Synthesis of a polar conjugated polythiophene for 3D-printing of complex coacervates

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(1)LiU-ITN-TEK-A--21/054-SE. Synthesis of a polar conjugated polythiophene for 3D-printing of complex coacervates Johanna Heimonen 2021-06-10. Department of Science and Technology Linköping University SE-601 74 Norrköping , Sw eden. Institutionen för teknik och naturvetenskap Linköpings universitet 601 74 Norrköping.

(2) LiU-ITN-TEK-A--21/054-SE. Synthesis of a polar conjugated polythiophene for 3D-printing of complex coacervates The thesis work carried out in Kemi at Tekniska högskolan at Linköpings universitet. Johanna Heimonen Norrköping 2021-06-10. Department of Science and Technology Linköping University SE-601 74 Norrköping , Sw eden. Institutionen för teknik och naturvetenskap Linköpings universitet 601 74 Norrköping.

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(4) ABSTRACT The aim of this thesis was to synthesize a functionalized polar conjugated polythiophene that could be (3D-) printed into form-stable structures for bio-interfacing. The material design rationale aimed for a water-processable polymer that had the capability of electronic and ionic conduction, by using a thiophene backbone and oligoethylene side chains. Functionalization of the oligoethylene side chains with carboxylate groups created a polyanion, which allowed for a bio-inspired approach to combine printability and form-stability through formation of complex coacervates. The synthesis of the conjugated monomer and polymer was optimized to provide a more sustainable and material efficient synthesis route. Combined structural analysis with 1H-NMR, FT-IR and UV-vis revealed successful synthesis of the target polymer. Spectro electrochemistry revealed that the polymer was optically and electrochemically active in both the protected and deprotected form. The obtained material is processable from water, and initial tests revealed that crosslinking can be achieved through formation of acid dimers, ionic crosslinks with Ca2+ ions and complex coacervation with a polycation.. 1.

(5) TABLE OF CONTENT Abstract ..............................................................................................................................................1 1. Introduction ................................................................................................................................5 1.1. Interfacing biology and technology ......................................................................................5. 1.2. Conjugated polymers...........................................................................................................5. 1.2.1. Conjugation .................................................................................................................5. 1.2.2. Energy levels and the band gap ....................................................................................6. 1.2.3. Electrical conductivity through doping .........................................................................7. 1.3. 1.3.1. Organic electrochemical transistors .............................................................................8. 1.3.2. Ion conductivity through chemical design ....................................................................9. 1.3.3. Advantages of conjugated polymers ............................................................................9. 1.4. 2. Interfacing biology and technology with conjugated polymers .............................................8. 3-D printing ....................................................................................................................... 10. 1.4.1. 3-D printing - general features ................................................................................... 10. 1.4.2. State of the art 3-D printing of conjugated polymers .................................................. 11. 1.4.3. Structural stabilization of hydrogels with ionic crosslinks ........................................... 11. 1.4.4. Crosslinking with divalent ions ................................................................................... 12. 1.4.5. Complex coacervates ................................................................................................. 12. Description of the work ............................................................................................................. 14 2.1. Aim.................................................................................................................................... 14. 2.2. Design rationale of the target polymer .............................................................................. 14. 2.2.1 2.3. Synthesis of p(g42T-T) ....................................................................................................... 16. 2.4. Synthesis of pCAT .............................................................................................................. 16. 2.4.1. Synthesis of the functionalized thiophene monomer ................................................. 16. 2.4.2. Polymerization ........................................................................................................... 17. 2.4.3. Deprotection of the polymer...................................................................................... 17. 2.5 3. Polymerization strategy ............................................................................................. 15. Ethical considerations ........................................................................................................ 17. Materials and methods ............................................................................................................. 18 3.1. Theory of methods ............................................................................................................ 18. 3.1.1. Thin layer chromatography ........................................................................................ 18. 3.1.2. Silica gel chromatography .......................................................................................... 18. 3.1.3. Nuclear magnetic resonance ...................................................................................... 19. 3.1.4. Fourier transform infrared spectroscopy .................................................................... 20. 3.1.5. Ultraviolet/visible light spectroscopy ......................................................................... 21 2.

