Synthesis of novel functional poly(1,4-ketone)s bearing pendant bioactive moieties [Elektronische Ressource] : an approach to design biocompatible materials / vorgelegt von Violeta Malinova

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• Gesundheit

Informations

• Publié par: universitat_ulm
• Publié le: 01 janvier 2006
• Nombre de lectures: 7
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Synthesis of Novel Functional Poly(1,4-ketone)s Bearing
Pendant Bioactive Moieties:
An Approach to Design Biocompatible Materials






Dissertation
zur Erlangung des Doktorgrades Dr. rer. nat.
der Fakultät für Naturwissenschaften
der Universität Ulm

vorgelegt von

Violeta Malinova
aus Dupnitza/Bulgarien

2006

Amtierender Dekan: Prof. Dr. K.-D. Spindler
1. Gutachter: Prof. Dr. B. Rieger
2. Gutachter: Prof. Dr. D. Volkmer
Tag der Promotion: 29.05.2006 Contents

Chapter 1. General Introduction………………………………………………………………. 1

Chapter 2. Polymers from Carbon Monoxide and α-Olefins ……………………………..… 7

2.1 Polyketones - highly attractive materials…………………………………………………… 7
2.2 Synthesis of polyketones - historical overview…………………………………………….. 8
2.3 Mechanism of polyketone formation………………………………………………………... 9
2.4 Structural diversity of polyketones………………………………………………………….. 16
2.5 Copolymers of CO and functional α-olefins ………………………………………………… 17
2.6 Terpolymers of CO, functional and non-functional α-olefins……………………………….. 20
2.7 References……………………………………………………………………………………. 22

Chapter 3. Functionalization of Propylene/CO with Bioactive Molecules via
Derivatization Reactions ……………………………..………………………………………... 25

3.1 Functionalization of polymers by chemical modification……………………………………. 25
3.2 Chemical modifications of polyketones……………………………………………………… 27
3.3 Reduction of polyketones…………………………………………………………………….. 29
3.4 Grafting of carbohydrates or amino acids onto partially reduced propylene/CO……………. 30
3.5 Experimental part…………………………………………………………………………….. 34
3.6 References……………………………………………………………………………………. 36

Chapter 4. Synthesis of Terpolymers Composed of Carbon Monoxide,
Propylene and α-Olefins Substituted with Bioactive Molecules……………………....……... 38

4.1 Introduction…………………………………………………………………………………. 38
4.2 Results and discussion………………………………………………………………………. 39
4.3 Experimental part……………………………………………………………………………. 51
4.4 References……………………………………………………………………………………. 57

Chapter 5. Synthesis of Novel Polyketone-Based Copolymers
Bearing Bioactive Molecules ……………………....…………………………………………... 59

5.1 Introduction…………………………………………………………………………………. 59
i 5.2 Polyketones bearing pendant monosaccharides ……………..……….……………………… 60
5.2.1 Synthetic glycopolymers: An overview…………………………………………………….. 60
5.2.2 Results and discussion……………………………………………………………………... 63
5.2.3 Structural formation of the amphiphilic copolymers ……………………………………... 68

5.3 Polyketones bearing pendant amino acids ……………..……….…………………………… 73
5.3.1 Synthetic amino acid-based polymers: An overview……………………………………… 73
5.3.2 Results and discussion74

5.4 Polyketones functionalized with vitamin E, testosterone or gallic acid ………………..…… 81
5.4.1 Overview…………………………………………………………………………………… 81
5.4.2 Results and discussion……………………………………………………………………... 82

5.5 Conclusions………………………………………………………………………………… 89

5.6 Experimental part…………………………………..………………………………………… 90

5.7 References…………………………………..…………………………………………...…… 104

Chapter 6. Studies Regarding the Biocompatibility
of Novel Functional Poly(1,4-ketone)s…………………………..……………………………... 108

6.1 Introduction…………………………………………………………………………………. 108

6.2 In vitro testing the polymer toxicity ………………………………………………………... 110
6.2.1 Results and discussion……………………………………………………………………... 112
6.2.2 Experimental part…………………………………..……………………………………… 124

6.3. Polyketones as potential scaffolds for applications in urology…………………..…………. 129

6.4 References…………………………………..…………………………………………...…… 132

Summary…………………………………..……………………………………...………...…… 133
Zusammenfassung …………………………….………………………………...………...…… 139

