
tionalized polyglycidol was compared to (i) a polyglycidol modified
with hydrophilic hydroxyethyl functionalities at the cationic center, (ii)
a polyglycidol with cationic and hydrophobic moieties at every repeat-
ing unit, and (iii) a polyglycidol with a cationic to hydrophobic balance
of 1:2. All polymers were tested in regard to their antimicrobial proper-
ties against Escherichia coli and Staphylococcus aureus to examine a possible
relationship between the structure and the biocidal effect of the
polymer.
Chapter 4
54
4.2 Experimental Section
4.2.1 Materials
Potassium tert-butoxide (1 M solution in THF), diglyme (≥99%, extra
dry, over molecular sieves), pyridine (99.5%, extra dry, over molecular
sieves), phenyl chloroformate (>97%), 4-nitrophenyl chloroformate
(>98), 3-(dimethylamino)-1-propylamine (99%), N-(3-aminopropyl)-
diethanolamine (>90%), dodecylamine (98%), 4-dimethylamino-
pyridine (>98%), DL-homocysteine thiolactone hydrochloride (98%),
triethylamine (≥99.5%, anhydrous), dodecyl acrylate (>98%), methyl
iodide (>99%), tetrahydrofuran (99.8%, stabilizer free, extra dry),
chloroform (99.9%, extra dry, over molecular sieves), N,N-dimethyl-
formamide (99.8%, extra dry, over molecular sieves), methanol
(≥99.8%, p.a.) and dichloromethane (≥99.8%, anhydrous) were used
as received.
3-phenyl-1-propanol (99%) was stirred with calcium hydride for 24 h
and then distilled. Ethoxyethyl glycidyl ether (EEGE) was synthesized
from 2,3-epoxypropan-1-ol (glycidol, 96%) and ethyl vinyl ether (99%)
according to Fitton et al.37, purified by distillation, and stored under a
nitrogen atmosphere over a molecular sieve (3 Å). Polyglycidol (PG)
(1) was synthesized according to literature.38
Water-sensitive reactions were carried out in a nitrogen atmosphere.
Nitrogen (Linde 5.0) was passed over a molecular sieve (4 Å) and finely
distributed potassium on aluminum oxide.
4.2.2 Bacteria
To determine the antibacterial activity polymers were tested against the
Gram-negative bacterium Escherichia coli (DSM498) and the Gram-
positive bacterium Staphylococcus aureus (ATCC6538). Overnight cul-
tures of E. coli and S. aureus with defined bacterial count in Mueller-
Hinton broth (pH = 7.4 ± 0.2) were used as inoculate in the
antibacterial test.
4.2.3 Antibacterial tests for polymer solutions
The antibacterial activity of the polymers in solution was determined
by measuring the minimal inhibitory concentration (MIC) using the
Chapter 4
55
test bacteria mentioned above. Suspensions of strains with known
colony forming units (CFU; 1‒2 · 106 CFU mL–1) were incubated at
37 °C in nutrient solutions (Mueller-Hinton Broth, MHB) with differ-
ent concentrations of the polymer samples. The polymer samples were
solubilized in bidistilled water and added to the nutrient solution at a
constant ratio of 1:10. The growth of the bacteria was followed during
the incubation over 20 h by measuring the optical density at 612 nm
every 30 min (with 1400 s of shaking at 100 rpm per 30 min cycle by
using a microplate reader/incubator (TECAN Infinite 200 Pro) The
testing is performed with defined concentrations specifically for each
polymer until within the monitoring time of 20 h no bacterial growth
curve is recorded. All experiments were performed in triplicate dupli-
cates and MIC determination was repeated on 3 different days. The
polymers were not sterilized. Sterile controls (defined polymer concen-
trations in nutrient solution without bacteria) were assessed in every
growth curve monitoring testing series. MICs were determined accord-
ing to broth microdilution in 96-well microtitre plates.39 Antimicrobial
polymer testing reference polymers/controls ε-polylysine and poly-
hexanide (poly(hexamethylene biguanide)) were used.
The minimal inhibitory concentration (MIC) corresponds to the
concentration of the test substance at which a complete inhibition of
the growth of the inoculated bacteria was observed by comparison
with control samples without test substance.
4.2.4 Hemolytic Activity
Hemolytic activity was assessed according to literature.40 Human ery-
throcytes (from healthy donors, red blood cells (RBC), 0, Rh positive,
citrate-stabilized) were obtained by centrifugation (3500 rpm, 12 min)
to remove plasma, washed 3 times in PBS, and diluted in PBS to obtain
a stock solution of 2.5–3.0 · 108 mL–1 RBC. Solutions of defined poly-
mer concentration (250 µL) were pipetted into 250 μL of the stock
solution; the final amount of RBC being 1.2–1.5 · 108 RBC mL–1. The
RBC were exposed for 60 min at 37 °C under 3D-shaking, centrifuged
thereafter (4000 rpm, 12 min), and the absorption of the supernatant
(diluted tenfold in PBS) was determined at 414 nm in a microplate
reader. As reference solutions (i) PBS for determining spontaneous
hemolysis and (ii) 1% Triton X-100 for 100% hemolysis (positive
Chapter 4
56
control) were used. Hemolysis was plotted as a function of polymer
concentration and the hemolytic activity was defined as the polymer
concentration that causes 50% hemolysis of human RBC relative to
the positive control (HC50).
4.2.5 Measurements
1H NMR and 13C NMR were recorded on a Bruker DPX-400 FT-
NMR spectrometer at 400 and 101 MHz, respectively. Deuterated
chloroform (CDCl3), deuterated dimethyl sulfoxide (DMSO-d6),
deuterated acetone (acetone-d6) and deuterated methanol (MeOD)
were used as solvents. The residual solvent signal was used as internal
standard. Coupling constants Jxy are given in Hz.
Molecular weights (Mn,SEC) and molecular weight distributions (Đ)
were determined by size exclusion chromatography (SEC). SEC
analyses were carried out with DMF as eluent. SEC with DMF (HPLC
grade) as eluent was performed using an Agilent 1100 system equipped
with a dual RI-/Visco detector (ETA-2020). The eluent contained
1 g L–1 LiBr (≥99%, Aldrich). The sample solvent contained traces of
distilled water as internal standard. For cationic samples the eluent
contained 2 g L–1 LiBr and 2 g L–1 tris(hydroxymethyl)aminomethane
(TRIS, ultrapure grade, ≥99.9%). One pre-column (8x50 mm) and
four GRAM gel columns (8x300 mm) were applied at a flow rate of
1.0 mL min–1 at 40 °C. The diameter of the gel particles measured
10 µm, the nominal pore widths were 30, 100, 1000 and 3000 Å.
Calibration was achieved using narrowly distributed poly(methyl
methacrylate) standards (Polymer Standards Service). Results were
evaluated using the PSS WinGPC UniChrom software (Version 8.1.1).
Dialysis was performed in methanol using Biotech CE Tubing
(MWCO: 100–500 D, 3.1 mL cm–1) and Biotech RC Tubing (MWCO:
1 kD, 6.4 mL cm–1), respectively. The membrane was washed for
15 min in water before use to remove the sodium azide solution.
4.2.6 Syntheses
Synthesis of poly(glycidyl phenyl carbonate) (P(GPC)27) (2)
PG27 (1) (2.018 g, 27.24 mmol OH) was dissolved in pyridine
(18.87 mL), and a solution of phenyl chloroformate (4.692 g,
Chapter 4
57
29.97 mmol) in dichloromethane (17.5 mL) was added in 30 min at
0 °C using a syringe pump. The reaction mixture was allowed to warm
to room temperature and stirred for 20 h. The precipitate was removed
by filtration. The solution was washed with water (15 mL), 1 M HCl
solution (aq.) (3 · 15 mL), and saturated NaCl solution (aq.) (15 mL).
The organic phase was dried over Na2SO4, filtrated, and the solvent
removed under reduced pressure. Polymer 2 was obtained as a brown
viscous liquid (3.650 g, 69%). Mn,NMR = 5243 g mol–1, Mn,SEC =
4800 g mol–1, Ð = 1.14. 1H NMR (400 MHz, CDCl3) (2): δ = 1.79 (m,
ArCH2CH2), 2.57 (t, 3JHH = 7.8 Hz, ArCH2CH2), 3.45–3.87 (m, ArCH2-
CH2CH2, OCH2CH(CH2OC=OOPh)O), 4.08–4.42 (m, OCH2CH-
(CH2OC=OOPh)O), 6.98–7.29 (m, ArCH2CH2, (OC=OOPh)O)
ppm. 13C NMR (101 MHz, CDCl3) (2): δ = 31.2 (ArCH2CH2), 32.3
(ArCH2CH2), 67.7–69.4 (ArCH2CH2CH2, OCH2CH(CH2OC=O-
OPh)O), 77.4 (OCH2CH(CH2OC=OOPh)O), 121.0 (OC=OOPh)O),
126.1 (ArCH2, OC=OOPh)O), 128.4 (ArCH2), 128.5 (ArCH2), 129.6
(OC=OOPh)O), 141.8 (ArCH2), 151.1 (OC=O-OPh)O), 153.6
(OC=OOPh)O) ppm.
Synthesis of poly(glycidyl 3-dimethylaminopropylcarbamate-co-glycidyl dodecyl-
carbamate) (P(GDMAPA15-co-GDDA
12)) (3)
P(GPC)27 (2) (1.509 g, 7.77 mmol carbonate) was dissolved in tetra-
hydrofuran (15 mL) and a solution of 3-(dimethylamino)-1-propyl-
amine (0.397 g, 3.89 mmol) and dodecylamine (0.721 g, 3.89 mmol) in
tetrahydrofuran (15 mL) was added in 1 h at 0 °C using a syringe pump.
The reaction was allowed to warm to room temperature and stirred
for 42 h. The solvent was removed under reduced pressure and the
polymer purified by dialysis in methanol. Polymer 3 was obtained as a
yellowish viscous liquid (1.153 g, 62%). Mn,NMR = 6459 g mol–1,
Mn,SEC = 7600 g mol–1, Ð = 1.38. 1H NMR (400 MHz, CDCl3) (3): δ =
0.84 (t, 3JHH = 7.0 Hz, NHCH2CH2(CH2)9CH3), 1.21 (s, NHCH2CH2-
(CH2)9CH3), 1.34–1.51 (m, NHCH2CH2(CH2)9CH3), 1.54–1.68 (m,
NHCH2CH2CH2N(CH3)2), 1.77–1.89 (m, ArCH2CH2), 2.16 (s, NH-
CH2CH2CH2N(CH3)2), 2.27 (t, 3JHH = 6.7 Hz, NHCH2CH2CH2N-
(CH3)2), 2.63 (t, 3JHH = 7.6 Hz, ArCH2CH2), 3.01–3.11 (m, NHCH2-
CH2(CH2)9CH3), 3.12–3.21 (m, 2H, NHCH2CH2CH2N(CH3)2), 3.45–
3.79 (m, ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 3.86–4.36
Chapter 4
58
(m, OCH2CH(CH2OC=ONHR)O), 5.88 (br. s, NH), 6.17 (br. s, NH),
7.09–7.25 (m, ArCH2CH2) ppm. 13C NMR (101 MHz, CDCl3) (3): δ =
14.2 (NHCH2CH2(CH2)9CH3), 22.7 (NHCH2(CH2)10CH3), 27.0 (NH-
CH2CH2CH2N(CH3)2, 27.5–32.0 (NHCH2(CH2)10CH3, ArCH2CH2),
39.9 (NHCH2(CH2)10CH3), 41.2 (NHCH2CH2CH2N(CH3)2), 45.5
(NHCH2CH2CH2N(CH3)2), 57.6 (NHCH2CH2CH2N(CH3)2), 64.2–
70.0 (ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 78.0 (OCH2-
CH(CH2OC=ONHR)O), 125.8 (ArCH2), 128.4 (ArCH2), 128.5
(ArCH2), 141.9 (ArCH2), 156.7 (OCH2CH(CH2OC=ONHR)O) ppm.
Synthesis of poly(glycidyl 3-aminopropyldiethanolcarbamate-co-glycidyl dodecyl-
carbamate) (P(GAPDEA16-co-GDDA
11)) (4)
P(GPC)27 (2) (0.707 g, 3.51 mmol carbonate) was dissolved in tetra-
hydrofuran (10 mL) and a solution of N-(3-aminopropyl)diethanol-
amine (0.284 g, 1.75 mmol), and dodecylamine (0.325 g, 1.75 mmol)
in tetrahydrofuran (5 mL) was added in 1 h at 0 °C using a syringe
pump. The reaction was allowed to warm to room temperature and
stirred for 42 h. The solvent was removed under reduced pressure and
the polymer purified by dialysis in methanol. Polymer 4 was obtained
as a colorless viscous liquid (0.655 g, 66%). Mn,NMR = 7337 g mol–1,
Mn,SEC = 14,100 g mol–1, Ð = 3.56. 1H NMR (400 MHz, MeOD) (4):
δ = 0.92 (t, 3JHH = 7.0 Hz, NHCH2CH2(CH2)9CH3), 1.31 (s, NHCH2-
CH2(CH2)9CH3), 1.44–1.59 (m, NHCH2CH2(CH2)9CH3), 1.62–1.76
(m, NHCH2CH2CH2N(CH2CH2OH)2), 1.85–1.92 (m, ArCH2CH2),
2.55–2.74 (m, CH2N(CH2CH2OH)2), 3.06–3.14 (m, NHCH2CH2-
(CH2)9CH3), 3.15–3.23 (m, NHCH2CH2CH2N(CH2CH2OH)2), 3.62 (t, 3JHH = 5.4 Hz, CH2N(CH2CH2OH)2), 3.66–3.81 (m, ArCH2CH2-CH2,
OCH2CH(CH2OC=ONHR)O), 4.00–4.34 (m, OCH2CH(CH2O-
C=ONHR)O), 7.17–7.32 (m, ArCH2CH2) ppm. 13C NMR (101 MHz,
MeOD) (4): δ = 14.6 (NHCH2CH2(CH2)9CH3), 23.8–30.9 (NH-
CH2CH2(CH2)9CH3), 28.2 (NHCH2CH2CH2N(CH2CH2OH)2), 33.1
(NHCH2CH2(CH2)9CH3), 40.1 (NHCH2CH2CH2N(CH2CH2OH)2),
42.0 (NHCH2CH2(CH2)9CH3), 53.6 (CH2N(CH2CH2OH)2), 57.6
(CH2N(CH2CH2OH)2), 60.8 (CH2N(CH2CH2OH)2), 65.3–79.3
(ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 129.4 (ArCH2),
129.6 (ArCH2), 158.7 (OCH2CH(CH2OC=ONHR)O) ppm.
Chapter 4
59
Synthesis of poly(glycidyl 3-trimethylaminopropylcarbamate-co-glycidyl dodecyl-
carbamate) (P(GTMAPA15-co-GDDA
12)) (5)
P(GDMAPA15-co-GDDA
12) (3) (0.147 g, 0.34 mmol ―NMe2) was dissolved
in THF (3.0 mL). Methyl iodide (0.058 g, 0.41 mmol) was added and
the solution was stirred for 20 h at room temperature. Excess methyl
iodide and the solvent were removed under reduced pressure and the
polymer purified by dialysis in methanol. Polymer 5 was obtained as a
yellowish crystalline solid (0.205 g, 89%). Mn,NMR = 10,111 g mol–1,
Mn,SEC = 4400 g mol–1, Ð = 1.18. 1H NMR (400 MHz, DMSO-d6) (5):
δ = 0.74–0.90 (m, NHCH2CH2(CH2)9CH3), 1.20 (s, NHCH2CH2-
(CH2)9CH3), 1.30–1.44 (m, NHCH2CH2(CH2)9CH3), 1.72–1.91 (m,
NHCH2CH2CH2N+(CH3)3, ArCH2CH2), 2.55–2.62 (m, 3JHH = 7.6 Hz,
ArCH2CH2), 2.85–2.99 (m, NHCH2CH2(CH2)9CH3), 3.00–3.17 (m,
NHCH2CH2CH2N+(CH3)3, NHCH2CH2CH2N+(CH3)3), 3.26–3.43
(m, NHCH2CH2CH2N+(CH3)3), 3.44–3.74 (m, ArCH2CH2CH2,
OCH2CH(CH2OC=ONHR)O), 3.82–4.19 (m, OCH2CH(CH2O-
C=ONHR)O), 7.10–7.30 (m, ArCH2CH2) ppm. 13C NMR (101 MHz,
DMSO-d6) (5): δ = 13.8 (NHCH2CH2(CH2)9CH3), 22.0–28.9 (NH-
CH2(CH2)10CH3), 26.2 (NHCH2CH2CH2N+(CH3)3), 31.2 (NHCH2-
(CH2)10CH3), 37.3 (NHCH2CH2CH2N+(CH3)3), 52.2 (NHCH2CH2-
CH2N+(CH3)3), 63.2 (NHCH2CH2CH2N+(CH3)3), 68.6–77.0 (ArCH2-
CH2CH2, OCH2CH(CH2OC=ONHR)O), OCH2CH(CH2OC=O-
NHR)O), 125.5 (ArCH2), 128.9 (ArCH2), 141.5 (ArCH2), 156.0
(OCH2CH(CH2OC=ONHR)O) ppm.
Synthesis of poly(glycidyl 3-aminopropyldiethanolmethylcarbamate-co-glycidyl
dodecylcarbamate) (P(GAPDEMA16-co-GDDA
11)) (6)
P(GAPDEA16-co-GDDA
11) (4) (0.216 g, 0.47 mmol ―NEtOH2) was
dissolved in THF (2.5 mL). Methyl iodide (0.081 g, 0.57 mmol) was
added and the solution was stirred for 20 h at room temperature.
Excess methyl iodide and the solvent were removed under reduced
pressure and the polymer purified by dialysis in methanol. Polymer 6
was obtained as a slightly yellow solid (0.238 g, 84%). Mn,NMR =
9608 g mol–1, Mn,SEC = not measurable. 1H NMR (400 MHz, MeOD)
(6): δ = 0.96 (t, 3JHH = 6.3 Hz, NHCH2CH2(CH2)9CH3), 1.35 (s,
NHCH2CH2(CH2)9CH3), 1.48–1.65 (m, NHCH2CH2(CH2)9CH3),
1.88–1.99 (m, ArCH2CH2), 2.05–2.23 (m, NHCH2CH2CH2N+(CH3-
Chapter 4
60
(CH2CH2OH)2)), 2.70–2.78 (m, ArCH2CH2), 3.09–3.20 (m,
NHCH2CH2(CH2)9CH3), 3.24–3.42 (m, NHCH2CH2CH2N+(CH3-
(CH2CH2OH)2)), 3.51–3.96 (m, ArCH2CH2CH2, OCH2CH(CH2-
OC=ONHR)O, CH2N+(CH3(CH2CH2OH)2)), 4.02–4.42 (m, OCH2-
CH(CH2OC=ONHR)O, CH2N+(CH3(CH2CH2OH)2)), 7.20–7.36 (m,
ArCH2CH2) ppm. 13C NMR (101 MHz, MeOD) (6): δ = 14.5
(NHCH2CH2(CH2)9CH3), 23.7–31.0 (NHCH2CH2(CH2)9CH3), 28.0
(NHCH2CH2CH2N+(CH3(CH2CH2OH)2), 33.0 (NHCH2CH2(CH2)9-
CH3), 38.9 (NHCH2CH2CH2N+(CH3(CH2CH2OH)2)), 42.0 (NHCH2-
CH2(CH2)9CH3), 50.9 (NHCH2CH2CH2N+(CH3(CH2CH2OH)2), 56.8
(NHCH2CH2CH2N+(CH3(CH2CH2OH)2), 62.8–79.1 (ArCH2CH2-
CH2, OCH2CH(CH2OC=ONHR)O), 65.4 (CH2N+(CH3(CH2CH2-
OH)2), 129.4 (ArCH2), 129.6 (ArCH2), 158.7 (OCH2CH(CH2OC=O-
NHR)O) ppm.