(6) 3.1.6 4. 5. Experimental ............................................................................................................................. 22 4.1. Synthetic procedures ......................................................................................................... 22. 4.2. Solubility tests of polymer JH050 in basic aqueous solutions.............................................. 27. 4.3. Testing the formation of complex coacervate .................................................................... 28. 4.4. Tests for redissolving the complex coacervate ................................................................... 28. 4.5. Absorbance measurements ............................................................................................... 28. 4.6. Electrochemical measurements ......................................................................................... 29. 4.7. Nuclear Magnetic Resonance............................................................................................. 29. 4.8. FT-IR .................................................................................................................................. 29. Results and discussion ............................................................................................................... 30 5.1. Synthesis of polar conjugated monomers .......................................................................... 30. 5.1.1. Synthesis of g42TBr2 .................................................................................................. 30. 5.1.2. Synthesis of the protected CAT-monomer - g3T-CATtBu-Br2 ....................................... 35. 5.2. Synthesis of polar conjugated polymers ............................................................................. 43. 5.2.1 5.3. Polymerization optimization ...................................................................................... 43. Deprotecting the polymer.................................................................................................. 49. 5.3.1. FTIR-analysis .............................................................................................................. 50. 5.3.2. Base treatment .......................................................................................................... 50. 5.4. 6. Cyclic voltammetry .................................................................................................... 21. Investigation of material properties ................................................................................... 51. 5.4.1. Complex formation with divalent cations ................................................................... 51. 5.4.2. Complex coacervation................................................................................................ 51. 5.4.3. Optical and electrochemical properties of pg3CAT ..................................................... 52. 5.4.4. Electrochemical analysis ............................................................................................ 56. Conclusion ................................................................................................................................ 59 6.1. Outlook ............................................................................................................................. 59. 7. References ................................................................................................................................ 61. 8. Appendix 1 ................................................................................................................................ 64. 3.

(7) Abbrevations In order of appearance: Conjugated polymer – CP Organic light emitting diodes – OLED´s Organic electrochemical transistor – OECT Highest occupied molecular orbital – HOMO Lowest unoccupied molecular orbital – LUMO Organic mixed ionic-electronic conductors - OMIECS’s Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate – PEDOT:PSS Thin layer chromatography - TLC Nuclear magnetic resonance - NMR Fourier transform infrared spectroscopy - FTIR Ultraviolet/visible light spectroscopy - UV/vis Cyclic voltammetry – CV Potassium tert-butoxide - KOtBu Diethyl ether – Et2O Tetrahydrofuran – THF Room temperature – RT Polyethyleneimine hydrochloride - PEIxHCl Field-effect transistor – FET. 4.

(8) 1 INTRODUCTION 1.1 INTERFACING BIOLOGY AND TECHNOLOGY Since Luigi Galvani discovered that applying a voltage to a frog leg makes it twitch in 1780, we have come a long way. The pacemaker for stabilizing heart rhythm and deep brain stimulation electrodes for reducing the tremors of Parkinson are clear examples of the benefits of interfacing technology with biology. This is however just the start. New devices can help further improve the quality of diagnostics and healthcare in the future. The ultimate goal for biological interfacing of technology is to seamlessly connect to, evaluate and interact with a biological system. So, what makes this challenging? A biological system uses both electrical and ionic signaling to control the thousands of processes active in the body at one time. The release and uptake of signaling substances takes place at low concentrations and at high speed. Tissues are soft and respond to invasive species with the formation of scar tissue to protect themself. These factors pose great challenges to the materials that can be used. Classical metal electrodes are limited both by the body’s adverse response to hard foreign objects and them being incapable of detecting the ionic signals. To come closer to the goal of seamless interfaces, new materials are needed. Materials that can conduct electrons and ions and that are softer and less invasive to the surrounding tissue. Materials such as conjugated polymers.. 1.2 CONJUGATED POLYMERS Polymers are commonly known as good isolators, meaning they do not conduct electricity, and are therefore often used protect (us from) electric components. However, a new class of polymers that actually can conduct electricity was discovered by Hideki Shirakawa, Alan MacDiarmid and Alan Heeger.[1] Their research effort awarded them the 2000 Nobel Prize in chemistry “for the discovery and development of conductive polymers”.[2] The discovery of this new characteristic in polymers has led to an expanding field of research – conjugated polymers (CP’s). CP’s offer great advantages due to their physical and chemical properties, they can be made softer and more flexible compared to most electrically conducting materials on today’s market.[3] Additionally, processing of CP’s can often be done at relatively low temperatures through costeffective printing techniques. However, the most valuable asset of CP’s is their chemical tunability. Accessibility to any desired physical and chemical properties resulted in a large growth in conjugated polymer research, branching off into multiple applications such as organic light emitting diodes (OLED’s), organic solar cells and organic electrochemical transistors (OECT’s). Although CP’s can be tuned in an almost infinite number of ways, they all contain 1 common feature – conjugation. 1.2.1 Conjugation A conjugated polymer contains (as the name implies) a chemical motif known as conjugation, meaning alternating single and double bonds along the carbon backbone of the polymer (figure 1).[4] This repetition gives rise to delocalized π-electrons that can interact with elementary particles (photons and electrons) without breaking the sigma bonds in the chemical structure.. 5.