Acknowledgments
Curriculum Vitae
ii List of Abbreviations and Symbols


BrdU 5’-Bromo-2’-deoxyuridine
BF Et O Boron trifluoride ethyl etherate 3 2
CO Carbon monoxide
13 C-NMR 13-Carbon nuclear magnetic resonance
CH Cl Dichloromethane 2 2
DMSO Dimethylsulfoxide
DEG Diethylene glycol
DCC N,N’-Dicyclohexylcarbodiimide
DP Degree of polymerization
dppp 1,3-Bis(diphenylphosphino)propane
DMAP 4-(Dimethylamino)pyridine
DSC Differential scanning calorimetry
ECO Ethylene-CO alternating copolymer
EDAC 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride
EDCI 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiim
hydrochloride
EtN Triethylamine 3
EPCO Ethylene-Propylene-CO terpolymer
GPC Gel permeation chromatography
HOBT 1-Hydroxybenzotriazole
HH Head to head sequence arrangement
1H-NMR Proton nuclear magnetic resonance
HT Head to tail sequence arrangement
HxCO (1-Hexene)-CO alternating copolymer IR Infrared spectroscopy
M Number average molecular weight n
M Weight average mow
mol-% Molar percentage
LDH Lactate dehydrogenase
MeOH Methanol
MALDI-TOF Matrix assisted laser desorption/ionization - time of
flight
MTT 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium
bromide
PCO Propylene-CO alternating copolymer
PCOH Poly(propylene-alcohol)
ppm Parts per million
PVA Poly(vinyl alcohol)
SEM Scanning electron microscopy
SFM Scanning force microscopy
TEM Transmission electron microscopy
T Glass transition temperature g
THF Tetrahydrofurane
T Melting temperature m
TT Tail to tail sequence arrangement
wt.-% Weight percentage
δ Chemical shift
θContact angle Chapter 1

Chapter 1

General Introduction


„I am inclined to think that the development

of polymerization is perhaps the biggest thing
chemistry has done, where it has had the
biggest impact on every day life.”
Lord A. Todd (Nobel lectures, president of

the Royal Society of London-1960-1962).

The age of polymers

The modern days world is unthinkable without man-made polymers. They replace traditional
materials such as wood, glass, ceramics and metals, offering a broad range of completely new
physical and chemical properties. These synthetic polymers do not posses drawbacks like high
density or corrosion and can be adapted to suit a limitless number of requirements and
applications.
Nowadays the use of polymers is endless. They are utilized for clothing, packaging materials,
containers, toys, car parts and other everyday purposes. The synthetic polymers have certainly
opened the door to an enormous amount of new daily-life and high-tech products.
Indeed, the revolution in the extraordinary polymer science and technology would not be
possible without the discoveries of K. Ziegler and G. Natta (Nobel prizes 1963), who put the
kick-off to a new polymerization mechanism (stereoselective olefin coordination
1,2polymerization). Since the 1990’s, polyolefins are also produced by single-site metallocene
catalysts (SSC). The polymers obtained in this way possess improved and novel properties due
to the possibility to control the polymer molecular weight, distribution, morphology, tacticity
and processibility. A further fascinating development in the polymer synthesis was made by
3,4the use of late transition metal catalysts. In contrast to metallocence catalysts, the late
transition metal complexes are able to carry out isomerization reactions and the incorporation
of polar monomers, which allow the synthesis of branched polymers and of functional
polymers via direct copolymerization, respectively. The attractive capability of late transition
metals to handle molecules with electron-rich heteroatoms made the recent advance in
1 Chapter 1

polymerization techniques like ROMP (Ring Opening Metathesis Polymerization) and
ADMET (Acyclic Diene Metathesis Polymerization) possible, which faced an extensive
5,6,7exploitation in the production of novel specialty polymers. Sophisticated catalytic processes
based on late transition catalysts enable even the synthesis of polymers with polar backbones
8e.g. polyethers, polyketones, polyesters and polycarbonates.
Material science has undergone a distinct trend from the development of structural to the
synthesis of functional materials. The trend continues in a direction exceeding functional
materials with “intelligent materials” (Figure 1.1).



Figure 1.1 Historical trends in polymer synthesis



Towards a New Paradigm

Functional Polymers
Structural control at atomic and • High strength resins
molecular level • High heat-resistance resins
• Conductive polymers Industrialization of • Biodegradable polymers
Polymers
• 6.6 Nylon
• Higher pressure PE polymerization
• Synthesis of PVA, PVC, etc.
Beginnings
Staudinger’s polymer
theory
• High level structural control
• Molecular assembly

Control of tacticity
Control of monomer sequence
Uniform molecular weight distribution
• Uneven structure
• Uneven molecular weight

(year)
2000 1900



2 Chapter 1

Following the scientific news the