Synthesis of poly(glycidyl-4-nitrophenyl carbonate) (P(GNPC)27) (7)
PG27 (1) (2.012 g, 27.16 mmol OH) was dissolved in pyridine
(18.85 mL). The 4-nitrophenyl chloroformate (6.023 g, 29.88 mmol)
was dissolved in dichloromethane (20 mL) and added to the polymer
solution via syringe pump in 30 min at 0 °C. The solution was stirred
for 20 h at room temperature. The crude product was washed with
water (30 mL), 1 M HCl (aq.) (3 · 30 mL), and saturated NaCl solution
(aq.) (30 mL). The organic phase was separated, dried over Na2SO4
and precipitated in cold MeOH. The solvent was removed under
reduced pressure and polymer 7 was obtained as a colorless solid
(5.782 g, 89%). Mn,NMR = 6458 g mol–1, Mn,SEC = 6600 g mol–1, Ð =
1.41. 1H NMR (400 MHz, DMSO-d6) (7): δ = 1.69–1.83 (m,
ArCH2CH2), 2.54–2.61 (m, ArCH2CH2), 3.54–3.95 (m, ArCH2CH2-
CH2, OCH2CH(CH2OC=OOArNO2)O), 4.15–4.56 (d, CH2OC=O-
OArNO2), 7.08–7.25 (m, ArCH2CH2), 7.42 (s, CH2OC=OOArNO2),
8.18 (s, CH2OC=OOArNO2) ppm. 13C NMR (101 MHz, DMSO-d6)
(7): δ = 30.8 (ArCH2CH2), 31.6 (ArCH2), 68.2 (OCH2CH(CH2OC=O-
OArNO2)O), 76.4 (OCH2CH(CH2OC=OOArNO2)O), 76.5 (ArCH2-
CH2CH2), 76.6 (OCH2CH(CH2OC=OOArNO2)O), 122.3 (CH2O-
C=OOArNO2), 125.2 (CH2OC=OOArNO2), 125.7 (ArCH2), 128.2
(ArCH2), 128.3 (ArCH2), 141.6 (ArCH2), 145.0 (CH2OC=OOAr-
NO2), 152.0 (OC=OO), 155.1 (CH2OC=OOArNO2) ppm.
Chapter 4
61
Synthesis of poly(glycidyl homocysteine thiolactonylcarbamate) (P(GHCTL)27) (8)
P(GNPC)27 (7) (1.020 g, 4.26 mmol carbonate) was dissolved in DMF
(10 mL), and 4-(dimethylamino)pyridine (0.053 g, 0.43 mmol) and DL-
homocysteine thiolactone hydrochloride (0.655 g, 4.26 mmol) were
added. The mixture was cooled to 0 °C and triethylamine (0.862 g,
8.52 mmol) was added over 1 h via syringe pump. The solution was
stirred for 20 h at room temperature. DMF was removed under
reduced pressure at 50 °C and the crude product was precipitated in
MeOH. Drying under reduced pressure at 50 °C gave polymer 8 as a
slightly yellow solid (0.694 g, 75%). Mn,NMR = 5865 g mol–1, Mn,SEC =
6900 g mol–1, Ð = 1.44. 1H NMR (400 MHz, DMSO-d6) (8): δ = 1.74–
1.83 (m, ArCH2CH2), 2.00–2.48 (m, C=OSCH2CH2CHR), 2.60 (t, 3JH,H = 7.5 Hz, ArCH2CH2), 3.17–3.45 (m, C=OSCH2CH2CHR), 3.47–
3.75 (m, ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 3.86–4.23
(m, CH2OC=ONHR), 4.26–4.42 (m, C=OSCH2CH2CHR), 7.14–7.29
(Ar), 7.55 (br s, NH) ppm. 13C NMR (101 MHz, DMSO-d6) (8): δ =
26.5 (C=OSCH2CH2CHR), 29.8 (C=OSCH2CH2CHR), 30.9
(ArCH2CH2), 31.6 (ArCH2), 59.9 (CH2OC=ONHR), 63.7, 68.7, 77.2
(ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 79.2 (C=OSCH2-
CH2CHR), 128.3 (ArCH2), 128.4 (ArCH2), 156.0 (OC=ONHR), 205.7
(C=OSCH2CH2CHR) ppm.
Synthesis of P(GDDAc)27 (9)
To a mixture of P(GHCTL)27 (8) (0.301 g, 1.386 mmol HCTL) and
dodecyl acrylate (0.833 g, 3.464 mmol) in chloroform (3.0 mL), 3-
(dimethylamino)-1-propylamine (0.353 g, 3.464 mmol) was added in
30 min via syringe pump at room temperature. The mixture was stirred
for 20 h at room temperature. Chloroform was removed under re-
duced pressure. Dialysis in acetone gave 9 as a colorless, viscous liquid
(0.628 g, 81%). Mn,NMR = 15,115 g mol–1, Mn,SEC = 15,300 g mol–1, Ð =
1.36. 1H NMR (400 MHz, CDCl3) (9): δ = 0.82 (t, 3JH,H = 6.8 Hz,
CH2CH2(CH2)9CH3), 1.20 (s, CH2CH2(CH2)9CH3), 1.48–1.69 (m,
CH2CH2N(CH3)2, CH2CH2(CH2)9CH3, ArCH2CH2), 1.76–2.08 (m,
CHCH2CH2SCH2), 2.15 (s, CH2N(CH3)2), 2.22–2.37 (m, CH2N-
(CH3)2), 2.43–2.61 (m, CHCH2CH2SCH2CH2), 2.64–2.78 (m, CHCH2-
CH2SCH2CH2), 3.07–3.37 (m, NHCH2CH2CH2N(CH3)2), 3.41–3.75
(m, ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 3.77–4.07 (m,
Chapter 4
62
CH2OC=ONHCH), 4.10–4.41 (m, O=COCH2CH2), 7.09–7.23 (m,
Ar), 7.76 (br. s, NH) ppm. 13C NMR (101 MHz, CDCl3) (9): δ = 14.1
(CH2CH2(CH2)9CH3), 22.7–31.9 (CH2CH2(CH2)9CH3, CHCH2CH2S-
CH2, ArCH2CH2), 26.8 (CHCH2CH2SCH2CH2), 28.2 (CH2CH2N-
(CH3)2), 28.6 (CHCH2CH2SCH2CH2), 34.7 (CHCH2CH2SCH2CH2),
38.7 (NHCH2CH2CH2N(CH3)2), 45.5 (CH2N(CH3)2), 54.1 (NHCH),
57.9 (CH2N(CH3)2), 64.9 (O=COCH2CH2), 125.9 (ArCH2), 128.3
(ArCH2), 128.5 (ArCH2), 140.0 (ArCH2), 156.4 (OC=ONH), 171.5
(CHC=ONH), 172.0 (CH2C=OO) ppm.
Synthesis of P(GDDAc, q)27 (10)
P(GDDAc)27 (9) (0.431 g, 0.770 mmol ―NMe2) was dissolved in THF
(9.0 mL), and methyl iodide (0.131 g, 0.923 mmol) was added. The
solution was stirred at room temperature for 20 h. Removal of THF
and excess methyl iodide under reduced pressure and dialysis in
methanol gave polymer 10 as a slightly yellow solid (0.475 g, 88%).
Mn,NMR = 18,947 g mol–1, Mn,SEC = 11,800 g mol–1, Ð = 1.36. 1H NMR
(400 MHz, CDCl3) (10): δ = 0.81 (t, 3JH,H = 6.5 Hz, CH2CH2(CH2)9-
CH3), 1.05–1.32 (m, CH2CH2(CH2)9CH3), 1.46–1.62 (m, CH2CH2-
(CH2)9CH3), 1.85–2.25 (m, CH2CH2N+(CH3)3, ArCH2CH2, CHCH2-
CH2SCH2), 2.39–2.64 (m, CHCH2CH2SCH2CH2), 2.66–2.82 (m,
CHCH2CH2SCH2CH2), 3.05–3.50 (m, NHCH2CH2CH2N+(CH3)3),
3.51–3.83 (m, ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 3.84–
4.50 (m, CH2OC=ONHCH, O=COCH2CH2), 7.08–7.24 (m, Ar), 7.77
(br. s, NH) ppm. 13C NMR (101 MHz, CDCl3) (10): δ = 14.1
(CH2CH2(CH2)9CH3), 22.6–31.9 (CH2CH2(CH2)9CH3, CHCH2CH2S-
CH2, ArCH2CH2), 26.7 (CHCH2CH2SCH2CH2), 28.3 (CH2CH2N+-
(CH3)3), 28.6 (CHCH2CH2SCH2CH2), 34.8 (CHCH2CH2SCH2CH2),
40.1 (NHCH2CH2CH2N+(CH3)3), 53.8 (CH2N+(CH3)3, NHCH), 64.9
(CH2N+(CH3)3, O=COCH2CH2), 156.5 (OC=ONH), 172.1 (CHC=O-
NH), 172.8 (CH2C=OO) ppm.
Synthesis of P(GDMAPA14-co-GDDADDAc
13) (11)
P(GNPC)27 (7) (0.541 g, 2.26 mmol carbonate) was dissolved in DMF
(11 mL) and 3-(dimethylamino)-1-propylamine (0.115 g, 1.13 mmol)
was added in 30 min via syringe pump. The mixture was stirred for
20 h at room temperature. DL-homocysteine thiolactone hydro-
Chapter 4
63
chloride (0.174 g, 1.13 mmol) and 4-(dimethylamino)pyridine (0.013 g,
0.11 mmol) were added. The mixture was cooled to 0 °C, and triethyl-
amine (0.229 g, 2.26 mmol) was added over 1 h via syringe pump. The
solution was stirred for 20 h at room temperature. DMF was removed
under reduced pressure at room temperature. The crude product was
dissolved in chloroform, and dodecyl acrylate (0.680 g, 2.83 mmol) was
added. The mixture was cooled to 0 °C, and dodecylamine (0.525 g,
2.83 mmol) was added in 30 min using a syringe pump. After stirring
for 20 h at room temperature, the solvent was removed and the crude
product was purified by dialysis in acetone. Polymer 11 was received
as a slightly yellow, viscous liquid (0.469 g, 48%). Mn,NMR =
11,631 g mol–1, Mn,SEC = 10,800 g mol–1, Ð = 1.36. 1H NMR
(400 MHz, CDCl3/acetone-d6 (6:4)) (11): δ = 0.81 (t, 3JH,H = 6.6 Hz
CH2CH2(CH2)9CH3), 1.20 (s, CH2CH2(CH2)9CH3), 1.38–1.50 (m,
NHCH2CH2(CH2)9CH3), 1.51–1.64 (m, OCH2CH2(CH2)9CH3), 1.70–
1.86 (m, CH2CH2N(CH3)2), 1.88–2.01 (m, CHCH2CH2SCH2), 2.29–
2.77 (m, CH2N(CH3)2, CHCH2CH2SCH2CH2), 2.97–3.30 (m,
NHCH2CH2CH2N(CH3)2, NHCH2CH2(CH2)9CH3), 3.44–3.79 (m,
ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 3.90–4.34 (m,
CH2OC=ONHR, CH2OC=ONHCH, O=COCH2CH2), 7.07–7.24
(m, Ar) ppm. 13C NMR (101 MHz, CDCl3/acetone-d6 (6:4)) (11): δ =
13.5 (CH2CH2(CH2)9CH3), 22.1–31.4 (CH2CH2(CH2)9CH3, CHCH2-
CH2SCH2, ArCH2CH2, CH2CH2N(CH3)2), 34.2 (CHCH2CH2SCH2-
CH2), 38.4 (NHCH2CH2CH2N(CH3)2), 39.0 (NHCH2CH2(CH2)9-
CH3), 43.7 (CH2N(CH3)2), 53.3 (NHCH), 56.0 (CH2N(CH3)2), 64.2
(O=COCH2CH2), 127.8 (ArCH2), 127.9 (ArCH2), 155.9 (OC=ONH),
156.2 (OC=ONH), 171.4 (CHC=ONH), 172.1 (CH2C=OO) ppm.
Synthesis of P(GTMAPA14-co-GDDADDAc
13) (12)
P(GDMAPA14-co-GDDADDAc
13) (11) (0.179 g, 0.20 mmol ―NMe2) was
dissolved in THF (2.0 mL), and methyl iodide (0.036 g, 0.25 mmol)
was added. The solution was stirred at room temperature for 20 h.
Removal of THF and excess methyl iodide under reduced pressure
and dialysis in methanol gave polymer 12 as a slightly yellow solid
(0.203 g, quant.). Mn,NMR = 13,476 g mol–1, Mn,SEC = 9400 g mol–1, Ð =
1.41. 1H NMR (400 MHz, CDCl3/acetone-d6 (6:4)) (12): δ = 0.80 (t, 3JH,H = 6.8 Hz CH2CH2(CH2)9CH3), 1.18 (s, CH2CH2(CH2)9CH3),
Chapter 4
64
1.36–1.48 (m, NHCH2CH2(CH2)9CH3), 1.50–1.66 (m, OCH2CH2-
(CH2)9CH3), 1.74–2.01 (m, CH2CH2N+(CH3)3, CHCH2CH2SCH2),
2.42–2.89 (m, CHCH2CH2SCH2CH2), 2.94–3.45 (m, NHCH2CH2-
CH2N+(CH3)3, NHCH2CH2(CH2)9CH3), 3.49–3.81 (m, ArCH2CH2-
CH2, OCH2CH(CH2OC=ONHR)O), 3.87–4.38 (m, CH2OC=O-
NHR, CH2OC=ONHCH, O=COCH2CH2), 7.03–7.23 (m, Ar) ppm. 13C NMR (101 MHz, CDCl3/acetone-d6 (6:4)) (12): δ = 13.4 (CH2CH2-
(CH2)9CH3), 22.1–31.3 (CH2CH2(CH2)9CH3, CHCH2CH2SCH2, Ar-
CH2CH2, CH2CH2N(CH3)2), 34.2 (CHCH2CH2SCH2CH2), 38.9 (NH-
CH2CH2(CH2)9CH3), 43.0 (NHCH2CH2CH2N+(CH3)2), 53.0 (CH2N+-
(CH3)3), 53.8 (NHCH), 64.1 (CH2N(CH3)2, O=COCH2CH2), 127.8
(ArCH2), 127.9 (ArCH2), 141.3 (ArCH2), 155.9 (OC=ONH), 156.4
(OC=ONH), 171.3 (CHC=ONH), 171.4 (CH2C=OO) ppm.
4.3 Results and Discussion
In this chapter, the synthesis and characterization of various novel
cationic/hydrophobic functionalized polyglycidols is presented. The
functional polyethers are evaluated in regard to their antibacterial acti-
vity against E. coli and S. aureus, induced by different microstructures.
Thereto, a polyglycidol with statistically distributed cationic and hydro-
phobic groups (cationic–hydrophobic ratio of 1:1) was compared to
(a) a polyglycidol with a hydrophilic modification at the cationic moie-
ties; (b) a polyglycidol with cationic and hydrophobic functionalities at
every repeating unit; and (c) a polyglycidol with a cationic–hydro-
phobic balance of 1:2 (Fig. 4.1).
Linear polyglycidol was synthesized by anionic ring-opening poly-
merization of ethoxyethyl glycidyl ether with 3-phenyl-1-propanol as
initiator, followed by removal of the acetal protecting groups under
acidic conditions.38 Polyglycidol with 27 repeating units (PG27 (1)) and
Mn,SEC = 2900 g mol–1 was obtained with a narrow molecular weight
distribution (Ð = 1.13). 1H, 13C NMR spectra and SEC analysis of
PG27 (1) can be found in the supporting information (Fig. A.2.1–A.2.3,
appendix A.2).
Chapter 4
65
Figure 4.1: Comparison of various cationic/hydrophobic functionalized poly-
glycidols in regard to their antibacterial activity against E. coli and S. aureus to
examine the structure–property relationship.
4.3.1 Synthesis of P(GTMAPA15-co-GDDA
12) (5) and P(GAPDEMA16-co-
GDDA11) (6)
The general approach for the functionalization of linear polyglycidol
with cationic and hydrophobic groups starts with the introduction of
active ester functionalities to the polymer backbone. The active esters
allow the reaction with primary amines under the selective formation
of carbamate moieties. Quaternization of introduced tertiary amines
gave the cationic component.
Chapter 4
66
PG27 (1) was reacted with phenyl chloroformate in pyridine/
dichloromethane at room temperature (Scheme 4.1a). For purification,
poly(glycidyl phenyl carbonate)27 (2) was washed with water, 1 M HCl
solution (aq.), and saturated NaCl solution (aq.) to remove pyridine
hydrochloride and excess pyridine. The successful functionalization
was confirmed by 1H NMR, 13C NMR spectroscopy (Fig. A.2.4–A.2.5,
appendix A.2), and SEC analysis (Fig. A.2.12, appendix A.2). The
introduced phenyl carbonate groups are excellent electrophiles for the
substitution reaction with non-functionalized, primary amines.
P(GPC)27 (2) was subsequently reacted with dodecylamine (DDA) and
3-(dimethylamino)-1-propylamine (DMAPA) or N-(3-aminopropyl)-
diethanolamine (APDEA) in THF at room temperature in a 1:1 ratio
(Scheme 4.1b). The prepared poly(glycidyl 3-dimethylaminopropyl-
carbamate-co-glycidyl dodecylcarbamate) (P(GDMAPA15-co-GDDA
12)) (3)
and poly(glycidyl 3-aminopropyldiethanolcarbamate-co-glycidyl do-
decylcarbamate) (P(GAPDEA16-co-GDDA
11)) (4) were purified by dialysis
in methanol and characterized by 1H NMR, 13C NMR spectroscopy
(Fig. A.2.6–A.2.9, appendix A.2), and SEC analysis (Fig. A.2.13–
A.2.14, appendix A.2).
Scheme 4.1: Synthetic pathway to P(GTMAPA15-co-GDDA
12) (5) and
P(GAPDEMA16-co-GDDA
11) (6). (a) Functionalization of PG27 (1) with phenyl
chloroformate, pyridine/DCM, rt, 20 h; (b) Reaction of P(GPC)27 (2) with
DDA and DMAPA/APDEA, THF, rt, 42 h; (c) Quaternization of tertiary
amines with methyl iodide, THF, rt, 20 h.