(9) Figure 1. Conducting polymers contain the chemical motif known as conjugation, shown here in a) polyacetylene, the first discovered conducting polymer, and b) a polythiophene (notice the same pattern of alternating double bonds marked in green), a modern approach to CP's that uses an aromatic backbone. R- denotes a sidechain. The conjugation length, meaning the number of unbroken alternating single and double bonds along the backbone, brings with it a change in electrical and optical properties. 1.2.2 Energy levels and the band gap As the polymer chain gets longer, the energy levels of the molecular orbitals merge to form bands; a valence band which is bordered by the highest occupied molecular orbital (HOMO), and a conduction band which is bordered by the lowest unoccupied molecular orbital (LUMO). The energy difference (typically expressed in eV) between the HOMO and LUMO is called the bandgap (E g). With increasing effective conjugation length, the energy of the HOMO and LUMO start to converge. This also decreases the bandgap and the energy (Eg) needed to excite an electron from the valence band to the conduction band (see figure 2). [5] The lowering of the bandgap energy in a CP manifests itself in a change in optical properties of the material which can be easily observed as a color change.[6] As doping introduces new energy states within the bandgap, it is possible to determine if polarons are present by analysis of the molecule’s absorption spectra, where these signatures typically appear in the near IR region.[7]. 6.

(10) Figure 2. Increasing the conjugation length (chain length) of a polythiophene decreases the bandgap (Eg), forming a valance and conduction band and a redshift of the optical absorption (a color change) of the molecule. 1.2.3 Electrical conductivity through doping Doping was first discovered by Shirakawa, MacDiarmid and Heeger when they saw an increase in conductivity of polyacetylene in the presence of iodine gas.[8] There are now several methods, both chemical and electrochemical, to inject holes (p-doping) or electrons (n-doping) to the polymer backbone and thereby transforming the CP to a conducting state. The conductivity of a conjugated polymer is dependent on the concentration of free charge carriers and the charge carrier mobility. The injection of a positive or negative charge gives rise to a polaron (see figure 3), where the charge is delocalized over several atoms, introducing changes in bond length and atom orientation. When the charge moves it drags this distortion along with it, making the charge carrier mobility an essential factor. Doping increases the number of free charge carriers in the polymer, and thereby increases the overall conductivity of the material. In its unmodified state a CP behaves like a semiconductor but by doping it the CP can be modified to act as a conductor.. 7.

(11) Figure 3. Treating a conjugated polymer with redox-agents or applying a voltage (electrochemical doping) causes doping of the backbone. P-type doping gives a delocalized positive charge on the backbone - a polaron. Electrochemical doping, charge injection through the application of a voltage, means that the CP can be switched between a semiconducting and a conducting state by a change in voltage. This is a useful property when applied in a field-effect transistor (FET), where the device is turned on/off by applying a gate voltage. For this work, a particular type of transistors known as an organic electrochemical transistor (OECT) is of special interest.. 1.3 INTERFACING BIOLOGY AND TECHNOLOGY WITH CONJUGATED POLYMERS 1.3.1 Organic electrochemical transistors Organic electrochemical transistors are devices that can be used in a wide variety of diagnostic and medicinal applications such as medical implants and biosensors.[9-11] The OECT works somewhat differently from a regular transistor, namely via the injection of counter-ions from an electrolyte to a semiconducting CP acting as a channel, instead of accumulating the charges at the channel surface (see figure 4) which occurs in a FET.[12] A voltage it applied at the gate electrode, as ions accumulate in the channel the device can either be turned on or off depending on the working mode of the device.[13]. Figure 4. A basic schematic of an OECT in the off-state, showing the basic components. The channel (purple) is made from a material that conducts both electrons and ions, the electrolyte (blue) can be a liquid or a solid. b) The on-stage when operating in accumulation mode. A positive voltage is applied at the gate electrode. Negative ions accumulate at the gate. Positive ions and holes accumulate in the channel, making conduction possible and the device turns on. In OECT’s, the channel material must be able to conduct both electrons and ions. Thus we need to find materials that display these properties.. 8.

(12) 1.3.2 Ion conductivity through chemical design Ion conductivity is electric conductivity made possible by the movement of ions, meaning electrically charged atoms or molecules.[14] Organic materials that combine electronic and ionic conductivity are commonly known as organic mixed ionic-electronic conductors (OMIECS’s).[15] The material contains a conjugated backbone for electron transfer and a motif that enables the mobility of ions within the material.[16] Modern CP’s often uses aromatic compounds as the backbone instead of polyacetylene, they are environmentally much more stable and have the potential for chemical engineering by adding sidechains without affecting backbone torsion angles to the same degree.[17] Sidechains can be used to modify both the electrical and chemical properties of the CP, increasing charge carrier mobility, modifying the solubility and enabling the transport of ions.[18] Ion transport functionality is often added to a CP by connecting a stabilized ionic moiety or a oligo-ethylene glycol chain, or by mixing polyanionic and polycationic materials.[19] Ionic conductivity increases the total conductivity per electrolyte thickness possible, making a material an even better conductor. An OMIEC can be a blend of an electron conducting polymer and an ion conducting one, a copolymer of the 2 or a polyelectrolyte with both electronic conduction and ionic conduction in the same molecule. The ions can either be part of the polymer/polymer blend or the ions can be introduced on casting/operation as free species. Two common examples of the design of these materials are depicted in figure 5 below.. Figure 5. OMIEC's have 2 general designs, they can either be in their conducting state, such as PEDOT:PSS (a) or the polarons and ions can be injected in a later step as for oligo-ethylene glycol substituted polythiophenes (b). 1.3.3 Advantages of conjugated polymers Conjugated polymers have several advantages in the quest to interface electric devices with biological systems. In the body, the main signaling pathways use ions as part of the signaling process. As mentioned, CP’s can be designed to conduct both electrons and ions. This can be used to great advantage if OMIEC’s are used in bioelectric devices, enabling the detection and release of ions as well as electrical signals or as artificial neurons. Another advantage of CP’s are their mechanical properties.[20] Biological tissues are very soft, sensitive to pressure and respond with scar-formation to intruding species such as metal electrodes.[21] Scar formation around an electrode will decrease the signal-to-noise ratio and will finally lead to an inactive electrode.[22] A soft electrode will give rise to less scar formation than a hard one; increasing the lifetime of the electrode, reducing the need to replace it and the amount of 9.