In both cases, the different functional groups are statistically
distributed along the polyglycidol backbone. However, the higher
reactivity of DMAPA and APDEA in comparison to DDA leads to a
Chapter 4
67
slightly uneven ratio of functionalities. P(GDMAPA15-co-GDDA
12) (3) and
P(GAPDEA16-co-GDDA
11) (4) were further reacted with an excess of
methyl iodide in THF at room temperature to quaternize the tertiary
amine moieties (Scheme 4.1c). The synthesized P(GTMAPA15-co-GDDA
12)
(5) and P(GAPDEMA16-co-GDDA
11) (6) were purified by dialysis in metha-
nol and analyzed by 1H NMR, 13C NMR, and SEC analysis. 1H and 13C NMR spectra of P(GTMAPA
15-co-GDDA12) (5) in DMSO-d6
show characteristic signals of the dodecyl and trimethylpropyl-
ammonium groups adjacent to the carbamate moieties, proving the
successful functionalization of PG27 (1). In the 1H NMR spectrum
(Fig. 4.2a), the characteristic signals of the dodecyl functionality appear
as three multiplets at δ = 0.74–0.90 (Signal 20), δ = 1.30–1.44 (Signal
18), and δ = 2.85–2.99 ppm (Signal 17), and a singlet at δ = 1.20 ppm
(Signal 19). The trimethylpropylammonium groups are shown as three
multiplets δ = 1.72–1.91 (Signal 11), δ = 3.00–3.17 (Signal 10/13), and
δ = 3.26–3.43 ppm (Signal 12). A multiplet at δ = 3.82–4.19 ppm
(Signal 9/16) shows the methylene group of the glycidol repeating unit.
In the 13C NMR spectrum (Fig. A.2.10, appendix A2), the distinctive
signals of the dodecyl groups are found at δ = 13.8 (Signal 23), δ =
22.0–28.9 (Signal 22), and δ = 31.2 ppm (Signal 21). The representative
signals of the trimethylpropylammonium functionality are shown at
δ = 26.2 (Signal 13), δ = 37.3 (Signal 12), δ = 52.2 (Signal 15), and δ
= 63.2 ppm (Signal 14). Further, the signal of the carbamate groups
can be found at δ = 156.0 ppm (Signal 11/19).
The number of DMAPA and DDA groups attached to PG27 (1) was
calculated by comparing the signal intensity of one methylene group
of the 3-phenyl-1-propanol (Signal 4) used in the synthesis of 1 with
signals 10/11/13 and signals 18–20, respectively. The absolute
molecular weight (Mn,NMR) was calculated using the 3-phenyl-1-propyl
end group as an internal reference (Mn,NMR = 10,111 g mol–1). Full
functionalization of PG27 (1) was reached.
SEC analysis using DMF as eluent confirms the synthesis of
P(GTMAPA15-co-GDDA
12) (5) with Mn,SEC = 4400 g mol–1 and a molecular
weight distribution of Ð = 1.18 (Fig. A.2.15, appendix A.2). However,
due to the amphiphilic nature of this polymer and resulting
interactions with the column, the molecular weight measured by SEC
Chapter 4
68
analysis is lower than the molecular weight calculated from the 1H
NMR spectrum.
Figure 4.2: 1H NMR spectra of P(GTMAPA15-co-GDDA
12) (5) measured in
DMSO-d6 (a) and P(GAPDEMA16-co-GDDA
11) (6) measured in MeOD (b).
1H and 13C NMR spectra of P(GAPDEMA16-co-GDDA
11) (6) were
measured in MeOD due to the poor solubility of the polymer in
DMSO-d6. In the 1H NMR spectrum (Fig. 4.2b), this leads to a shift
of all signals to lower field. Thus, the characteristic signals for the
dodecyl functionality and the cationic moiety can be found in analogy
to P(GTMAPA15-co-GDDA
12) (5). Additionally, the signals of the hydroxy-
ethyl group can be found in the multiplets at δ = 3.51–3.96 (Signal 13)
and δ = 4.02–4.42 ppm (Signal 14). In the 13C NMR spectrum (Fig.
A.2.11, appendix A.2), the signals are also shifted to lower fields in
comparison with P(GTMAPA15-co-GDDA
12) (5), except for signals of the
methyl group and methylene group adjacent to the cationic moiety that
are shifted to higher fields. The methyl group can be found at δ =
Chapter 4
69
50.9 ppm (Signal 17) and the methylene group is found at δ =
56.8 ppm (Signal 14). Additionally, the hydroxyethyl group is shown
at δ = 65.4 ppm (Signal 15/16). The number of functionalities and the
absolute molecular weight was calculated as described previously
(Mn.NMR = 9608 g mol−1). Both spectra confirm the successful
synthesis of P(GAPDEMA16-co-GDDA
11) (6).
SEC analysis of P(GAPDEMA16-co-GDDA
11) (6) using DMF was not
possible. SEC analysis of the precursor P(GAPDEA16-co-GDDA
11) (4) con-
firmed the successful synthesis with Mn,SEC = 14,100 g mol–1 and a
molecular weight distribution of Ð = 3.56 (Fig. A.2.14, appendix A.2).
However, hydrogen bonding between polymer molecules leads to the
generation of polymer aggregates and, thus, a high molecular weight
and a broad distribution.
4.3.2 Synthesis of P(GDDAc, q)27 (10)
The previous part showed that phenyl carbonates are excellent
electrophiles for the substitution reaction of non-functionalized,
reactive, primary amines. For the reaction with homocysteine
thiolactone the electrophilicity of the carbonate needs to be higher
than that of the carbonyl group of the thiolactone ring to prevent the
reaction of the homocysteine thiolactone with itself. We have shown
in our previous work that 4-nitrophenyl carbonates show a higher
reactivity compared to phenyl carbonates in aminolysis reactions and
are suitable for the reaction with functional, primary amines.41,42
PG27 (1) was reacted with 4-nitrophenyl chloroformate in pyridine/
dichloromethane at room temperature (Scheme 4.2a). For purification,
poly(glycidyl 4-nitrophenyl carbonate)27 (7) was washed with water,
1 M HCl solution (aq.), and saturated NaCl solution (aq.) to remove
pyridine hydrochloride and excess pyridine, and precipitated in metha-
nol. The successful functionalization was confirmed by 1H, 13C NMR
spectroscopy (Fig. A.2.16–A.2.17, appendix A.2), and SEC analysis
(Fig. A.2.23, appendix A.2). P(GNPC)27 was afterwards reacted with DL-
homocysteine thiolactone hydrochloride in DMF at room temperature
using catalytic amounts of 4-DMAP and Et3N as a base (Scheme 4.2b).
The resulting poly(glycidyl homocysteine thiolactonylcarbamate)27
(P(GHCTL)27) (8) was purified by precipitation in methanol and charac-
terized by 1H, 13C NMR spectroscopy (Fig. A.2.18–A.2.19, appendix
Chapter 4
70
A.2), and SEC analysis (Fig. A.2.24, appendix A.2). In a one-pot reac-
tion, P(GHCTL)27 (8) was reacted with DMAPA under ring-opening in
CHCl3 at room temperature, and the generated thiol was converted
with dodecyl acrylate in a thiol-ene reaction. The synthesized
P(GDDAc)27 (9) was purified by dialysis in acetone and characterized by 1H NMR, 13C NMR spectroscopy (Fig. A.2.20–A.2.21, appendix A.2),
and SEC analysis (Fig. A.2.25, appendix A.2). P(GDDAc)27 (9) was
subsequently quaternized with methyl iodide in THF at room
temperature. The crude product was dialyzed in methanol to remove
excess methyl iodide, and P(GDDAc, q) (10) was described by 1H, 13C
NMR spectroscopy, and SEC analysis.
Scheme 4.2: Synthetic pathway to P(GDDAc, q)27 (10). (a) Functionalization of
PG27 (1) with 4-nitrophenyl chloroformate, pyridine/DCM, rt, 20 h; (b)
Reaction of P(GNPC)27 (7) with DL-homocysteine thiolactone hydrochloride,
4-DMAP, Et3N, DMF, rt, 20 h; (c) Ring-opening reaction with DMAPA,
followed by thiol-ene reaction with dodecyl acrylate, CHCl3, rt, 20 h; (d)
Quaternization of tertiary amines with methyl iodide, THF, rt, 20 h.
P(GDDAc, q)27 (10) exhibits characteristic signals of the introduced
functionalities in the 1H and 13C NMR spectra measured in DMSO-d6.
In the 1H NMR spectrum (Fig. 4.3a), the trimethylpropylammonium
group is described by two multiplets at δ = 1.85–2.25 (Signal 13) and
δ = 3.05–3.50 ppm (Signals 12/14/15). The dodecyl acrylate moiety is
shown as a triplet at δ = 0.81 ppm (Signal 23) and two multiplets at δ
= 1.05–1.32 (Signal 22) and δ = 1.46–1.62 ppm (Signal 21). Two
multiplets at δ = 2.39–2.64 (Signals 17/19) and δ = 2.66–2.82 ppm
(Signal 18) are distinctive for the methylene groups adjacent to the
thioether. The signals at δ = 3.84–4.50 ppm (Signals 10/11/20) show
Chapter 4
71
the methylene groups adjacent to the ester functionality and the single
proton adjacent to the carbamate moiety. The multiplet also contains
the methylene groups of the PG repeating unit adjacent to the
carbamate. In the 13C NMR spectrum (Fig. A.2.22, appendix A.2), the
distinctive signals can be found at δ = 28.3 (Signal 15), δ = 40.1 (Signal
14), δ = 53.8 (Signal 17), and δ = 64.9 ppm (Signal 16) for the
trimethylpropylammonium functionality; at δ = 14.1 (Signal 26), δ =
22.6–31.9 (Signals 24/25), and δ = 64.9 ppm (Signal 23) for the
dodecyl acrylate; and at δ = 26.7, δ = 28.6 (Signal 18–20) and δ =
34.8 ppm (Signal 21) for the methylene groups adjacent to the
thioether.
Figure 4.3: 1H NMR spectra of P(GDDAc, q)27 (10) measured in CDCl3 (a) and
P(GTMAPA14-co-GDDADDAc
13) (12) measured in CDCl3/acetone (6:4) (b).
Chapter 4
72
The number of functionalities and the absolute molecular weight were
calculated as described previously (Mn.NMR = 18,947 g mol−1). Both
spectra confirm the successful synthesis of P(GDDAc, q) (10).
SEC analysis using DMF as eluent also confirms the successful
synthesis of P(GDDAc, q)27 (10) with Mn,SEC = 11,800 g mol−1 and a
molecular weight distribution of Ð = 1.36 (Fig. A.2.26, appendix A.2).
4.3.3 Synthesis of P(GTMAPA14-co-GDDADDAc
13) (12)
The preparation of P(GTMAPA14-co-GDDADDAc
13) (12) combines both
previously described synthetic approaches. In a one-pot synthesis,
P(GNPC)27 (7) was first reacted with DMAPA in DMF at room
temperature for 20 h (Scheme 4.3a). After full conversion of the
primary amine (monitored by 1H NMR spectroscopy), 4-DMAP, DL-
homocysteine thiolactone hydrochloride, and triethylamine were
added, and the reaction was stirred for another 20 h at room tem-
perature. The crude product was reacted without further purification
with dodecylamine and dodecyl acrylate in chloroform at room
temperature (Scheme 4.3b). The crude product was purified by dialysis
in acetone and P(GDMAPA14-co-GDDADDAc
13) (11) characterized by 1H
NMR, 13C NMR spectroscopy (Fig. A.2.27–A.2.28, appendix A.2), and
SEC analysis (Fig. A.2.30, appendix A.2).
P(GDMAPA14-co-GDDADDAc
13 (11) was subsequently quaternized with
methyl iodide in THF at room temperature, purified by dialysis in
methanol, and characterized by the previously described methods
(Scheme 4.3c).
Due to the strong amphiphilic nature of P(GTMAPA14-co-GDDADDAc
13)
(12), 1H and 13C NMR spectroscopy were performed in a mixture of
CDCl3 and acetone-d6. In the 1H NMR spectrum (Fig. 4.3b), the
distinctive signals of the hydrophobic moiety are found at δ = 0.80
(Signal 14/22), δ = 1.18 (Signal 13/21), δ = 1.36–1.48 (Signal 12), and
δ = 1.50–1.66 ppm (Signal 20). The methylene group adjacent to the
ester is shown at δ = 3.87–4.38 ppm (Signal 19). This signal also
includes the methylene groups (Signal 9/25) and the single proton
(Signal 10) adjacent to the carbamate moieties. Specific signals of the
cationic functionalities are found at δ = 1.74–2.01 (Signal 27) and δ =
2.94–3.45 ppm (Signal 26/28/29). The shift of the signals of all
functional groups is in good comparison with the polymers described
Chapter 4
73
earlier. In the 13C NMR spectrum, the shifts of the various signals are
also in good comparison to the previously characterized cationic/
hydrophobic polymers (Fig. A.2.29, appendix A.2). Both spectra
confirm the successful synthesis of P(GTMAPA14-co-GDDADDAc
13) (12).
Scheme 4.3: Synthetic pathway to P(GTMAPA14-co-GDDADDAc
13) (12). (a) (I)
Reaction of P(GNPC)27 (7) with DMAPA, DMF, rt, 20 h, (II) Reaction with DL-
homocysteine thiolactone hydrochloride, 4-DMAP, Et3N, DMF, 20 h; (b)
Ring-opening reaction with dodecylamine, followed by thiol-ene reaction with
dodecyl acrylate, CHCl3, rt, 20 h; (c) Quaternization of tertiary amines with
methyl iodide, THF, rt, 20 h.
The number of functionalities and the absolute molecular weight were
calculated as described previously (Mn.NMR = 13,476 g mol–1).
Although, the integral values shown in the 1H NMR spectra are too
low to be accurate for a polyether with 27 repeating units, the ratio of
hydrophobic to cationic moieties is accepted as accurate. The absolute
values of hydrophobic to cationic groups is extrapolated to match the
expected number of repeating units. Fractionation towards lower
molecular weights is excluded based on the method of purification.
SEC analysis using DMF as eluent also confirms the successful synthe-
sis of P(GTMAPA14-co-GDDADDAc
13) (12) with Mn,SEC = 9400 g mol–1 and
a molecular weight distribution of Ð = 1.41 (Fig. A.2.31, appendix A.2)
4.3.4 Antibacterial Efficacy
To assess the influence of the microstructure of the functional
polyglycidols on their antibacterial efficacy, the minimal inhibitory
Chapter 4
74
concentrations of the four synthesized polymers against E. coli and S.
aureus were determined (Table 4.1). In comparison to the other three
polymers (6, 10, and 12) P(GTMAPA15-co-GDDA
12) (5)—with cationic and
hydrophobic groups statistically distributed at the polyglycidol
backbone—exhibited the lowest MIC against both E. coli and S. aureus.
A hydrophilic functionalization at the quaternary amine (P(GAPDEMA16-
co-GDDA11) (6)) does not affect the efficacy against E. coli, but slightly
impairs the efficacy against S. aureus.
Table 4.1: Minimal inhibitory concentration against E. coli and S. aureus and
hemolytic activity of functional polyglycidols with defined microstructures
P(GTMAPA15-co-GDDA
12) (5), P(GAPDEMA16-co-GDDA
11) (6), P(GDDAc, q)27 (10),
P(GTMAPA14-co-GDDADDAc
13) (12).
Polymer Mn,NMR a
[g mol–1]
MIC100 b,c
[µg mL–1]
HC50 d
[µg mL–1]
E. coli S. aureus
5 10,111 30 20 >>500 f
6 9608 30 30 100
10 18,947 30 >200 <10
12 13,476 200 d >200‒500 e <10
a Molecular weight (Mn,NMR) calculated from 1H NMR with an accuracy of integration of ±5%; b Minimum inhibitory concentration which prevents the visible growth of 100% of the bacteria within 20 h monitoring time; c Inoculum size = 1–2 · 106 CFU·mL−1; d HC50: concentration causing 50% lysis (hemolysis) of red blood cells (RBCs) relative to Triton X-100 (positive control, 100%), linear polyglycidol PG27 (1) HC50 >> 500 µg mL–1; e Non-growth value due to turbidity of solution caused by the polymer; f 10–500 µg mL–1 of polymer 5 causing agglutination of RBC, and about 6% (at 10 µg mL–1) –40% (at 500 µg mL–1) hemolysis.
When the cationic and the hydrophobic residues are located at every
repeating unit of the polymer and are connected by a short spacer
(P(GDDAc, q)27 (10)), the efficacy against E. coli remains the same as for
5 and 6. However, the efficacy against S. aureus decreases significantly
by a factor of 10. The molecular weight of polymer 10 is approximately
twice as high as the molecular weight of polymers 5 and 6. Thus, the
higher MIC values in the case of S. aureus compared to E. coli might
result from a sieving effect by the thick peptidoglycan layer of the
Gram-positive bacterium. This was also discussed by Lienkamp et al.43
Chapter 4
75
In polymer 10, the hydrophobic and cationic residues are connected
by a spacer and are not directly linked to each other. Opposite to the
resulting antibacterial effect of the latter (polymer 10), functionalized
branched poly(ethylene imine)s (PEI) with amphiphilic grafts had
better antibacterial properties against S. aureus than PEI with randomly
linked cationic and hydrophobic grafts. However, best results were
obtained with the cationic residue directly linked to the aliphatic
residue without a spacer in between.30 Thus, an influence of the kind
of polymer backbone on the polymer architecture and of the kind of
amphiphilic functionality on the antibacterial effect can be discussed.
Enhancing the hydrophobic share in comparison to the cationic
functionality (P(GTMAPA14-co-GDDADDAc
13) (12) with two hydrophobic
residues in the same polymer segment, connected by a spacer) leads to
a decrease of efficacy by a factor of 10 for both E. coli and S. aureus.
The high amount of hydrophobic residues induces aggregation in
aqueous media, which might lead to a partial unavailability of func-
tional groups of the polymer. Thus, interaction with the bacterial cell
envelope is impaired, since a certain amount of cationic charge is
necessary to initiate the binding to the bacterial cell envelope as the
first step in the cascade of amphipathic polymers’ mode of action.
Compared to the 1:2 ratio of cationic to hydrophobic residues in
polymer 12, branched PEI with functionalities introduced via
carbonate coupler chemistry and a higher ratio of cationic to hydro-
phobic residues resulted in higher efficacies in the case of E. coli.29
Furthermore, azetidinium functionalized poly(vinylamine)s with a
higher ratio of hydrophobic to cationic moieties resulted in better
antibacterial efficacies against E. coli and against S. aureus.44 Thus,
apparently there is a strong influence of the polymer backbone and the
structure of the cationic and hydrophobic side chains on the micro-
structure and the efficacy besides the hydrophilic to lipophilic balance
of the respective polymer.
Additionally, polymers functionalized with amphiphilic couplers
where the cationic moiety was directly linked to the hydrophobic
residue exhibited the lowest MIC compared to randomly distributed
cationic and hydrophobic groups linked via a spacer. Ganewatta et al.
refer to a “same-centered” repeat unit structure with the hydrophobic
moiety being directly accompanied by the charged moiety, i.e., the
Chapter 4
76
functional groups not being spatially separated over the backbone,
leading to an amphiphilic balance at the monomer level.45
4.3.5 Hemolytic Activity
To understand the selectivity of polymers 5, 6, 10, and 12 to affect
bacterial cells and mammalian cells, a hemolysis test was performed,
and the concentration required for 50% lysis of human red blood cells
(RBCs) was determined (HC50, Table 4.1). Linear polyglycidol PG27 (1)
did not show any significant lysis of RBCs even at the highest
concentration (500 μg mL–1) tested. For polymer 5 at the concen-
trations tested (10–500 µg mL–1), no HC50 value could be given at the
tested concentrations (10–500 µg mL–1). Hemolysis amounted to a-
bout 6% at 10 µg mL–1, 30% at 30 µg mL–1, and 40% at 500 µg mL–1.
However, agglutination of RBCs occurred at tested concentrations.
HC50 value for polymer 6 amounted to 100 μg mL–1. The higher value
of HC50 compared to the MIC100 against E. coli and S. aureus
(30 µg mL–1) proved that polymer 6 has a selectivity to differentiate
between mammalian cells and bacterial cell walls. For comparison, the
HC50 values of polymers 10 and 12 were below the lowest concen-
tration (10 µg mL–1) tested and thus, had a low selectivity for bacterial
cell envelopes.