(13) procedures a patient has to go through.[23] A CP can be tuned to have mechanical properties that closely resemble that of biological tissue while retaining its electrical properties. A final advantage might be the use of conjugated polymer in different form factors than the typical thin-film devices. Due to the possibilities for chemical engineering of CP properties, they could be used as inks in additive manufacturing (3D-printing) of new devices.. 1.4 3-D PRINTING 1.4.1 3-D printing - general features 3D-printing is used for printing a wide array of materials – from steel to sensitive cell solutions.[24, 25] The technique is of particular interest because it enables material-efficient printing of complex form factors and the improved printing of existing ones. The printing of gels from materials such as collagen and alginate has been done successfully for applications within cell culturing and tissue engineering.[26] The basic technique for printing gels is not very complex. The printing ink is loaded into a cartridge that can be temperature controlled. The ink is pushed out through the microneedle by applying pressure (pneumatic, screw or other) and the extruded filament is deposited on the substrate (see figure 6). The 3D-structure is built up by depositing filaments in layer upon layer.. Figure 6. General procedure for gel-3D-printing. The ink is loaded into a cartridge and extruded through a microneedle as pressure is applied. The extruded filament is stabilized and by printing in layer upon layer, a 3D-structure can be obtained. To be able to print a three-dimensional gel-structure, the material ink must possess a number of general properties: •. The ink must be stable while in the cartridge and have a low to moderate viscosity to allow for extrusion from the printing nozzle.. •. The ink must be stable under the processing conditions, such as temperature, pressure, atmosphere and ambient light.. •. The material must be possible to stabilize so that the structure does not collapse. This can be achieved by curing with heat, UV-light or by chemical crosslinking.. •. The interactions between printed layers must be strong enough that they do not peel off from each other, but instead create stable interfaces. 10.

(14) The chemical tunability of CP’s should make it possible to make a material that has suitable properties both as an ink for 3D-printing and in the finished device. CP’s can also form gels that are closer to tissue in mechanical properties, reducing stress on the biological system. 1.4.2 State of the art 3-D printing of conjugated polymers 3D-printing of OECT’s is of interest because it can enable the manufacturing of soft electrodes for injectrodes, biosensing and deep tissue probes.[27] 3D-printing of pure CP’s into stable structures is difficult because it requires CP-based inks with suitable rheological properties before (processability), and mechanical properties after printing (structural stability). An emerging topic within the field of organic bioelectronics is 3D-printing of CP hydrogels, where the rheological properties can be tuned by the amount of water present. So far, only PEDOT:PSS has been explored as the charge- and/or ionconducting material in ink formulations for this purpose.[28] Several issues can be identified from using PEDOT:PSS as the electronic transport material for 3D printed CP gels: •. PEDOT:PSS lacks functional groups for crosslinking and has instead been processed as a blend with crosslinkable polymers into composite hydrogels.[29] Such formulations are characterized by low electrical conductivity (10-2 cm-1), which arises from the compounding itself and a sub-optimal microstructure. Swelling of the non-conjugated phase in the material blend also has a negative effect.. •. Commercially available PEDOT:PSS is sold as a water dispersion. It requires isolation through lyophilization or centrifugation to achieve appreciable electrical conductivity, after which the final ink can be produced.. •. Ink formulations that allow for chemical crosslinking typically employ an additional UVcuring step. The UV-light has difficulties penetrating deep enough into the material and can cause incomplete curing in case thicker layers are to be printed.. As has been presented above, 3D-printing of a gel structure needs a material with the ability to form stable crosslinks, preferably is a fast and easy way. 1.4.3 Structural stabilization of hydrogels with ionic crosslinks Stabilization of a gel-like material could be done in several ways; photo-crosslinking, hydrogen bonding self-assembly or thermal treatment are all concepts that have been used.[30] Stabilizing the structure with ionic crosslinks is another avenue that is of great interest due to its speed and ease of use.. 11.