4.4 Conclusions
Various novel cationic/hydrophobic functionalized polyglycidols were
successfully synthesized. A polyglycidol with statistically distributed
cationic and hydrophobic groups (cationic–hydrophobic ratio of 1:1),
a polyglycidol with a hydrophilic modification at the cationic moieties,
a polyglycidol with cationic and hydrophobic functionalities at every
repeating unit, and a polyglycidol with a cationic–hydrophobic balance
of 1:2 were characterized by 1H NMR, 13C NMR spectroscopy, and
SEC analyses and evaluated in regard to their antibacterial activity.
Antibacterial polyglycidols with statistic distribution of cationic and
hydrophobic residues are equally active against a Gram-negative and a
Gram-positive bacterial strain. In contrast to this, the efficacy of
amphipathic poly(ethylene imine)s is higher by a factor of 10 against
Chapter 4
77
Gram-positive bacteria than against Gram-negative ones. However,
antibacterial polyglycidols are equally or better active against E. coli
than against S. aureus. The best efficacy against both bacterial strains
resulted from the polyglycidol with statistic distribution of the cationic
and hydrophobic residues with polymer 6, showing also the best
selectivity to differentiate between mammalian cells and bacterial cell
walls compared with the other polymers tested in this study.
When cationic and hydrophobic residues are located in the same
polyglycidol repeating unit being connected by a spacer, the impact on
the cell envelope of S. aureus is significantly less effective than against
E. coli. The outer part of the cell envelope of Gram-positive bacteria is
composed of a thick peptidoglycan layer with integrated lipoteichoic
acids followed by the inner cell membrane. Here, a sieving effect might
be discussed, retarding the interaction of this polymer with the
underlying cell membrane. Additionally, the vicinity of the cationic and
hydrophobic groups in these polyglycidols compared to those
prepared with statistic distribution of cationic and hydrophobic
residues might disturb the interaction cascade of amphipathic
polymers with the components of the cell envelope.
Changing the hydrophilic–lipophilic balance (HLB) to a higher lipo-
philic–cationic ratio in amphipathic polyglycidol with statistically
distributed cationic and hydrophobic residues leads to a decrease in
efficacy in the same order of magnitude against both bacterial strains
E. coli and S. aureus. Antimicrobial efficacy of an amphipathic polymer
strongly depends on its HLB, the microstructure induced by the type
of polymer backbone, and the distribution and kind of the cationic and
hydrophobic functionalities.
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Hayball, J.D.; Qu, Y.; Traven, A.; Griesser, H.J.; Meagher, L.;
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Chapter 5
83
Chapter 5
Homoserine Lactone as a
Structural Key Element for
Multifunctional Polyglycidols
5.1 Introduction
In recent years, the increasing resource shortage and the consequential
sustainable awareness has led to a change of mindset of chemists
towards bio-based and renewable resources. The development of
enzymatic polymer synthesis1, multifunctional high performance
fibers2, membranes for water purification3 and transparent substrates
for use in electronics from wood4,5, or amino-acid based ionic liquids6,
and asymmetric building blocks7 are results of this rethinking process.
Another approach towards sustainability involves the utilization of
bio-based by-products. Glycerol is a readily available, major by-
product in the production of biodiesel and thus, used as a starting
material for the synthesis of monomers, such as epichlorohydrin and
glycidol8, or building blocks, as glycerol carbonate (Scheme 5.1).9
Glycidol acts as the monomer in the synthesis of linear, branched and
star-like polyglycidols.10-12 Polyglycidol is soluble in aqueous media,
shows no toxicity towards cells and is licensed by the FDA.13,14 It is a
highly functionalized polymer with a hydroxy group in every repeating
unit, allowing various further modifications.15,16 Hans et al. presented
Chapter 5
84
the application of polyglycidol as a multifunctional macroinitiator for
the ring-opening polymerization of -caprolactone.17,18 The reaction
was carried out by chemical and enzymatic catalysis, leading to densely
and loosely grafted polyglycidols, respectively. The loosely grafted
polymers showed enhanced hydrolytic degradation of the poly(capro-
lactone) side chains, allocated to the free hydroxy groups of the poly-
glycidol backbone.
Scheme 5.1: Strategies for the synthesis of glycerol carbonate and glycidol
from glycerol.9
The hydrolytic degradation of poly(caprolactone) was further
increased by functionalization of the polyglycidol macroinitiator with
phosphonate/phosphonic acid groups.19,20 Polyglycidol was function-
alized in a Michael-type addition with diethylvinyl phosphonate and
subsequent dealkylation of the pendant phosphonate groups.21 Addi-
tionally, multifunctional polyglycidols carrying phosphonic acid and
acrylate moieties were examined as UV-active adhesion promoters for
a hydrogel coating on stainless steel wires.22
Recently, a synthetic strategy for the post-polymerization function-
alization of polyglycidol with pendant phosphate groups by reaction
with diethyl chlorophosphate was developed (see chapter 3).23 The
diethyl phosphate moieties were subsequently (mono-)dealkylated.
This method allowed the tailoring of the concentration of pendant
phosphate/phosphoric acid groups introduced into the polyglycidol.
In this chapter, a strategy for the introduction of homoserine lactone
as a bio-based building block into polyglycidol is presented. The
synthetic protocol comprises (i) functionalization of polyglycidol with
homoserine lactone, (ii) ring-opening of the lactone with an amine, and
(iii) investigation of further modification possibilities.
Chapter 5
85
5.2 Experimental Section
5.2.1 Materials
Potassium tert-butoxide (1 M solution in THF, Aldrich), diglyme
(≥99%, extra dry, over molecular sieves, Acros Organics), pyridine
(99.5%, extra dry, over molecular sieves, Acros Organics), 4-
nitrophenyl chloroformate (>98%, TCI), 3-(dimethylamino)-1-
propylamine (99%, Acros Organics), DL-homoserine lactone hydro-
bromide (99%, Sigma-Aldrich), 4-dimethylaminopyridine (>98%,
Fluka), triethylamine (≥99.5%, anhydrous, Sigma-Aldrich), methyl
iodide (>99%, Sigma-Aldrich), tetrahydrofuran (99.8%, stabilizer free,
extra dry, Acros Organics), chloroform (99.9%, extra dry, over
molecular sieves, Acros Organics), N,N-dimethylformamide (99.8%,
extra dry, over molecular sieves, Acros Organics), methanol (≥99.8%,
p.a., CHEMSOLUTE®) and dichloromethane (≥99.8%, anhydrous,
Sigma-Aldrich) were used as received.
3-Phenyl-1-propanol (99%, Aldrich) was stirred with calcium hydride
for 24 h and distilled. Ethoxyethyl glycidyl ether (EEGE) was
synthesized from 2,3-epoxypropan-1-ol (glycidol) and ethyl vinyl ether
according to Fitton et al.24, purified by distillation, and stored under a
nitrogen atmosphere over molecular sieve (3 Å).
Water-sensitive reactions were carried out in a nitrogen atmosphere.
Nitrogen (Linde 5.0) was passed over molecular sieve (4 Å) and finely
distributed potassium on aluminum oxide.
5.2.2 Measurements
1H NMR and 13C NMR spectra were recorded on a Bruker DPX-400
FT-NMR spectrometer at 400 and 101 MHz, respectively. Deuterated
dimethyl sulfoxide (DMSO-d6), deuterated dimethylformamide
(DMF-d7) and deuterium oxide (D2O) were used as solvents. The
residual solvent signal was used as internal standard. Coupling
constants Jxy are given in Hz.
Molecular weights (Mn,SEC) and molecular weight distributions (Đ)
were determined by size exclusion chromatography (SEC). SEC
analyses were carried out with DMF (HPLC grade, VWR) as eluent.
SEC was performed using an Agilent 1100 system equipped with a
Chapter 5
86
dual RI-/Visco detector (ETA-2020, WGE). The eluent contained
1 g L–1 LiBr (≥99%, Aldrich). The sample solvent contained traces of
distilled water as internal standard. One pre-column (8x50 mm) and
four GRAM gel columns (8x300 mm, Polymer Standards Service)
were applied at a flow rate of 1.0 mL min–1 at 40 °C. The diameter of
the gel particles measured 10 µm, the nominal pore widths were 30,
100, 1000 and 3000 Å. Calibration was achieved using narrowly
distributed poly(methyl methacrylate) standards (Polymer Standards
Service). Results were evaluated using the PSS WinGPC UniChrom
software (Version 8.1.1).
Dialysis was performed in methanol using Biotech CE Tubing
(MWCO: 100–500 D, 3.1 mL cm–1, Spectrumlabs). The membrane
was washed for 15 min in water before use to remove the sodium azide
solution.
5.2.3 Syntheses
Synthesis of poly(glycidyl-4-nitrophenylcarbonate)26 (P(GNPC)26) (2)
PG26 (1) (0.990 g, 13.36 mmol OH) was dissolved in pyridine
(9.28 mL). 4-Nitrophenyl chloroformate (2.963 g, 14.70 mmol) was
dissolved in DCM (9.0 mL) and added to the polymer solution via
syringe pump in 30 min at 0 °C. The solution was stirred for 20 h at
room temperature. The crude product was washed with water (30 mL),
1 M HCl (aq.) (3 · 30 mL) and saturated NaCl solution (aq., 30 mL).
The organic phase was separated, dried over Na2SO4 and precipitated
in cold MeOH. The solvent was removed under reduced pressure and
polymer 2 was obtained as a colorless solid (2.922 g, 91%). Mn,NMR =
6219 g mol–1, Mn,SEC = 6100 g mol–1, Ð = 1.37. 1H-NMR (400 MHz,
DMSO-d6): δ = 1.69–1.83 (m, ArCH2CH2), 2.54–2.61 (m, ArCH2CH2),
3.68–3.72 (m, ArCH2CH2CH2, OCH2CH(CH2OC=OOArNO2)O),
4,26–4.42 (d, CH2OC=OOArNO2), 7.12–7.21 (m, ArCH2CH2), 7.41
(s, CH2OC=OOArNO2), 8.17 (s, CH2OC=OOArNO2) ppm. 13C
NMR (101 MHz, DMSO-d6): δ = 30.8 (ArCH2CH2), 31.6 (ArCH2),
68.3 (OCH2CH(CH2OC=OOArNO2)O), 76.4 (OCH2CH(CH2O-
C=OOArNO2)O), 76.5 (ArCH2CH2CH2), 76.6 (OCH2CH(CH2O-
C=OOArNO2)O), 122.3 (CH2OC=OOArNO2), 125.2 (CH2OC=O-
OArNO2), 125.7 (ArCH2), 128.2 (ArCH2), 128.3 (ArCH2), 141.6
Chapter 5
87
(ArCH2), 145.0 (CH2OC=OOArNO2), 152.0 (OC=OO), 155.1
(CH2OC=OOArNO2) ppm.
Synthesis of poly(glycidyl homoserine lactonylcarbamate)26 (P(GHSL)26) (3)
Polymer 2 (1.000 g, 4.181 mmol OH) was dissolved in DMF (20 mL)
and 4-(dimethylamino)pyridine (0.051 g, 0.418 mmol) and DL-
homoserine lactone hydrobromide (0.761 g, 4.181 mmol) were added.
The mixture was cooled to 0 °C and triethylamine (0.846 g,
8.361 mmol) was added over 1 h via syringe pump. The solution was
stirred for 20 h at room temperature. DMF was removed under
reduced pressure at 50 °C and the crude product was precipitated in
MeOH. Drying under reduced pressure at 50 °C gave polymer 3 as a
colorless solid (0.648 g, 77%). Mn,NMR = 5247 g mol–1, Mn,SEC = 6900
g mol–1, Ð = 1.36. 1H NMR (400 MHz, DMF-d7): δ = 1.81–1.90 (m,
ArCH2-CH2), 2.27–2.45 (m, NHCHCH2), 2.49–2.63 (m, NHCHCH2),
2.65–2.71 (m, ArCH2CH2), 3.61–3.86 (m, ArCH2CH2CH2, OCH2CH-
(CH2OC=OR)O), 4.09 (s, OCH2CH(CH2OC=OR)O), 4.20–4.37 (m,
NHCHCH2, OCH2CH(CH2OC=OR)O), 4.37–4.49 (m, NHCHCH2-
CH2), 4.51–4.66 (m, NHCHCH2CH2), 7.23–7.36 (m, ArCH2CH2),
7.66 (s, NH) ppm. 13C NMR (101 MHz, DMF-d7): δ = 28.7
(NHCHCH2), 31.6 (ArCH2CH2), 32.2 (ArCH2), 50.3 (NHCHCH2),
65.7 (NHCHCH2CH2), 64.7, 69.5, 78.0 (ArCH2CH2CH2, OCH2CH-
(CH2OR)O), 128.7 (ArCH2), 128.8 (ArCH2), 156.6 (OC=ONH), 175.8
(NHCHC=OO) ppm.
Synthesis of P(GHSL,o)26 (4)
Polymer 3 (0.263 g, 1.307 mmol HSL) was dissolved in DMF
(4 mL) and 3-(dimethylamino)-1-propylamine (0.339 g, 3.268 mmol)
and 4-(dimethylamino)pyridine (0.016 g, 0.131 mmol) were added. The
mixture was stirred for 20 h at room temperature. DMF was removed
under reduced pressure at 50 °C and the crude product was precipi-
tated in diethyl ether. Dialysis in MeOH gave 4 as a slightly yellow solid
(0.373 g, 94%). Mn,NMR = 7887 g mol–1, Mn,SEC = 8900 g mol–1, Ð =
1.32. 1H NMR (400 MHz, DMSO-d6): δ = 1.41–1.58 (m, NHCH2-
CH2CH2NMe2), 1.66–1.77 (m, ArCH2CH2, NHCHCH2CH2OH), 2.09
(s, NMe2), 2.18 (m, NHCH2CH2CH2NMe2), 2.55–2.61 (m, ArCH2-
CH2), 3.03–3.10 (m, NHCH2CH2CH2NMe2), 3.47–3.73 (m, ArCH2-
Chapter 5
88
CH2CH2, OCH2CH(CH2OR)O, NHCHCH2CH2OH), 3.81–4.25 (m,
OCH2CH(CH2OR)O, NHCHCH2CH2OH), 7.14–7.36 (m, ArCH2,
NH), 7.81–8.02 (m, NH) ppm. 13C NMR (101 MHz, DMSO-d6): δ =
26.9 (NHCH2CH2CH2NMe2), 31.0 (ArCH2CH2), 31.7 (ArCH2CH2),
35.1 (NHCHCH2CH2OH), 37.2 (NHCH2CH2CH2NMe2), 45.2
(NMe2), 52.2 (NHCHCH2CH2OH), 56.8 (NHCHCH2CH2OH), 57.7
(NHCH2CH2CH2NMe2), 63.8, 68.7, 77.8 (ArCH2CH2CH2, OCH2CH-
(CH2OR)O), 125.8 (ArCH2), 128.3 (ArCH2), 128.4 (ArCH2), 141.8
(ArCH2), 156.0 (OC=ONH), 171.9 (CHC=ONH) ppm.
Synthesis of P(GHSL,o,q)26 (5)
Polymer 4 (0.250 g, 0.824 mmol ―NMe2) was dissolved in MeOH
(5 mL) and methyl iodide (0.175 g, 1.236 mmol) was added. The
solution was stirred under reflux for 20 h. Removal of MeOH and
excess methyl iodide under reduced pressure at 50 °C gave polymer 5
as a yellow solid (0.324 g, 88%). 1H NMR (400 MHz, D2O): δ = 1.95–
2.08 (m, ArCH2CH2, NHCH2CH2CH2NMe3, NHCHCH2CH2OH),
2.66–2.74 (m, ArCH2CH2), 3.18 (s, NMe3), 3.25–3.47 (m, NHCH2CH2-
CH2NMe3), 3.72–3.87 (m, ArCH2CH2CH2, OCH2CH(CH2OR)O,
NHCHCH2CH2OH), 4.12–4.37 (m, OCH2CH(CH2OR)O, NHCH-
CH2CH2OH), 7.33–7.42 (m, ArCH2) ppm. 13C NMR (101 MHz,
D2O): δ = 22.8 (NHCH2CH2CH2NMe3), 33.8 (NHCHCH2CH2OH),
36.2 (NHCH2CH2CH2NMe3), 52.8 (NHCHCH2CH2OH), 53.2
(NMe3), 58.0 (NHCHCH2CH2OH), 64.2 (NHCH2CH2CH2NMe3),
64.5 (OCH2CH(CH2OR)O), 68.8, 76.6, 77.3 (ArCH2CH2CH2, OCH2-
CH(CH2OR)O), 128.2 (ArCH2), 128.8 (ArCH2), 141.0 (ArCH2), 157.5
(OC=ONH), 174.7 (CHC=ONH) ppm.
5.3 Results and Discussion
In this chapter, homoserine lactone derived from the bio-based
building block homoserine is presented as the structural key element.
Polyglycidol is functionalized with homoserine lactone in a two-step
reaction to prepare multifunctional polyethers.
Chapter 5
89
5.3.1 Functionalization of polyglycidol (1) with DL-homoserine lactone
hydrobromide
Linear polyglycidol was prepared by anionic ring-opening polymeri-
zation of ethoxyethyl glycidyl ether with 3-phenyl-1-propanol as
initiator and removal of the acetal protecting groups under acidic
conditions.18 A polyglycidol with 26 repeating units (PG26) and
Mn,SEC = 3100 g mol–1 was obtained with a narrow molecular weight
distribution (Ð = 1.14). The 1H, 13C NMR spectra and SEC analysis
of PG26 (5) can be found in the supporting information (Fig. A.3.1–
A.3.3, appendix A3).
In preliminary experiments it was observed that phenyl carbonates are
excellent electrophiles for the substitution reaction with non-
functionalized, primary amines. For the reaction with functionalized
amines, such as homoserine lactone, the electrophilicity of the
carbonate needs to be higher than the electrophilicity of the carbonyl
group of the lactone ring. Phenyl carbonates are not electrophilic
enough, leading to a reaction of the homoserine lactone with itself. In
hydrolysis reactions 4-nitrophenyl carbonates react faster by a factor
of five compared to phenyl carbonates.25 We expected an equal
increase in reactivity for the aminolysis reaction.
Scheme 5.2: Synthetic pathway to P(GHSL)26 (3). a) Functionalization of PG26
(1) with 4-nitrophenyl chloroformate, pyridine/DCM, rt, 20 h. b) Reaction of
P(GNPC)26 (2) with DL-homoserine lactone hydrobromide, 4-DMAP, Et3N,
DMF, rt, 20 h.
PG26 (1) was reacted with 4-nitrophenyl chloroformate in pyridine/
DCM at room temperature (Scheme 5.2a). For purification poly-
(glycidyl-4-nitrophenylcarbonate)26 (2) was washed with water, 1 M
HCl solution (aq.), and saturated NaCl solution (aq.) to remove excess
Chapter 5
90
pyridine and pyridine hydrochloride, and precipitated in methanol.
The successful functionalization was confirmed by 1H, 13C NMR
spectroscopy (Fig. A.3.4–A.3.5, appendix A.3), and SEC analysis (Fig.
A.3.7, appendix A.3). P(GNPC)26 was subsequently reacted with DL-
homoserine lactone hydrobromide in DMF at room temperature using
catalytic amounts of 4-(dimethylamino)pyridine (4-DMAP) and Et3N
as a base (Scheme 5.2b). The prepared poly(glycidyl homoserine lac-
tonylcarbamate)26 (P(GHSL)26) (3) was purified by precipitation in
methanol and characterized by 1H, 13C NMR spectroscopy, and SEC
analysis. 1H and 13C NMR spectra of P(GHSL)26 (3) in DMF-d7 show characteris-
tic signals of the homoserine lactonyl groups adjacent to the carbamate
moieties, proving the successful functionalization of PG26. In the 1H
NMR spectrum (Fig. 5.1) the characteristic signals of the lactonyl
functionality appear as four multiplets at δ = 2.27–2.45 and 2.49–2.63
(Signal 11) ppm for one methylene group and δ = 4.37–4.49 and 4.51–
4.66 (Signal 12) ppm for the other methylene group. A multiplet at δ =
4.20–4.37 ppm (Signal 9, 10) shows the methylene group of the
glycidol repeating unit and the single proton of the lactone ring
adjacent to the carbamate moiety. In the 13C NMR spectrum (Fig.
A.3.6, appendix A.3) the distinctive signals of the homoserine lactone
are found at δ = 28.7 (Signal 13), 50.3 (Signal 12) and 65.7 (Signal 14)
ppm. Additionally, the specific signal of the carbamate groups is found
at δ = 156.6 ppm (Signal 11).
Figure 5.1: 1H NMR spectrum of P(GHSL)26 (3) measured in DMF-d7.
Chapter 5
91
The number of HSL groups attached to PG26 (1) was calculated by
comparing the signal intensity of one methylene group of the 3-
phenyl-1-propanol (Signal 5) used in the synthesis of 1 with signal 11
and 12. The absolute molecular weight (Mn,NMR) was calculated
likewise using the 3-phenyl-1-propyl end group as an internal reference
(Mn,NMR = 5247 g mol–1). Full functionalization of PG26 (1) was
reached.
SEC analysis using DMF as eluent confirms the synthesis of P(GHSL)26
(3) with Mn,SEC = 6900 g mol–1 and a molecular weight distribution of
Ð = 1.36 (Fig. A.3.8, appendix A.3).
5.3.2 Ring-opening of P(GHSL)26 (3)
P(GHSL)26 (3) was reacted with 3-(dimethylamino)-1-propylamine
(DMAPA) and 4-DMAP as a nucleophilic catalyst in a ring-opening
reaction in DMF at room temperature (Scheme 5.3a). The synthesized
P(GHSL,o)26 (4) was purified by precipitation in diethyl ether, followed
by dialysis in MeOH and characterized by 1H, 13C NMR spectroscopy
and SEC analysis (Fig. A.3.9–A.3.11, appendix A.3).
Scheme 5.3: Synthetic pathway to P(GHSL,o,q)26 (5). a) Addition of DMAPA
to P(GHSL)26 (3), DMF, rt, 20 h. b) Quaternization of P(GHSL,o)26 (4) with MeI,
MeOH, reflux, 20 h.
1H and 13C NMR spectra in DMSO-d6 exhibit characteristic signals for
the DMAPA group and the opened lactone. In the 1H NMR spectrum
the distinctive signals of the DMAPA functionality appear as two
multiplets at δ = 1.41–1.58 ppm (Signal 14) and δ = 3.03–3.10 ppm
(Signal 13) and a multiplet at δ = 2.18 ppm (Signal 15). The singlet at
Chapter 5
92
δ = 2.09 ppm (Signal 16) represents the methyl groups vicinal to the
amine. The characteristic signals of the opened lactone appear as two
multiplets at 1.66–1.77 ppm (Signal 11) and 3.81–4.25 ppm (Signal 10).
The second multiplet also contains the methylene groups of the
polyglycidol repeating unit adjacent to the carbamate. In the 13C NMR
spectrum the distinctive signals appear at δ = 26.9 (Signal 17), 37.2
(Signal 16), 45.2 (Signal 19) and 57.7 (Signal 18) ppm for the DMAPA
group and at δ = 35.1 (Signal 13), 52.2 (Signal 12) and 56.8 (Signal
14) ppm for the opened lactone. The number of DMAPA moieties
attached to PG26 was calculated as described previously.
SEC analysis using DMF as eluent confirms the successful ring-
opening of P(GHSL)26 (3) with Mn,SEC = 8900 g mol–1 and a molecular
weight distribution of Ð = 1.32.
5.3.3 Quaternization of P(GHSL,o)26 (4)
As a model reaction for further functionalization, the quaternization
of P(GHSL,o)26 (4) was conducted with methyl iodide in methanol under
reflux (Scheme 5.3b). The solvent and excess methyl iodide were re-
moved under reduced pressure and P(GHSL,o,q)26 (5) characterized by 1H and 13C NMR spectroscopy (Fig. A.3.12–A.3.13, appendix A.3). 1H and 13C NMR spectra in D2O show distinctive signals of the
quaternary amine functionality. In the 1H NMR the singlet at δ =
3.18 ppm (Signal 16) represents the methyl groups vicinal to the amine
and the multiplet at δ = 3.25–3.47 ppm (Signal 15) shows the
methylene groups adjacent to the amine and the carbamate. The third
methylene group appears at δ = 1.95–2.08 (Signal 14) ppm. In the 13C
NMR spectrum the characteristic signals of the quaternary amine
moiety appear at δ = 22.8 (Signal 17), 36.2 (Signal 16), 53.2 (Signal 19)
and 64.2 (Signal 18) ppm. Both spectra confirm the successful
quaternization of P(GHSL,o)26 (4).
5.4 Conclusions
In this chapter, a synthetic strategy using homoserine lactone for the
preparation of multifunctional polyethers was developed. The strategy
includes the functionalization of linear polyglycidol with homoserine
Chapter 5
93
lactone. The successful synthesis was confirmed by 1H, 13C NMR
spectroscopy, and SEC analysis. Homoserine lactone groups were
subsequently opened by addition of 3-(dimethylamino)-1-propylamine
and the tertiary amine was quaternized with methyl iodide.
Future work will further exploit the possibility of the introduction of
multifunctionality into polymers this synthetic strategy offers.
5.5 References
1. Kobayashi, S.; Makino, A. Enzymatic polymer synthesis: An
opportunity for green polymer chemistry. Chem. Rev. 2009,
109, 5288.
2. Walther, A.; Timonen, J.V.; Diez, I.; Laukkanen, A.; Ikkala,
O. Multifunctional high-performance biofibers based on
wet-extrusion of renewable native cellulose nanofibrils. Adv.
Mater. 2011, 23, 2924.
3. Ma, H.Y.; Burger, C.; Hsiao, B.S.; Chu, B. Ultra-fine cellulose
nanofibers: New nano-scale materials for water purification.
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4. Zhu, H.L.; Xiao, Z.G.; Liu, D.T.; Li, Y.Y.; Weadock, N.J.;
Fang, Z.Q.; Huang, J.S.; Hu, L.B. Biodegradable transparent
substrates for flexible organic-light-emitting diodes. Energ.
Environ. Sci. 2013, 6, 2105.
5. Fang, Z.; Zhu, H.; Preston, C.; Han, X.; Li, Y.; Lee, S.; Chai,
X.; Chen, G.; Hu, L. Highly transparent and writable wood
all-cellulose hybrid nanostructured paper. J. Mater. Chem. C
2013, 1, 6191.
6. Tao, G.H.; He, L.; Liu, W.S.; Xu, L.; Xiong, W.; Wang, T.;
Kou, Y. Preparation, characterization and application of ami-
no acid-based green ionic liquids. Green Chem. 2006, 8, 639.
7. Calaza, M.I.; Cativiela, C. Heterocycles from amino acids. In
Amino acids, peptides and proteins in organic chemistry, Hughes,
A.B., Ed. WILEY-VCH Verlag & KGaA: Weinheim,
Germany, 2011; Vol. 3, pp 83.
8. Sutter, M.; Silva, E.D.; Duguet, N.; Raoul, Y.; Metay, E.;
Lemaire, M. Glycerol ether synthesis: A bench test for green
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chemistry concepts and technologies. Chem. Rev. 2015, 115,
8609.
9. Sonnati, M.O.; Amigoni, S.; de Givenchy, E.P.T.; Darmanin,
T.; Choulet, O.; Guittard, F. Glycerol carbonate as a versatile
building block for tomorrow: Synthesis, reactivity, properties
and applications. Green Chem. 2013, 15, 283.
10. Gosecki, M.; Gadzinowski, M.; Gosecka, M.; Basinska, T.;
Slomkowski, S. Polyglycidol, its derivatives, and polyglycidol-
containing copolymers—synthesis and medical applications.
Polymers 2016, 8.
11. Mohammadifar, E.; Bodaghi, A.; Dadkhahtehrani, A.;
Nemati Kharat, A.; Adeli, M.; Haag, R. Green synthesis of
hyperbranched polyglycerol at room temperature. ACS
Macro Lett. 2016, 6, 35.
12. Dworak, A.; Slomkowski, S.; Basinska, T.; Gosecka, M.;
Walach, W.; Trzebicka, B. Polyglycidol - how is it synthesized
and what is it used for? Polimery 2013, 58, 641.
13. Kainthan, R.K.; Janzen, J.; Levin, E.; Devine, D.V.; Brooks,
D.E. Biocompatibility testing of branched and linear
polyglycidol. Biomacromolecules 2006, 7, 703.
14. Frey, H.; Haag, R. Dendritic polyglycerol: A new versatile
biocompatible material. Rev. Mol. Biotechnol. 2002, 90, 257.
15. Keul, H.; Möller, M. Synthesis and degradation of biomedical
materials based on linear and star shaped polyglycidols. J.
Polym. Sci. Pol. Chem. 2009, 47, 3209.
16. Thomas, A.; Müller, S.S.; Frey, H. Beyond poly(ethylene
glycol): Linear polyglycerol as a multifunctional polyether for
biomedical and pharmaceutical applications. Biomacromolecules
2014, 15, 1935.
17. Hans, M.; Keul, H.; Moeller, M. Poly(ether-ester) conjugates
with enhanced degradation. Biomacromolecules 2008, 9, 2954.
18. Hans, M.; Gasteier, P.; Keul, H.; Moeller, M. Ring-opening
polymerization of ε-caprolactone by means of mono- and
multifunctional initiators: Comparison of chemical and
enzymatic catalysis. Macromolecules 2006, 39, 3184.
19. Koehler, J.; Marquardt, F.; Teske, M.; Keul, H.; Sternberg,
K.; Moeller, M. Enhanced hydrolytic degradation of
Chapter 5
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heterografted polyglycidols: Phosphonoethylated monoester
and polycaprolactone grafts. Biomacromolecules 2013, 14, 3985.
20. Koehler, J.; Marquardt, F.; Keul, H.; Moeller, M.
Phosphonoethylated polyglycidols: A platform for tunable
enzymatic grafting density. Macromolecules 2013, 46, 3708.
21. Koehler, J.; Keul, H.; Möller, M. Post-polymerization
functionalization of linear polyglycidol with diethyl
vinylphosphonate. Chem. Commun. 2011, 47, 8148.
22. Koehler, J.; Kuehne, A.J.C.; Piermattei, A.; Qiu, J.; Keul,
H.A.; Dirks, T.; Keul, H.; Moeller, M. Polyglycidol-based
metal adhesion promoters. J. Mater. Chem. B 2015, 3, 804.
23. Marquardt, F.; Keul, H.; Möller, M. Straightforward synthesis
of phosphate functionalized linear polyglycidol. Eur. Polym. J.
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24. Fitton, A.O.; Hill, J.; Jane, D.E.; Millar, R. Synthesis of simple
oxetanes carrying reactive 2-substituents. Synthesis 1987,
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25. Marlier, J.F.; O'Leary, M.H. Carbon kinetic isotope effects on
the hydrolysis of aryl carbonates. J. Am. Chem. Soc. 1990, 112,
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Chapter 6
97
Chapter 6
Light-induced Cross-linking
and Post-cross-linking
Modification of Polyglycidol
6.1 Introduction
The continuous advancement in technological and medical applica-
tions leads to a high demand in materials with well-defined, tailored
properties.1 The properties of a given polymer are among others
defined by its architecture, morphology, molecular weight, as well as
type and degree of functionalization.2 Though, most of the polymer
characteristics are generated during the polymerization process, post-
polymerization modification is also possible.3 One approach is the
modification of functional groups of a polymer by subsequent reac-
tion(s) after the polymerization.4 Hydrophilic polymers carrying car-
boxylic acid, amine or hydroxy groups in the main or side chains are
an interesting platform for the synthesis of multifunctional materials.5
An excellent example for this class of polymers is polyglycidol. Every
repeating unit of the polyglycidol carries a hydroxy moiety, leading to
water solubility and a high degree of functionalization. Additionally,
linear and branched polyglycidols are biocompatible and certified by
the Food and Drug Administration (FDA).6,7 The hydroxy groups can
be reacted with various compounds to modify the properties of the
Chapter 6
98
polyether, e.g. introduction of phenyl carbonates and subsequent reac-
tion with primary amines, phosphorylation with diethyl chlorophos-
phate or phosphonoethylation via Michael-addition with vinyl phos-
phonate.8-10
A second approach to modify the polymer properties after the poly-
merization is cross-linking. Chemical cross-linking is based on the
reaction of a functional group in the polymer with a suitable multifunc-
tional cross-linking agent. Various protocols have been reported from
the reaction of carboxylic acid moieties with carbodiimides11,12 or aziri-
dines13,14, to the ring-opening of epoxides with amines and thiols15,16,
and the toolbox of “click chemistry”, e.g. the alkyne-azide [3+2]-cyclo-
addition and the thiol-ene reaction.17-19 Radiation cross-linking is based
on the generation of radicals by irradiation with UV-light20, electron
beams, X-rays or -rays.21 The photoinduced radical generation pro-
cess has received renewed interest as it meets a wide range of economic
and ecological expectations. The major use of this process involves
photopolymerization which has been the basis of numerous conven-
tional applications in coatings, adhesives, inks, printing plates, optical
waveguides, and micro-electronics.22,23 In these applications, the
radicals are generated by using photoinitiators via homolytic cleavage
of covalent bonds (Type I) and H-abstraction type (Type II) reactions.
Certain aromatic carbonyl compounds such as benzoin and deriva-
tives, benzyl ketals, acetophenones, aminoalkyl phenones, O-acyl-
oximino ketones, hydroxyalkyl ketones, acylphosphine oxides and
acylgermanes act as Type I photoinitiators and upon absorption of light
spontaneously undergo “α-cleavage”, generating free radicals. Type II
photoinitiators, belonging to the class of aromatic ketones, such as
benzophenone, thioxanthones, benzil, and quinones, generate radicals
by a bimolecular reaction. Their triplet excited states readily react with
hydrogen donors, such as alcohols, ethers, amines, and thiols thereby
producing radicals. Among various Type II photoinitiators, thioxan-
thones (TX) and camphorquinone (CQ) derivatives were widely used
due to the more favorable absorption characteristics in near UV and
visible range.24-32 The overall mechanism of their radical generation
process is represented in Scheme 1.
Chapter 6
99
Scheme 6.1: Photoinduced radical generation process by camphorquinone in
the presence of hydrogen donors.
In this chapter, a straightforward protocol for the light-induced cross-
linking and subsequent post-cross-linking modification of polyglycidol
is presented. The synthetic pathway comprises (i) functionalization of
linear polyglycidol (PG) with phenyl chloroformate under alkaline
conditions, (ii) substitution of the phenoxy groups of the introduced
phenyl carbonates with 3-(dimethylamino)-1-propylamine (DMAPA),
(iii) cross-linking of tertiary amine groups of the functionalized
polymer in a light-mediated reaction using camphorquinone as the
photoiniator and (iv) post-cross-linking quaternization with various
organoiodine compounds.
6.2 Experimental Section
6.2.1 Materials
Phenyl chloroformate (>97%, Fluka), pyridine (99.5%, dry over mole-
cular sieve, Acros Organics), dichloromethane (99.8%, anhydrous,
Sigma-Aldrich), 3-(dimethylamino)-1-propylamine (99%, Acros
Organics), tetrahydrofuran (99.8%, extra dry, stabilizer free, Acros
Organics), camphorquinone (99%, Acros Organics), N,N-dimethyl-
formamide (99.8%, VWR), methyl iodide (99%, Sigma-Aldrich), 1-
iodooctane (>97%, TCI), triethylene glycol monomethyl ether (95%,
Sigma-Aldrich), and 1H, 1H, 2H, 2H-heptadecafluorodecyl iodide
(>98%, TCI) were used as received.
Ethoxyethyl glycidyl ether (EEGE) was synthesized from 2,3-epoxy-
propan-1-ol (glycidol) and ethyl vinyl ether according to Fitton et al.33,
Chapter 6
100
purified by distillation, and stored under a nitrogen atmosphere over
molecular sieve (3 Å).
1-Iodo-3,6,9-trioxadecane was synthesized from the corresponding
tosylate by reaction with sodium iodide.34 The tosylate was prepared
according to literature from tri(ethylene glycol) monomethyl ether and
tosyl chloride.35
Water-sensitive reactions were carried out in a nitrogen atmosphere.
Nitrogen (Linde 5.0) was passed over molecular sieve (4 Å) and finely
distributed potassium on aluminum oxide.
6.2.2 Measurements
1H NMR and 13C NMR spectra were recorded on a Bruker DPX-400
FT-NMR spectrometer at 400 and 101 MHz, respectively. Chloroform
(CDCl3) and deuterated dimethyl sulfoxide (DMSO-d6) were used as
solvents. The residual solvent signal was used as internal standard.
Coupling constants Jxy are given in Hz.
FTIR spectra were recorded on a Thermo Nicolet Nexus 470 FTIR
spectrometer at 25 °C. The samples were prepared as KBr pellets and
scanned over a range of 400–4000 cm–1.
DSC measurements were performed on a Netzsch DSC 204 differen-
tial scanning calorimeter under a nitrogen atmosphere. Samples were
prepared in perforated closed aluminum pans using 5 mg of the
sample. The sample was heated and cooled with a rate of 10 °C min–1
in various temperature ranges. The heat flow was measured as a
function of the temperature. Transitions were reported during the
second heating cycle.
Molecular weights (Mn,SEC) and molecular weight distributions (Đ)
were determined by size exclusion chromatography (SEC). SEC with
DMF (HPLC grade, VWR) as eluent was performed using an Agilent
1100 system equipped with a dual RI-/Visco detector (ETA-2020,
WGE). The eluent contained 1 g L–1 LiBr (≥99%, Aldrich). The
sample solvent contained traces of distilled water as internal standard.
One pre-column (8x50 mm) and four GRAM gel columns (8x300 mm,
Polymer Standards Service) were applied at a flow rate of
1.0 mL min–1 at 40 °C. The diameter of the gel particles measured
10 µm, the nominal pore widths were 30, 100, 1000 and 3000 Å.
Calibration was achieved using narrowly distributed poly(methyl
Chapter 6
101
methacrylate) standards (Polymer Standards Service). Results were
evaluated using the PSS WinGPC UniChrom software (Version 8.1.1).
Dynamic light scattering was performed on an ALV system equipped
with a helium-neon laser (633 nm, 35 mW, JDS Uniphase), a
goniometer (CGS-8F, ALV), two avalanche photodiodes (SPCM-
CD2969, Perkin Elmer), a light scattering electronics unit (LSE-5003,
ALV), a digital hardware correlator (ALV 5000), an external
programmable thermostate (Julabo F32) and an index-match bath
filled with toluene. All measurements were recorded pseudo cross-
correlated at room temperature.