(15) 1.4.4 Crosslinking with divalent ions A proven concept for crosslinking polymers is using di- or trivalent ions to form stabilizing ion-bonds by exploiting the electrostatic interaction between positively and negatively charged ions. The polymer chain needs to contain a charged moiety, such as an acid group, which acts like a fixed ion. The polyion is combined with a counterion that enables the formation of an ionic bond (see figure 7).. Figure 7. Intermolecular stabilization of polymer-strands through the formation of ionic bonds. The negatively charged side groups of the polymer electrostatically interacts with a divalent cation. Divalent ion crosslinks can give hydrogels with tunable viscosity depending on the concentration of ions that are available.[31] Some ion combinations can give bonds that are breakable by changing the temperature, making the formation of gels reversible.[32] Divalent ion stabilization is very fast compared to other crosslinking strategies, such as hydrogen bonding self-assembly, making it a viable strategy for applications like 3D-printing.. 1.4.5 Complex coacervates Nature has already developed an elegant crosslinking strategy, namely complex coacervates. Mussels, barnacles, sandcastle worms and caddisflies use bioadhesives to either anchor themselves to submerged structures or to protect their frail bodies with an armor made of glue and hard materials such as wood chips and tiny pebbles.[33] These bioadhesives have remarkable rheological and mechanical properties. They can be a liquid when extruded but quickly solidify through the formation of a complex coacervate, triggered by external factors. In addition, a complex coacervate incorporates many different functionalities (cations, anions, polar and apolar groups) that enhance adhesion to any surface.[34] A substantial research effort has already been done to study these materials, and harness the potential of complex coacervation for i.e. underwater glues and encapsulation.[35, 36] A complex coacervate forms as polyelectrolytes of opposite charges, a polyanion and a polycation, are combined (see figure 8).. 12.

(16) Figure 8. Complex coacervation through the electrostatic interaction between a polyanion (pink) and a polycation (blue). The concentration of groups available for bonding will impact the mechanical properties of the material. The polymer sidechains will interact and form ionic bonds, as seen in figure 8 above, self-assembling and encapsulating the surrounding solvent. It can therefore be used as a technique to quickly form stable gels of varying viscosity by changing the amount of one charged species.[37] The gel formation can be designed to respond to different triggers, such as salinity, temperature or pH.[38] Once formed, the volume of the gel can be constant to the starting volume, meaning no swelling due to extra water being absorbed, during device operation which is a useful property for use in biological systems as they are sensitive to mechanical stress.. 13.

(17) 2 DESCRIPTION OF THE WORK 2.1 AIM The aim of this thesis is to synthesize a functionalized polar polythiophene for 3D-printing of OECT’s for biomedical applications/interfacing with biological systems. In the following section, the design rationale of the functionalized conjugated polymer and planned synthesis route are presented.. 2.2 DESIGN RATIONALE OF THE TARGET POLYMER From the requirements that have been established in this introduction, we can extract several key properties that a conjugated polymer for 3D-printable OECT devices should display: -. The material must have the ability to transport both charge carriers and ions for OECT device operation. -. The material must carry a chemical functionality that allows for dynamic crosslinking, to stabilize the printed structures after processing and fuse printed layers. -. Biocompatible materials require the material to be processable from water, saline or buffered solutions. -. The synthesis must be relatively benign, easy and scalable as large amounts will be needed for 3d-printing (~300 mg is needed for 1 print run). The functionalized polar conjugated polymer shown in figure 9 below will be synthesized.. Figure 9. The target polymer (pCAT) should provide good electric conductivity through a polythiophene backbone (blue), ionic conductivity by the triethylene glycol sidechain (pink) and crosslinking capability by a carboxylate terminal group (red). The sidechain should also make the polymer soluble in water to enable easy and non-toxic processing and bio-interfacing applications. Polythiophenes (blue) are well researched as p-type semiconductors and offer good charge carrier mobility. The side chain (pink) will make the CP more hydrophilic and as such potentially more water soluble and processable in a 3D-printing application. Functionalization of the backbone with an oligoethylene side chain generally results in a material that has ion transport capability. The addition of the terminal carboxylate group (red) on the glycol side chain should further increase hydrophilicity, prospectively making processing as an ink easier. It also introduces the possibility of ionic crosslinking (by addition of Ca+2 or complex coacervation) of the polymer chains for increased stability of a printed structure. The carboxyl groups themselves can also form dimers through shared hydrogen-bonding and interact with the glycol sidechains to further increase stability.[39] Since it is 14.