Zeta potential measurements were performed on a Zetasizer Nano ZS
(Malvern Instruments) at room temperature using folded capillary
cells.
XPS measurements were performed using a K-Alpha+ XPS
spectrometer (Thermo Fisher Scientific, East Grinstead, UK). Data
acquisition and processing using the Thermo Avantage software is
described elsewhere.36 All samples were analyzed using a micro-
focused, monochromated Al Kα X-ray source (30–400 µm spot size).
The spectra were fitted with one or more Voigt profiles (binding
energy uncertainty: ± 0.2 eV). The analyzer transmission function,
Scofield sensitivity factors37, and effective attenuation lengths (EALs)
for photoelectrons were applied for quantification. EALs were
calculated using the standard TPP-2M formalism.38 All spectra were
referenced to the C 1s peak of hydrocarbon at 285.0 eV binding energy
controlled by means of the well-known photoelectron peaks of
metallic Cu, Ag, and Au.
Dialysis was performed in methanol and water using Biotech CE
Tubing (MWCO: 100–500 D, 3.1 mL cm–1, Spectrumlabs) and Biotech
RC Tubing (MWCO: 8–10 kD, 3.3 mL cm–1, Spectrumlabs),
respectively. The membrane was washed for 15 min in water before
use to remove the sodium azide solution.
Polymer films were prepared on Si-wafers by evaporation of water
from the aqueous dispersions at 50 °C in vacuo.
Chapter 6
102
6.2.3 Syntheses
Poly(ethoxyethyl glycidyl ether) (P(EEGE)) and polyglycidol (PG) (1)
were synthesized according to literature.39 The results of the chemical
analyses for PG27 are summarized in Figure A.4.1–A.4.3 of appendix
A.4.
Synthesis of poly(glycidyl phenyl carbonate) P(GPC)27 (2)
Polyglycidol (PG27) (1) (2.018 g, 27.24 mmol OH) was dissolved in
pyridine (18.87 mL) and a solution of phenyl chloroformate (4.692 g,
29.97 mmol) in dichloromethane (17.50 mL) was added in 30 min at
0 °C using a syringe pump. The reaction mixture was allowed to warm
to room temperature and stirred for 20 h. The precipitate was removed
by filtration. The solution was washed with water (15 mL), 1 M HCl
solution (aq.) (3 · 15 mL), and sat. NaCl solution (aq.). The organic
phase was dried over Na2SO4, filtrated and the solvent removed under
reduced pressure. Precipitation in methanol gave P(GPC)27 (2) as a
brown viscous liquid (3.629 g, 69%). Mn, NMR = 5243 g mol–1, Mn, SEC =
4400 g mol–1, Ð = 1.15. 1H NMR (400 MHz, CDCl3) (2): δ = 1.82–
1.92 (m, ArCH2CH2), 2.66 (t, 2H, 3JHH = 7.7 Hz ArCH2CH2), 3.48–
3.93 (m, ArCH2CH2CH2, OCH2CH(CH2OC=OOPh)O), 4.15–4.48
(m, OCH2CH(CH2OC=OOPh)O), 7.05–7.39 (m, ArCH2CH2,
(OC=OOPh)O) ppm. 13C NMR (101 MHz, CDCl3) (2): δ = 31.2
(ArCH2CH2), 32.3 (ArCH2CH2), 67.7‒ 69.4 ArCH2CH2CH2, OCH2-
CH(CH2OC=OOPh)O), 77.4 (OCH2CH(CH2OC=OOPh)O), 121.0
(OC=OOPh)O), 126.1 (Ar, OC=OOPh)O), 128.4 (Ar), 128.5 (Ar),
129.6 (OC=OOPh)O), 141.8 (Ar), 151.1 (OC=OOPh)O), 153.6
(OC=OOPh)O) ppm.
Synthesis of poly(3-(dimethylamino)-1-propyl glycidyl carbamate) P(GDMAPA)27 (3)
P(GPC)27 (2) (1.422 g, 7.32 mmol carbonate) was dissolved in tetra-
hydrofuran (18.0 mL) and a solution of 3-(dimethylamino)-1-propyl-
amine (DMAPA) (0.436 g, 4.27 mmol) in tetrahydrofuran (10.0 mL)
was added in 1 h at 0 °C using a syringe pump. The reaction was
allowed to warm to room temperature and stirred for 42 h. The solvent
was removed under reduced pressure and the polymer purified by
dialysis in methanol. P(GDMAPA)27 (3) was obtained as a slightly yellow,
Chapter 6
103
viscous liquid (1.194 g, 81%) Mn, NMR = 5461 g mol–1, Mn, SEC =
6200 g mol–1, Ð = 1.21. 1H NMR (400 MHz, CDCl3) (3): δ = 1.51–
1.67 (m, NHCH2CH2CH2N(CH3)2), 1.77–1.86 (m, ArCH2CH2), 2.14
(s, NHCH2CH2CH2N(CH3)2), 2.25 (t, 2H, 3JHH = 7.0 Hz, NHCH2CH2-
CH2N(CH3)2), 2.60 (t, 3JHH = 7.6 Hz, ArCH2CH2), 3.04–3.19 (m,
NHCH2CH2CH2N(CH3)2), 3.46–3.70 (m, ArCH2CH2CH2, OCH2CH-
(CH2OC=ONHR)O), 3.88–4.27 (m, OCH2CH(CH2OC=ONHR)O),
5.83–6.34 (m, NH), 7.06–7.24 (m, ArCH2CH2) ppm. 13C NMR
(101 MHz, CDCl3) (3): δ = 27.5 (NHCH2CH2CH2N(CH3)2, 31.2
(ArCH2CH2), 32.2 (ArCH2CH2), 39.7 (NHCH2CH2CH2N(CH3)2),
45.4 (NHCH2CH2CH2N(CH3)2), 57.5 (NHCH2CH2CH2N(CH3)2),
64.3‒ 69.9 (ArCH2CH2CH2, OCH2CH(CH2OC=ONHR)O), 77.9
(OCH2CH(CH2OC=ONHR)O), 125.8 (Ar), 128.3 (Ar), 128.5 (Ar),
141.9 (Ar), 156.7 (OCH2CH(CH2OC=ONHR)O) ppm. FTIR (3):
υmax = 3322 (w), 2923 (m), 2853 (m), 2816 (w), 2765 (w), 1690 (s), 1537
(m), 1461 (m), 1255 (s), 1138 (m), 1039 (m), 849 (w), 780 (w) cm–1.
Light-promoted cross-linking of P(GDMAPA)27 (3)
P(GDMAPA)27 (3) (0.336 g, 1.66 mmol ―NMe2) was dissolved in N,N-
dimethylformamide (12 mL) and camphorquinone (0.276 g,
1.66 mmol) was added. The mixture was irradiated for 20 h with a
25 W solarium lamp emitting light at 400–500 nm at room
temperature. The polymer was purified by dialysis in methanol
followed by dialysis in water. The cross-linked product [P(GDMAPA)27]X
(4) was obtained as an opaque, aqueous dispersion. FTIR (4): υmax =
3324 (w), 2926 (m), 2854 (m), 1699 (s), 1535 (m), 1461 (m), 1251 (s),
1117 (m), 1076 (m), 836 (w), 780 (w) cm–1.
Quaternization of [P(GDMAPA)27]X (4) with MeI
Methyl iodide (0.026 g, 0.178 mmol) was added to an aqueous disper-
sion of 5 (4.5 mg mL–1, 22 µmol mL–1 ―NR3) and the mixture was
stirred for 24 h at 40 °C. The product was purified by dialysis in water.
[P(GTMAPA)27]X (5) (TMAPA: 3-(trimethylamino)-1-propylamine) was
obtained as an opaque, aqueous dispersion.
Chapter 6
104
Quaternization of [P(GDMAPA)27]X (4) with 1-iodooctane
Without the purification step a solution of [P(GDMAPA)27]X (4) in DMF
(28 mg mL–1, 138 µmol mL–1 ―NR3) was reacted with 1-iodooctane
(0.199 g, 0.830 mmol) for 20 h at 100 °C. The polymer was purified by
dialysis in methanol followed by dialysis in water. [P(GODMAPA)27]X (6)
(ODMAPA: 3-(octyldimethylamino)-1-propylamine) was obtained as
an opaque, aqueous dispersion.
Quaternization of [P(GDMAPA)27]X (4) with 1-iodo-3,6,9-trioxadecane
Without the purification step a solution of [P(GDMAPA)27]X (4) in DMF
(28 mg mL–1, 138 µmol mL–1 ―NR3) was reacted with 1-iodo-3,6,9-
trioxadecane (0.228 g, 0.830 mmol) for 20 h at 100 °C. The polymer
was purified by dialysis in methanol followed by dialysis in water.
[P(GPDMAPA)27]X (7) (PDMAPA: 3-(PEG-dimethylamino)-1-propyl-
amine) was obtained as an opaque, aqueous dispersion.
Quaternization of [P(GDMAPA)27]X (4) with 1H, 1H, 2H, 2H-heptadecafluoro-
decyl iodide
Without the purification step a solution of [P(GDMAPA)27]X (4) in DMF
(28 mg mL–1, 138 µmol mL–1 ―NR3) was reacted with 1H, 1H, 2H,
2H-heptadecafluorodecyl iodide (0.476 g, 0.830 mmol) for 20 h at
100 °C. The polymer was purified by dialysis in methanol followed by
dialysis in water. [P(GFDMAPA)27]X (8) (FDMAPA: fluorinated 3-
(dimethylamino)-1-propylamine) was obtained as an opaque, aqueous
dispersion.
6.3 Results and Discussion
In this chapter, a novel approach for the synthesis and characterization
of various, novel cationic/hydrophilic, cationic/hydrophobic and
cationic/superhydrophobic functionalized, cross-linked polyglycidols
is presented. The polyglycidol microgels are prepared by func-
tionalization of polyglycidol with phenyl chloroformate to have an
active ester unit that is subsequently reacted with 3-(dimethylamino)-
1-propylamine (DMAPA). The generated tertiary amine moieties are
cross-linked in a light-promoted reaction with CQ as photoinitiator
Chapter 6
105
and quaternized with various organoiodine compounds. The aqueous
dispersions and films are characterized.
6.3.1 Functionalization of polyglycidol (1) with DMAPA
Linear polyglycidol was prepared by anionic ring-opening
polymerization of ethoxyethyl glycidyl ether using 3-phenyl-1-propa-
nol as initiator and subsequent removal of the acetal protecting groups
under acidic conditions. A polyalcohol with 27 repeating units (PG27)
and Mn,SEC = 2500 g mol–1 was obtained with a narrow molecular
weight distribution (Ð = 1.13). The NMR and SEC analysis of PG27
(1) can be found in the supporting information (Fig. A.4.1–A.4.3,
appendix A.4).
Scheme 6.2: Synthetic pathway to P(GDMAPA)27 (3). (a) Functionalization of
PG27 (1) with phenyl chloroformate, pyridine/DCM, rt, 20 h. (b) Reaction of
P(GPC)27 (2) with 3-(dimethylamino)-1-propylamine, THF, rt, 42 h.
Afterwards, PG27 (1) was reacted with an excess of phenyl chloro-
formate in pyridine/DCM at room temperature. The synthesized
poly(glycidyl phenyl carbonate) (P(GPC)27) (2) was washed with water,
1 M HCl solution (aq.), and saturated NaCl solution (aq.) to remove
excess pyridine and pyridine hydrochloride and purified by
precipitation in methanol (Scheme 6.2a). The successful function-
alization was confirmed by 1H, 13C NMR spectroscopy (Fig. A.4.4–
A.4.5, appendix A.4) , and SEC analysis (Fig. A.4.7, appendix A.4).
P(GPC)27 (2) was reacted with DMAPA in THF at room temperature
(Scheme 6.2b). The prepared poly(3-(dimethylamino)-1-propyl
glycidyl carbamate), P(GDMAPA)27 (3) was purified by dialysis in
methanol and characterized by 1H, 13C NMR spectroscopy, FTIR
spectroscopy, and SEC analysis.
Chapter 6
106
P(GDMAPA)27 (3) shows characteristic signals of the introduced 3-
(dimethylamino)-1-propyl groups in the 1H and 13C NMR spectra
measured in CDCl3. In the 1H NMR spectrum (Fig. 6.1) the distinctive
signals are shown as two multiplets at δ = 1.51–1.67 ppm (Signal 11)
and δ = 3.04–3.19 ppm (Signal 10), a singlet at δ = 2.14 ppm (Signal
13) and a triplet at δ = 2.25 ppm (Signal 12). A multiplet at δ = 3.88–
4.27 ppm (Signal 9) shows the characteristic signal of the methylene
groups of the glycidol repeating unit adjacent to the carbamate
moieties. In the 13C NMR the 3-(dimethylamino)-1-propyl groups are
distinguished by signals at δ = 27.5 (Signal 13), 39.7 (Signal 12), 45.4
(Signal 15) and 57.5 (Signal 14) ppm (Fig. A.4.6, appendix A.4).
Additionally, the specific signal of the carbamate groups is found at
δ = 156.7 ppm (Signal 11).
Figure 6.1: 1H NMR spectrum of P(GDMAPA)27 (3) measured in CDCl3.
The number of DMAPA groups attached to PG27 (1) was calculated
by comparing the signal intensity of the phenyl group of the 3-phenyl-
1-propanol (Fig. 6.1, Signal 1–3) used in the synthesis of 1 with signal
11 of P(GDMAPA)27 (3). The absolute molecular weight (Mn,NMR) was
calculated likewise using the 3-phenyl-1-propyl end group as an
internal reference.
FTIR spectra of P(GDMAPA)27 (3) exhibit characteristic absorption
bands of the 3-(dimethylamino)-1-propyl groups.40 The symmetric
C―H stretching vibrations of the methyl groups of the tertiary amine
give two weak bands at 2816 and 2765 cm–1. Additionally, two strong
bands are found at 1690 and 1537 cm–1, which are distinctive for
carbamate moieties (Fig. 6.2a).
Chapter 6
107
SEC analysis using DMF as eluent confirms the synthesis of
P(GDMAPA)27 (3) with Mn,SEC = 6200 g mol–1 and a narrow molecular
weight distribution of Ð = 1.21 (Fig. A.4.8, appendix A.4).
Figure 6.2: FTIR spectra of P(GDMAPA)27 (3) (a) and [P(GDMAPA)27]X (4) (b).
6.3.2 Light-promoted cross-linking of P(GDMAPA)27 (3)
The cross-linking of P(GDMAPA)27 (3) was performed in a light-
promoted reaction in DMF using CQ as Norrish Type II photoiniator
and a 25 W solarium lamp (λ = 400–500 nm) as the light source
(Scheme 6.3a). Light-induced activation of the CQ leads to the
formation of triplet state CQ (3CO*) that abstracts hydrogen from the
methyl groups of the tertiary amine.41 Intermolecular recombination
of the aminoalkyl radicals leads to the cross-linked product
[P(GDMAPA)27]X (4). Although hydrogen abstraction from the polyether
groups present in the structure is also possible, its occurrence is less
likely due to the steric effect and higher reaction rates of the tertiary
amine groups. However, even if the hydrogen abstraction from the
polyether groups would happen, coupling would essentially yield the
same networked structure. [P(GDMAPA)27]X (4) was purified by dialysis
in methanol to remove the remaining CQ and its coupling products.
Chapter 6
108
Complete removal of the photoinitiator was monitored by UV/VIS
spectroscopy (Fig. A.4.9, appendix A.4). The cross-linked polymer was
subsequently dialyzed in water to exchange the solvent, yielding an
opaque dispersion showing a Tyndall effect. Polymer particles were
stable in dispersion. However, upon drying coalescence of the particles
leads to the vanishing of the particle structure and a non-redispersable,
solid coating. [P(GDMAPA)27]X (4) was characterized by FTIR spec-
troscopy, dynamic light scattering, DSC and XPS.
Scheme 6.3: Synthesis of cross-linked, cationic polyglycidols (5–8). (a) Cross-
linking of P(GDMAPA)27 (3) with camphorquinone, hυ, DMF, rt, 20 h. (b)
Quaternization of [P(GDMAPA)27]X (4) with MeI, H2O, 40 °C, 24 h, or
quaternization of [P(GDMAPA)27]X (4) with 1-iodooctane/1-iodo-3,6,9-trioxa-
decane/1H, 1H, 2H, 2H-heptadecafluorodecyl iodide, DMF, 100 °C, 20 h.
FTIR spectroscopy confirms the successful cross-linking of
P(GDMAPA)27 (3) by absence of the distinctive absorption bands of the
methyl functionalized tertiary amines at 2816 and 2765 cm–1 (Fig.
6.2b). No other difference in the absorption bands is observed
(compare Fig. 6.2a and Fig. 6.2b).
Microgel 4 was analyzed by DLS. A hydrodynamic radius of Rh =
198.8 ± 14.4 nm with a PDI of 0.443 ± 0.061 was found. Additionally,
a zeta potential of 14.0 ± 2.9 mV (Table 6.1, entry 1) indicated a
growing stability of the aqueous dispersion.
The successful cross-linking of P(GDMAPA)27 (3) is further confirmed
by DSC measurements. In general cross-linking of a polymer restricts
the chain mobility, leading to an increase in the glass transition
Chapter 6
109
temperature.42 For polymer 3 and microgel 4 an increase from Tg =
-7.7 °C to Tg = 70.8 °C was observed. DSC curves are found in the
supporting information (Fig. A.4.10a/b, appendix A.4).
Table 6.1: Hydrodynamic radii (Rh), polydispersity indices (PDI), zeta
potentials and glass transition temperatures (Tg) of P(GDMAPA)27 (3),
[P(GDMAPA)27]X (4), [P(GTMAPA)27]X (5), [P(GODMAPA)27]X (6), [P(GPDMAPA)27]X
(7), [P(GFDMAPA)27]X (8).
Entry Polymer Rh
[nm]
PDI Zeta
potential
[mV]
Tg
[°C]
1 [P(GDMAPA)27]X
(4)
198.8 ±
14.4
0.443 ±
0.061
14.0 ±
2.9
70.8
2 [P(GTMAPA)27]X
(5)
268.2 ±
15.9
0.365 ±
0.149
37.0 ±
2.7
120.0
3 [P(GODMAPA)27]X
(6)
77.9 ±
0.7
0.443 ±
0.029
36.3 ±
3.5
79.6
4 [P(GPDMAPA)27]X
(7)
330.1 ±
11.5
0.513 ±
0.098
42.1 ±
1.9
49.7
5 [P(GFDMAPA)27]X
(8)
243.1 ±
25.1
0.144 ±
0.103
39.0 ±
5.2
95.0
6.3.3 Quaternization of [P(GDMAPA)27]X (4)
[P(GDMAPA)27]X (4) was quaternized with various organoiodine
compounds to prepare cationic/hydrophilic, cationic/hydrophobic
and cationic/superhydrophobic microgels (Scheme 6.3b). The quater-
nization with methyl iodide was performed in an aqueous dispersion
of [P(GDMAPA)27]X (4) at 40 °C for 24 h. Purification by dialysis in water
gave [P(GTMAPA)27]X (5) as an opaque, aqueous dispersion. Quarter-
nization of [P(GDMAPA)27]X (4) with 1-iodooctane, 1-iodo-3,6,9-trioxa-
decane and 1H, 1H, 2H, 2H-heptadecafluorodecyl iodide was
performed in DMF at 100 °C for 20 h. Due to the low solubility of the
organoiodine compounds and the low reaction rates the quaternization
was not possible in water. Purification by dialysis in methanol,
followed by a solvent exchange by dialysis in water gave
[P(GODMAPA)27]X (6), [P(GPDMAPA)27]X (7) and [P(GFDMAPA)27]X (8) as
Chapter 6
110
opaque, aqueous dispersions. The quaternized polymer dispersions
were characterized by DLS, DSC and XPS measurements.
DLS measurements of the aqueous polymer dispersions show
differences in the hydrodynamic radius and PDI dependent on the
quaternization agent, compared to the non-quaternized starting
material. [P(GTMAPA)27]X (5) exhibits an increase in the hydrodynamic
radius to Rh = 268.2 ± 15.9 nm with a PDI of 0.365 ± 0.149 (Table
6.1, entry 2). Quaternization with octyl iodide leads to more compact
particles with Rh = 77.9 ± 0.7 nm and no change in the polydispersity
of the particles (Table 6.1, entry 3). For [P(GPDMAPA)27]X (7) Rh
increases to 330.1 ± 11.5 nm with a PDI of 0.513 ± 0.098 (Table 6.1,
entry 4). [P(GFDMAPA)27]X (8) shows an increased hydrodynamic radius
of Rh = 243.1 ± 25.1 nm. The PDI decreases to 0.144 ± 0.103,
indicating collapsed fluorinated side chains and the formation of more
uniform particles (Table 6.1, entry 5). The zeta potential increases to
~40 mV for all samples, confirming the successful quaternization.
Additionally, the introduction of cationic charges and thus,
intermolecular repulsive forces leads to a higher stability of the
polymer dispersions.
The quaternization of [P(GDMAPA)27]X (4) and ammonium salt
formation causes the modification of the glass transition temperature
of the cross-linked polymers 5, 6, 7 and 8. Quaternization with methyl
iodide causes an increase from Tg = 70.8 °C to Tg = 120 °C. The
introduction of octyl groups leads to a slight increase of the glass
transition temperature to Tg = 79.6 °C. Functionalization with
poly(ethylene glycol) moieties decreases Tg to 49.7 °C, due to the high
chain mobility of the PEG side groups. Quaternization with 1H, 1H,
2H, 2H-heptadecafluorodecyl iodide leads to a higher glass transition
temperature of Tg = 95.0 °C (Fig. A.4.10c–f, appendix A.4).
In-depth chemical characterization of the [P(GDMAPA)27]X (4),
[P(GTMAPA)27]X (5), [P(GODMAPA)27]X (6) and [P(GPDMAPA)27]X (7) and
[P(GFDMAPA)27]X (8) was performed by XPS (Fig. 6.3 and Fig. A.4.11,
appendix A4). The C 1s region of polymers 4–8 shows a dominant
signal for the C―O bonds of the polyether backbone at 286.4 eV
which in this particular case cannot be distinguished from C―N bonds
of the tertiary amine.43 Additionally, the carbamate moieties show a
distinctive C 1s peak at 289.5 eV for the O―(O═C)―N group.44,45
Chapter 6
111
Figure 6.3: High-resolution XPS spectra of the C 1s region (top left), the O 1s
region (top right), the N 1s region (bottom left), and the I 3d5/2 region (bottom
right) of P[(GDMAPA)27]X (4), P[(GTMAPA)27]X (5), P[(GODMAPA)27]X (6),
P[(GPDMAPA)27]X (7), and P[(GFDMAPA)27]X (8).
Chapter 6
112
In good agreement with literature the corresponding O 1s peaks at
532.1 eV (C═O groups) and 533.1 eV (C―O groups) corroborate
these assignments.43,45 However, the very weak peak at C 1s =
287.8 eV which usually is attributed to C═O and O―C―O groups
cannot be assigned unambiguously, but might be due to contamination
residues. The N 1s region of all cross-linked polymers show the C―N
bond of the carbamate group at 400.0 eV. The quaternized polymers,
moreover, reveal an additional peak at 402.5 eV for the NR4+ bond,
clearly evidencing the successful functionalization of [P(GDMAPA)27]X
(4).46 These findings are supported by the corresponding I 3d5/2 =
618.5 eV peak stemming from the I--counterion of the ammonium
groups in polymers 4–8. Finally, [P(GFDMAPA)27]X (8) exhibits a C 1s
peak at 292.0 eV and the corresponding F 1s = 689.2 eV peak assigned
to the CF2―CF2 group, additionally proving the successful func-
tionalization of [P(GDMAPA)27]X (4).47
6.4 Conclusions
In this chapter, a synthetic strategy to functionalize polyglycidol after
cross-linking was developed. First, linear polyglycidol was func-
tionalized with pendant tertiary amine groups at every repeating unit.
The successful functionalization was confirmed by 1H NMR, 13C
NMR spectroscopy, and SEC analysis. Polyglycidol was cross-linked
at the methyl groups of the tertiary amines in a light-induced reaction
using CQ as a photoinitiator. The cross-linked polymer was further
quaternized by reaction with four different organoiodine compounds
to obtain cationic/hydrophobic, cationic/hydrophilic and cationic/
superhydrophobic polyether particles. Aqueous dispersions of all
polyglycidols were evaluated by DLS and zeta potential measurements.
Polymer films were further evaluated by DSC and XPS. All analytical
methods confirm the successful cross-linking of the functional
polyglycidol and post-cross-linking modification. The simple strategy described here can be extended to other
polyglycidols and functional groups with the purpose of tuning the
hydrophilic to hydrophobic balance for specific bio applications.
Further studies in this line are now in progress.
Chapter 6
113
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47. Vesel, A.; Mozetic, M.; Zalar, A. XPS characterization of
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Surf. Interface Anal. 2008, 40, 661.
Chapter 7
119
Chapter 7
Summary
In this work, various functionalities have been introduced to the
polyglycidol backbone. First, a synthetic strategy for the preparation
of polyglycidols with pendant phosphate groups by reaction of the
hydroxymethyl side groups with diethyl chlorophosphate has been
developed. The successful synthesis was confirmed by 1H, 13C, 31P
{1H} NMR spectroscopy, FTIR spectroscopy, and SEC analysis.
Diethyl phosphate groups were subsequently (mono-)dealkylated by
reaction with sodium iodide or bromotrimethylsilane, respectively.
The reaction protocol allows the tailoring of pendant phosphate/
phosphoric acid groups introduced into polyglycidol.
Secondly, various novel cationic/hydrophobic functionalized
polyglycidols were successfully synthesized. A polyglycidol with
statistically distributed cationic and hydrophobic groups (cationic to
hydrophobic ratio of 1:1), a polyglycidol with a hydrophilic modifica-
tion at the cationic moieties, a polyglycidol with cationic and hydro-
phobic functionalities at every repeating unit, and a polyglycidol with
a cationic to hydrophobic balance of 1:2 were characterized by 1H
NMR, 13C NMR spectroscopy, and SEC analyses and evaluated in
regard to their antibacterial activity. Antibacterial polyglycidols with
statistic distribution of cationic and hydrophobic residues are equally
active against a Gram-negative and a Gram-positive bacterial strain.
The best efficacy against both bacterial strains resulted from
Chapter 7
120
polyglycidol with statistic distribution of the cationic and hydrophobic
groups (cationic to hydrophobic ratio of 1:1). If cationic and hydro-
phobic residues are located in the same repeating unit connected by a
spacer, the impact on the cell envelope of S. aureus is significantly less
effective than against E. coli. Changing the cationic to hydrophobic
balance to a higher hydrophobic content in amphipathic polyglycidol
with statistically distributed cationic and hydrophobic residues leads to
a decrease in efficacy against both bacterial strains.
Thirdly, the usage of bio-based building blocks in the synthesis of
functional polyglycidols was investigated. Linear polyglycidol was
functionalized with homoserine lactone in a two-step reaction. The
successful synthesis was confirmed by 1H, 13C NMR spectroscopy, and
SEC analysis. Homoserine lactone groups were subsequently opened
by addition of 3-(dimethylamino)-1-propylamine and the tertiary
amine was quaternized with methyl iodide.
In the last chapter, the concept of post-cross-linking functionalization
of polyglycidol has been presented. Therefore, linear polyglycidol was
functionalized with pendant tertiary amine groups at every repeating
unit in a two-step reaction. The successful functionalization was
confirmed by 1H NMR, 13C NMR spectroscopy, and SEC analysis.
Polyglycidol was cross-linked at the methyl groups of the tertiary
amines in a UV-light-mediated reaction with camphorquinone as a
Type II photoinitiator. The cross-linked polymer was quaternized by
reaction with four different organoiodine compounds to obtain
cationic/hydrophobic, cationic/hydrophilic and cationic/superhydro-
phobic polyether particles. Aqueous dispersions of all polyglycidols
were evaluated by DLS and zeta potential measurements. Polymer
films were further evaluated concerning their thermal properties by
DSC and their chemical structure by XPS. All analytical methods
confirm the successful cross-linking of the functional polyglycidol and
the subsequent post-cross-linking modification.
Appendix A
121
Appendix A
Additional Information
A.1 Phosphate Functionalized Polyglycidols
A.1.1 Synthesis of polyglycidol, PG24
Figure A.1.1: 1H NMR spectrum of PG24 (2) measured in DMSO-d6.
Figure A.1.2: 13C NMR spectrum of PG24 (2) measured in DMSO-d6.
Appendix A
122
Figure A.1.3: DMF-SEC traces of PG24 (2)
A.1.2 Synthesis of poly(glycidyl diethyl phosphate-co-glycidol) (P(GDEP-co-G))
(3a–d)
Table A.1.1: Synthesis of linear P(GDEP-co-G) (3a–d) (t = 20 h, T = rt):
Reagent ratios and yields after dialysis in MeOH.
Polymer PG
[mmol
OH]
DECP
[mmol]
4-DMAP
[mmol]
Pyridine
[mmol]
Yield a
[%]
3a 23.53 5.88 2.35 202.36 23
3b 23.46 11.73 2.35 201.76 41
3c 20.09 15.07 2.01 172.77 38
3d 13.16 13.16 1.32 113.18 27
a Yield obtained after purification by dialysis in MeOH for two days.
Appendix A
123
A.1.3 Synthesis of poly(glycidyl ethyl phosphate-co-glycidol) (P(GEP-co-G))
(4a–d)
Table A.1.2: Synthesis of linear P(GEP-co-G) (4a–d) (t = 48 h, T = 130 °C):
Reagent ratios and yields.
Polymer P(GEP-co-G)
[mmol DEP]
NaI
[mmol]
2-Hexanone
[mL]
Yield
[%]
4a 0.24 0.29 20 99
4b 0.45 0.54 20 100
4c 0.83 0.99 20 97
4d 0.15 0.18 20 97
Figure A.1.4: 13C NMR spectrum of P(GEP22-co-G8) (4c) measured in D2O.
Figure A.1.5: 31P NMR spectrum of P(GEP22-co-G8) (4c) measured in D2O.
Appendix A
124
A.1.4 SEC trace of higher molecular weight polyglycidol (PG100) and its
phosphate functionalized equivalent (P(GDEP50-co-G50)
Figure A.1.6: DMF-SEC traces of PG100 (black) and P(GDEP50-co-G50) (red).
A.1.5 Titration curve of P(GP22-co-G8) (5c)
Figure A.1.7: Titration curve of P(GP22-co-G8) (5c).
Appendix A
125
A.1.6 Synthesis of poly(glycidyl ethyl phosphate-co-glycidol) (P(GP-co-G))
(5a–d)
Table A.1.3: Synthesis of linear P(GP-co-G) (5a–d) (t = 17 h, T = rt): Reagent
ratios and yields.
Polymer P(GP-co-G)
[mmol DEP]
TMSBr
[mmol]
DCM
[mL]
Yield
[%]
5a 0.43 1.72 10 92
5b 3.06 12.23 35 81
5c 1.73 6.92 20 91
5d 0.33 1.32 5.0 94
Figure A.1.8: 13C NMR spectrum of P(GP22-co-G8) (5c) measured in D2O.
Figure A.1.9: 31P NMR spectrum of P(GP22-co-G8) (5c) measured in D2O.
Appendix A
126
A.1.7 IR Analysis
Figure A.1.10: FTIR analysis of P(GDEP22-co-G8) (3c) (blue), P(GEP
22-co-G8)
(4c) (red) and P(GP22-co-G8) (5c) (black).
A.2 Antibacterial Polyglycidols
A.2.1 Synthesis of linear polyglycidol (1)
Figure A.2.1: 1H NMR spectrum of PG27 (1) measured in DMSO-d6.
Appendix A
127
Figure A.2.2: 13C NMR spectrum of PG27 (1) measured in DMSO-d6.
Figure A2.3: DMF-SEC traces of PG27 (1).
Appendix A
128
A.2.2 Synthesis of P(GTMAPA15-co-GDDA
12) (5) and P(GAPDEMA16-co-
GDDA11) (6)
Figure A.2.4: 1H NMR spectrum of P(GPC)27 (2) measured in CDCl3.
Figure A.2.5: 13C NMR spectrum of P(GPC)27 (2) measured in CDCl3.
Figure A.2.6: 1H NMR spectrum of P(GDMAPA15-co-GDDA
12) (3) measured in
CDCl3.
Appendix A
129
Figure A.2.7: 13C NMR spectrum of P(GDMAPA15-co-GDDA
12) (3) in CDCl3.
Figure A.2.8: 1H NMR spectrum of P(GAPDEA16-co-GDDA
11) (4) in MeOD.
Figure A.2.9: 13C NMR spectrum of P(GAPDEA16-co-GDDA
11) (4) in MeOD.
Appendix A
130
Figure A.2.10: 13C NMR spectrum of P(GTMAPA15-co-GDDA
12) (5) measured in
DMSO-d6.
Figure A.2.11: 13C NMR spectrum of P(GAPDEMA16-co-GDDA
11) (6) measured
in MeOD.
Appendix A
131
Figure A.2.12: DMF-SEC traces of P(GPC)27 (2).
Figure A.2.13: DMF-SEC traces of P(GDMAPA15-co-GDDA
12) (3).
Appendix A
132
Figure A.2.14: DMF-SEC traces of P(GAPDEA16-co-GDDA
11) (4).
Figure A.2.15: DMF-SEC traces of P(GTMAPA15-co-GDDA
12) (5).
Appendix A
133
A.2.3 Synthesis of P(GDDAc, q)27 (10)
Figure A.2.16: 1H NMR spectrum of P(GNPC)27 (7) measured in DMSO-d6.
Figure A.2.17: 13C NMR spectrum of P(GNPC)27 (7) measured in DMSO-d6.
Figure A.2.18: 1H NMR spectrum of P(GHCTL)27 (8) measured in DMSO-d6.
Appendix A
134
Figure A.2.19: 13C NMR spectrum of P(GHCTL)27 (8) measured in DMSO-d6.
Figure A.2.20: 1H NMR spectrum of P(GDDAc)27 (9) measured in CDCl3.
Figure A.2.21: 13C NMR spectrum of P(GDDAc)27 (9) measured in CDCl3.
Appendix A
135
Figure A.2.22: 13C NMR spectrum of P(GDDAc, q)27 (10) measured in CDCl3.
Figure A.2.23: DMF-SEC traces of P(GNPC)27 (7).
Appendix A
136
Figure A.2.24: DMF-SEC traces of P(GHCTL)27 (8).
Figure A.2.25: DMF-SEC traces of P(GDDAc)27 (9).
Appendix A
137
Figure A.2.26: DMF-SEC traces of P(GDDAc, q)27 (10).
A.2.4 Synthesis of P(GTMAPA14-co-GDDADDAc
13) (12)
Figure A.2.27: 1H NMR spectrum of P(GDMAPA14-co-GDDADDAc
13) (11)
measured in CDCl3/acetone-d6.
Appendix A
138
Figure A.2.28: 13C NMR spectrum of P(GDMAPA14-co-GDDADDAc
13) (11)
measured in CDCl3/acetone-d6.
Figure A.2.29: 13C NMR spectrum of P(GTMAPA14-co-GDDADDAc
13) (12)
measured in CDCl3/acetone-d6.
Appendix A
139
Figure A.2.30: DMF-SEC traces of P(GDMAPA14-co-GDDADDAc
13) (11).
Figure A.2.31: DMF-SEC traces of P(GTMAPA14-co-GDDADDAc
13) (12).
Appendix A
140
A.3 Homoserine Lactone Functionalized Polyglycidol
A.3.1 Synthesis of PG26 (1)
Figure A.3.1: 1H NMR spectrum of PG26 (1) measured in DMSO-d6.
Figure A.3.2: 13C NMR spectrum of PG26 (1) measured in DMSO-d6.
Figure A.3.3: DMF-SEC traces of PG26 (1).
Appendix A
141
A.3.2 Functionalization of polyglycidol (1) with DL-homoserine lactone
hydrobromide
Figure A.3.4: 1H NMR spectrum of P(GNPC)26 (2) measured in DMSO-d6.
Figure A.3.5 13C NMR spectrum of P(GNPC)26 (2) measured in DMSO-d6.
Figure A.3.6: 13C NMR spectrum of P(GHSL)26 (3) measured in DMF-d7.
Appendix A
142
Figure A.3.7: DMF-SEC traces of P(GNPC)26 (2).
Figure A.3.8: DMF-SEC traces of P(GHSL)26 (3).
Appendix A
143
A.3.3 Ring-opening of P(GHSL)26 (3)
Figure A.3.9: 1H NMR spectrum of P(GHSL,o)26 (4) measured in DMSO-d6.
Figure A.3.10: 13C NMR spectrum of P(GHSL,o)26 (4) measured in DMSO-d6.
Appendix A
144
Figure A.3.11: DMF-SEC traces of P(GHSL,o)26 (4).
A.3.4 Quaternization of P(GHSL,o)26 (4)
Figure A.3.12: 1H NMR spectrum of P(GHSL,o,q)26 (5) measured in D2O.
Appendix A
145
Figure A.3.13: 13C NMR spectrum of P(GHSL,o,q)26 (5) measured in D2O.
A.4 Post-cross-linking Modification
A.4.1 Synthesis of linear polyglycidol (1)
Figure A.4.1: 1H NMR spectrum of PG27 (1) measured in DMSO-d6.
Figure A.4.2: 13C NMR spectrum of PG27 (1) measured in DMSO-d6.
Appendix A
146
Figure A.4.3: DMF-SEC traces of PG27 (1).
A.4.2 Synthesis of P(GDMAPA)27 (3)
Figure A.4.4: 1H NMR spectrum of P(GPC)27 (2) measured in CDCl3.
Appendix A
147
Figure A.4.5: 13C NMR spectrum of P(GPC)27 (2) measured in CDCl3.
Figure A.4.6: 13C NMR spectrum of P(GDMAPA)27 (3) measured in CDCl3.
Figure A.4.7: DMF-SEC traces of P(GPC)27 (2).
Appendix A
148
Figure A.4.8: DMF-SEC traces of P(GDMAPA)27 (3).
A.4.3 Determination of camphorquinone concentration by UV/Vis
spectroscopy
Figure A.4.9: UV/Vis spectra of [P(GDMAPA)27]X (4) (black) after dialysis in
methanol and after addition of 1% of the amount of camphorquinone used
during the reaction (red).
Appendix A
149
A.4.4 DSC measurements
Figure A.4.10: DSC curves of the second heating cycle of P(GDMAPA)27 (3) (a),
P[(GDMAPA)27]X (4) (b), P[(GTMAPA)27]X (5) (c), P[(GODMAPA)27]X (6) (d),
P[(GPDMAPA)27]X (7) (e) and P[(GFDMAPA)27]X (8) (f).
Appendix A
150
A.4.5 F 1s XPS measurement
Figure A.4.11: High-resolution XPS spectra of the F 1s region of
P[(GDMAPA)27]X (4) and P[(GFDMAPA)27]X (8).
List of Abbreviations
151
List of Abbreviations
AGE allyl glycidyl ether
AIBN azobisisobutyronitrile
APDEA N-(3-aminopropyl)-diethanolamine
APDEMA N-(3-aminopropyl)-diethanolmethylammonium
ATRP atom transfer radical polymerization
CFU colony forming unit
Ð dispersity (Mw/Mn)
DCC N,N'-dicyclohexylcarbodiimide
DCM dichloromethane
DDA dodecylamine
DECP diethyl chlorophosphate
DEP diethyl phosphate
DLS dynamic light scattering
DMAP dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DSC differential scanning calorimetry
E. coli Escherichia coli
EEGE ethoxyethyl glycidyl ether
EP ethyl phosphate
eq. equivalent(s)
FDA Food and Drug Administration
FDMAPA fluorinated 3-(dimethyl-amino)-1-propylamine
FTIR Fourier-transform infrared spectroscopy
HC hemolytic concentration
List of Abbreviations
152
HCTL homocysteine thiolactone
HSL homoserine lactone
J coupling constant
MHB Mueller-Hinton broth
MIC minimum inhibitory concentration
Mn number average molecular weight
NMR nuclear magnetic resonance (spectroscopy)
NPC 4-nitrophenyl carbonate
ODMAPA 3-(octyldimethylamino)-1-propylamine
P phosphate
PBS phosphate-buffered saline
PC phenyl carbonate
PDI polydispersity index
PDMAPA 3-(PEG-dimethylamino)-1-propylamine
PE polyethylene
PEG polyethylene glycol
PEI polyethylenimine
PET polyethylene terephthalate
PG polyglycidol
PP polypropylene
PS polystyrene
PVC polyvinyl chloride
RBC red blood cells
S. aureus Staphylococcus aureus
SEC size exclusion chromatography
tBuGE tert-butyl glycidyl ether
TCEP tris(2-carboxyethyl)phosphine
TGE tetrahydropyranyl glycidyl ether
THF tetrahydrofuran
TMAPA trimethylammoniumpropylamine
TX thioxanthones
UV ultraviolet
XPS X-ray photoelectron spectroscopy
δ chemical shift
List of Figures
153
List of Figures
Figure 3.1: 1H NMR (a), 13C NMR (b) and 31P {1H} NMR (c) spectra
of P(GDEP22-co-G8) (3c) measured in DMSO-d6. 40
Figure 3.2: DMF-SEC traces of P(GDEP22-co-G8) (3c) (black line) and
fractions separated by preparative SEC with THF as eluent (red and
blue dotted lines). 41
Figure 3.3: 1H NMR spectra of P(GEP22-co-G8) (4c) (top) and P(GP
22-
co-G8) (5c) (bottom) measured in D2O. 44
Figure 4.1: Comparison of various cationic–hydrophobic func-
tionalized polyglycidols in regard to their antibacterial activity against
E. coli and S. aureus to examine the structure–property relationship.
65
Figure 4.2: 1H NMR spectra of P(GTMAPA15-co-GDDA
12) (5) measured
in DMSO-d6 (a) and P(GAPDEMA16-co-GDDA
11) (6) measured in MeOD
(b). 68
Figure 4.3: 1H NMR spectra of P(GDDAc, q)27 (10) measured in CDCl3
(a) and P(GTMAPA14-co-GDDADDAc
13) (12) measured in CDCl3/acetone
(6:4) (b). 71
Figure 5.1: 1H NMR spectrum of P(GHSL)26 (3) measured in DMF-d7.
90
Figure 6.1: 1H NMR spectrum of P(GDMAPA)27 (3) measured in CDCl3.
106
List of Figures
154
Figure 6.2: FTIR spectra of P(GDMAPA)27 (3) (a) and [P(GDMAPA)27]X
(4) (b). 107
Figure 6.3: High-resolution XPS spectra of the C 1s region (top left),
the O 1s region (top right), the N 1s region (bottom left), and the
I 3d5/2 region (bottom right) of P[(GDMAPA)27]X (4), P[(GTMAPA)27]X (5),
P[(GODMAPA)27]X (6), P[(GPDMAPA)27]X (7), and P[(GFDMAPA)27]X (8).
111
Figure A.1.1: 1H NMR spectrum of PG24 (2) measured in DMSO-d6.
121
Figure A.1.2: 13C NMR spectrum of PG24 (2) measured in DMSO-d6.
121
Figure A.1.3: DMF-SEC traces of PG24 (2). 122
Figure A.1.4: 13C NMR spectrum of P(GEP22-co-G8) (4c) measured in
D2O. 123
Figure A.1.5: 31P NMR spectrum of P(GEP22-co-G8) (4c) measured in
D2O. 123
Figure A.1.6: DMF-SEC traces of PG100 (black) and P(GDEP50-co-G50)
(red). 124
Figure A.1.7: Titration curve of P(GP22-co-G8) (5c). 124
Figure A.1.8: 13C NMR spectrum of P(GP22-co-G8) (5c) measured in
D2O. 125
Figure A.1.9: 31P NMR spectrum of P(GP22-co-G8) (5c) measured in
D2O. 125
Figure A.1.10: FTIR analysis of P(GDEP22-co-G8) (3c) (blue), P(GEP
22-
co-G8) (4c) (red) and P(GP22-co-G8) (5c) (black). 126
Figure A.2.1: 1H NMR spectrum of PG27 (1) measured in DMSO-d6.
126
Figure A.2.2: 13C NMR spectrum of PG27 (1) measured in DMSO-d6.
127
Figure A2.3: DMF-SEC traces of PG27 (1). 127
List of Figures
155
Figure A.2.4: 1H NMR spectrum of P(GPC)27 (2) measured in CDCl3.
128
Figure A.2.5: 13C NMR spectrum of P(GPC)27 (2) measured in CDCl3.
128
Figure A.2.6: 1H NMR spectrum of P(GDMAPA15-co-GDDA
12) (3)
measured in CDCl3. 128
Figure A.2.7: 13C NMR spectrum of P(GDMAPA15-co-GDDA
12) (3) in
CDCl3. 129
Figure A.2.8: 1H NMR spectrum of P(GAPDEA16-co-GDDA
11) (4) in
MeOD. 129
Figure A.2.9: 13C NMR spectrum of P(GAPDEA16-co-GDDA
11) (4) in
MeOD. 129
Figure A.2.10: 13C NMR spectrum of P(GTMAPA15-co-GDDA
12) (5)
measured in DMSO-d6. 130
Figure A.2.11: 13C NMR spectrum of P(GAPDEMA16-co-GDDA
11) (6)
measured in MeOD. 130
Figure A.2.12: DMF-SEC traces of P(GPC)27 (2). 131
Figure A.2.13: DMF-SEC traces of P(GDMAPA15-co-GDDA
12) (3). 131
Figure A.2.14: DMF-SEC traces of P(GAPDEA16-co-GDDA
11) (4). 132
Figure A.2.15: DMF-SEC traces of P(GTMAPA15-co-GDDA
12) (5). 132
Figure A.2.16: 1H NMR spectrum of P(GNPC)27 (7) measured in
DMSO-d6. 133
Figure A.2.17: 13C NMR spectrum of P(GNPC)27 (7) measured in
DMSO-d6. 133
Figure A.2.18: 1H NMR spectrum of P(GHCTL)27 (8) measured in
DMSO-d6. 133
Figure A.2.19: 13C NMR spectrum of P(GHCTL)27 (8) measured in
DMSO-d6. 134
List of Figures
156
Figure A.2.20: 1H NMR spectrum of P(GDDAc)27 (9) measured in
CDCl3. 134
Figure A.2.21: 13C NMR spectrum of P(GDDAc)27 (9) measured in
CDCl3. 134
Figure A.2.22: 13C NMR spectrum of P(GDDAc, q)27 (10) measured in
CDCl3. 135
Figure A.2.23: DMF-SEC traces of P(GNPC)27 (7). 135
Figure A.2.24: DMF-SEC traces of P(GHCTL)27 (8). 136
Figure A.2.25: DMF-SEC traces of P(GDDAc)27 (9). 136
Figure A.2.26: DMF-SEC traces of P(GDDAc, q)27 (10). 137
Figure A.2.27: 1H NMR spectrum of P(GDMAPA14-co-GDDADDAc
13) (11)
measured in CDCl3/acetone-d6. 137
Figure A.2.28: 13C NMR spectrum of P(GDMAPA14-co-GDDADDAc
13) (11)
measured in CDCl3/acetone-d6. 138
Figure A.2.29: 13C NMR spectrum of P(GTMAPA14-co-GDDADDAc
13) (12)
measured in CDCl3/acetone-d6. 138
Figure A.2.30: DMF-SEC traces of P(GDMAPA14-co-GDDADDAc
13) (11).
139
Figure A.2.31: DMF-SEC traces of P(GTMAPA14-co-GDDADDAc
13) (12).
139
Figure A.3.1: 1H NMR spectrum of PG26 (1) measured in DMSO-d6.
140
Figure A.3.2: 13C NMR spectrum of PG26 (1) measured in DMSO-d6.
140
Figure A.3.3: DMF-SEC traces of PG26 (1). 140
Figure A.3.4: 1H NMR spectrum of P(GNPC)26 (2) measured in
DMSO-d6. 141
Figure A.3.5 13C NMR spectrum of P(GNPC)26 (2) measured in
DMSO-d6. 141
List of Figures
157
Figure A.3.6: 13C NMR spectrum of P(GHSL)26 (3) measured in DMF-
d7. 141
Figure A.3.7: DMF-SEC traces of P(GNPC)26 (2). 142
Figure A.3.8: DMF-SEC traces of P(GHSL)26 (3). 142
Figure A.3.9: 1H NMR spectrum of P(GHSL,o)26 (4) measured in
DMSO-d6. 143
Figure A.3.10: 13C NMR spectrum of P(GHSL,o)26 (4) measured in
DMSO-d6. 143
Figure A.3.11: DMF-SEC traces of P(GHSL,o)26 (4). 144
Figure A.3.12: 1H NMR spectrum of P(GHSL,o,q)26 (5) measured in
D2O. 144
Figure A.3.13: 13C NMR spectrum of P(GHSL,o,q)26 (5) measured in
D2O. 145
Figure A.4.1: 1H NMR spectrum of PG27 (1) measured in DMSO-d6.
145
Figure A.4.2: 13C NMR spectrum of PG27 (1) measured in DMSO-d6.
145
Figure A.4.3: DMF-SEC traces of PG27 (1). 146
Figure A.4.4: 1H NMR spectrum of P(GPC)27 (2) measured in CDCl3.
146
Figure A.4.5: 13C NMR spectrum of P(GPC)27 (2) measured in CDCl3.
147
Figure A.4.6: 13C NMR spectrum of P(GDMAPA)27 (3) measured in
CDCl3. 147
Figure A.4.7: DMF-SEC traces of P(GPC)27 (2). 147
Figure A.4.8: DMF-SEC traces of P(GDMAPA)27 (3). 148
Figure A.4.9: UV/Vis spectra of [P(GDMAPA)27]X (4) (black) after
dialysis in methanol and after addition of 1% of the amount of
camphorquinone used during the reaction (red). 148
List of Figures
158
Figure A.4.10: DSC curves of the second heating cycle of
P(GDMAPA)27 (3) (a), P[(GDMAPA)27]X (4) (b), P[(GTMAPA)27]X (5) (c),
P[(GODMAPA)27]X (6) (d), P[(GPDMAPA)27]X (7) (e) and P[(GFDMAPA)27]X
(8) (f). 149
Figure A.4.11: High-resolution XPS spectra of the F 1s region of
P[(GDMAPA)27]X (4) and P[(GFDMAPA)27]X (8). 150
List of Schemes
159
List of Schemes
Scheme 2.1: Synthesis of glycidol by (a) hydrolysis of epichlorohydrin,
(b) epoxidation of allyl alcohol, and (c) decarboxylation of glycerol
carbonate. 10
Scheme 2.2: Mechanism of the anionic ring-opening polymerization
of glycidol. 11
Scheme 2.3: Synthesis of branched polyglycidol with primary (blue)
and secondary (red) hydroxyl groups along the polymer chain. 12
Scheme 2.4: a) Protected glycidol monomers used in the
polymerization of polyglycidol. b) Synthesis of linear polyglycidol from
EEGE using potassium alkoxide as initiator. 13
Scheme 2.5: Cationic polymerization of glycidol by active chain-end
mechanism (top) and activated monomer mechanism (bottom). 14
Scheme 2.6: -End-functionalization of hyperbranched polyglycidol.
17
Scheme 2.7: Backbone functionalization of polyglycidol. 21
Scheme 3.1: Functionalization of linear polyglycidol with diethyl
chlorophosphate. 39
Scheme 3.2: Synthesis of poly(glycidyl ethyl phosphate-co-glycidol)
(4a–d). 43
Scheme 3.3: Synthesis of poly(glycidyl phosphate-co-glycidol) (5a–d)
by dealkylation of P(GDEP-co-G) (3a–d). 45
List of Schemes
160
Scheme 4.1: Synthetic pathway to P(GTMAPA15-co-GDDA
12) (5) and
P(GAPDEMA16-co-GDDA
11) (6). (a) Functionalization of PG27 (1) with
phenyl chloroformate, pyridine/DCM, rt, 20 h; (b) Reaction of
P(GPC)27 (2) with DDA and DMAPA/APDEA, THF, rt, 42 h; (c)
Quaternization of tertiary amines with methyl iodide, THF, rt, 20 h.
66
Scheme 4.2: Synthetic pathway to P(GDDAc, q)27 (10). (a)
Functionalization of PG27 (1) with 4-nitrophenyl chloroformate,
pyridine/DCM, rt, 20 h; (b) Reaction of P(GNPC)27 (7) with DL-
homocysteine thiolactone hydrochloride, 4-DMAP, Et3N, DMF, rt,
20 h; (c) Ring-opening reaction with DMAPA, followed by thiol-ene
reaction with dodecyl acrylate, CHCl3, rt, 20 h; (d) Quaternization of
tertiary amines with methyl iodide, THF, rt, 20 h. 70
Scheme 4.3: Synthetic pathway to P(GTMAPA14-co-GDDADDAc
13) (12). (a)
(I) Reaction of P(GNPC)27 (7) with DMAPA, DMF, rt, 20 h, (II)
Reaction with DL-homocysteine thiolactone hydrochloride, 4-DMAP,
Et3N, DMF, 20 h; (b) Ring-opening reaction with dodecylamine,
followed by thiol-ene reaction with dodecyl acrylate, CHCl3, rt, 20 h;
(c) Quaternization of tertiary amines with methyl iodide, THF, rt, 20 h.
73
Scheme 5.1: Strategies for the synthesis of glycerol carbonate and
glycidol from glycerol. 84
Scheme 5.2: Synthetic pathway to P(GHSL)26 (3). a) Functionalization
of PG26 (1) with 4-nitrophenyl chloroformate, pyridine/DCM, rt, 20 h.
b) Reaction of P(GNPC)26 (2) with DL-homoserine lactone
hydrobromide, 4-DMAP, Et3N, DMF, rt, 20 h. 89
Scheme 5.3: Synthetic pathway to P(GHSL,o,q)26 (5). a) Addition of
DMAPA to P(GHSL)26 (3), DMF, rt, 20 h. b) Quaternization of
P(GHSL,o)26 (4) with MeI, MeOH, reflux, 20 h. 91
Scheme 6.1: Photoinduced radical generation process by
camphorquinone in the presence of hydrogen donors. 99
Scheme 6.2: Synthetic pathway to P(GDMAPA)27 (3). (a) Func-
tionalization of PG27 (1) with phenyl chloroformate, pyridine/DCM,
List of Schemes
161
rt, 20 h. (b) Reaction of P(GPC)27 (2) with 3-(dimethylamino)-1-
propylamine, THF, rt, 42 h. 105
Scheme 6.3: Synthesis of cross-linked, cationic polyglycidols (5–8). (a)
Cross-linking of P(GDMAPA)27 (3) with camphorquinone, hυ, DMF, rt,
20 h. (b) Quaternization of [P(GDMAPA)27]X (4) with MeI, H2O, 40 °C,
24 h, or quaternization of [P(GDMAPA)27]X (4) with 1-iodooctane/1-
iodo-3,6,9-trioxa-decane/1H, 1H, 2H, 2H-heptadecafluorodecyl
iodide, DMF, 100 °C, 20 h. 108
List of Tables
163
List of Tables
Table 1.1: Industrially processed polymers, their abbreviation and
fields of application. 2
Table 3.1: Ratio of diethyl chlorophosphate (DECP) to hydroxyl
groups, degree of functionalization (FDEP) and molecular weight
(Mn,NMR) calculated from 1H NMR and SEC data of linear P(GDEP9-co-
G29) (3a), P(GDEP16-co-G18) (3b), P(GDEP
22-co-G8) (3c), P(GDEP26-co-G4)
(3d). 42
Table 3.2: Degree of functionalization (FEP) and molecular weight
(Mn,NMR) calculated from 1H NMR of linear P(GEP9-co-G29) (4a),
P(GEP16-co-G18) (4b), P(GEP
22-co-G8) (4c) and P(GEP26-co-G4) (4d).
44
Table 3.3: Degree of functionalization (FP) and molecular weight
(Mn,NMR) calculated from 1H NMR of P(GP9-co-G29) (5a), P(GP
16-co-
G18) (5b), P(GP22-co-G8) (5c) and P(GP
26-co-G4) (5d). 46
Table 4.1: Minimal inhibitory concentration against E. coli and S.
aureus and hemolytic activity of functional polyglycidols with defined
microstructures P(GTMAPA15-co-GDDA
12) (5), P(GAPDEMA16-co-GDDA
11)
(6), P(GDDAc, q)27 (10), P(GTMAPA14-co-GDDADDAc
13) (12). 74
Table 6.1: Hydrodynamic radii (Rh), polydispersity indices (PDI), zeta
potentials and glass transition temperatures (Tg) of P(GDMAPA)27 (3),
[P(GDMAPA)27]X (4), [P(GTMAPA)27]X (5), [P(GODMAPA)27]X (6),
[P(GPDMAPA)27]X (7), [P(GFDMAPA)27]X (8). 109
List of Tables
164
Table A.1.1: Synthesis of linear P(GDEP-co-G) (3a–d) (t = 20 h, T =
rt): Reagent ratios and yields after dialysis in MeOH. 122
Table A.1.2: Synthesis of linear P(GEP-co-G) (4a–d) (t = 48 h, T =
130 °C): Reagent ratios and yields. 123
Table A.1.3: Synthesis of linear P(GP-co-G) (5a–d) (t = 17 h, T = rt):
Reagent ratios and yields. 125
Curriculum Vitae
165
Curriculum Vitae
Personal Details
Name Fabian Marquardt
Date of Birth October 20th, 1987
Place of Birth Rüdersdorf, Germany
Citizenship German
Education
Jan 2014 – Feb 2018 PhD in Polymer Chemistry with Prof.
Dr. M. Möller, DWI - Leibniz Institute for Interactive Materials, Rheinisch-Westfälische Technische Hochschule, Aachen (Germany)
Nov 2013 Master of Science RWTH Aachen (1.7,
good), Rheinisch-Westfälische Techni-
sche Hochschule, Aachen (Germany)
July 2011 Bachelor of Science RWTH Aachen (2.8,
satisfactory), Rheinisch-Westfälische
Technische Hochschule, Aachen
(Germany)