(18) very hard to predict the exact chemical and physical properties, these will be investigated when the polymer has been synthesized. 2.2.1 Polymerization strategy The polymerization of conjugated polymers requires the creation of a carbon-carbon bond. A route commonly used is Stille coupling, using organo-tin and halide reactants. The advantage of Stille crosscoupling polymerization is that is very robust and extremely tolerant towards a large number of functional groups.[40] This synthesis route is well developed, and it is possible to make a large number of complex molecules.[41] A major downside of Stille couplings is the creation of one equivalent of a toxic organistannyl by-product, which warrants the use of a reliable, yet much less toxic polymerization method. Suzuki coupling (or Suzuki-Miyaura reaction) is an alternative polymerization technique. The formation of a new carbon bond is made possible by the use of a boronic acid monomer, a brominated monomer and a palladium catalyst (see figure 10). The polymerization can be carried out at room temperature with bench stable reactants.[42] It can also be done in aqueous solutions and without strong acids.[43] Compared to Stille coupling, Suzuki coupling is more environmentally friendly, less hazardous for the health of the person performing the synthesis and can be done under relatively mild conditions.[44]. Figure 10. Basic reaction scheme for a polymerization by Suzuki coupling. The organoboron species can have different configurations, boronic esters are commonly used due to their stability. The main problem to avoid when performing Suzuki polymerization is the breakdown of the monomers. The organohalide species can be broken down by substitution of one bromine, this can be avoided by storing the compound in a cool place. The organoboron species can be broken down by protodeborylation (see figure 11). In the presence of base and water, the boron functionality can react and be substituted by a proton. This renders the monomer unable to react further and introduces unwanted chain stops that will limit the molecular weight of the polymer.. Figure 11. Protodeborylation, a breakdown of the boronic ester functionality, can render the monomer unable to keep reacting. This gives unwanted stops in the chain growth and limits the molecular weight.. 15.

(19) A main goal of this work is to optimize the Suzuki coupling reaction conditions for the synthesis of p(g3TT-CAT). As different polymers require varying reaction conditions to obtain good molecular weight, this will likely require several experiments. To facilitate this, the known polymer p(g42T-T) will be used as a model molecule to perform the initial polymerizations on. This polymer has been synthesized with Stille coupling and provides a reference for how well the Suzuki coupling performs. When the reaction conditions have been improved, the target PCAT will be used for further optimization.. 2.3 SYNTHESIS OF P(G42T-T) To get familiar with the synthesis of monomers and polymerization, a polymer that is well described in literature will be synthesized.[45] This provides a suitable monomer to perform the first trials of polymerization with, as the properties of p(g42T-T) are well known and can provide a refence for the Suzuki coupling product.. 2.4 SYNTHESIS OF PCAT The functionalized polar thiophene polymer, henceforth designated pCAT, will be synthesized from basic building blocks as this is a novel material that is not commercially available (see figure 10).. Figure 12. Proposed synthesis scheme for the functionalized polar polythiophene p(g3TT-CAT) or PCAT. 2.4.1 Synthesis of the functionalized thiophene monomer The synthesis of the monomer will be performed in several steps (see figure 12), the first two will be optimized during the project. Starting from 3-bromothiophene and triethylene glycol, a 1-step neat (without solvents) Ullman aryl ether synthesis of the aryl ether will be explored.[46, 47] The typical synthesis method uses pyridine as a solvent, that would be beneficial to avoid. The neat reaction would make the synthesis faster and greener compared to the 3-step route using a protection group (as seen in the scheme above), decreasing the amount of solvents and chemicals needed for the first 16.

(20) intermediate. If this route turns out not to work, the more classic route ensures that the synthesis can continue. The protected carboxylic acid functionality will be added by a Michael addition of a tert-butyl acrylate to the glycol sidechain.[48] The reaction will be tried out neat, as a further step to make the synthesis of the final polymer safer and greener. As a final step, the functionalized thiophene will be di-brominated to functionalize it for polymerization. This step will be performed in the same manner as for the training p(g42T-T), as it is a commonly used reaction that would take time outside the scope of this project to optimize.[45] 2.4.2 Polymerization The polymerization will we performed by a Suzuki Miyaura coupling, as discussed in section 2.2.1. 2.4.3 Deprotection of the polymer After polymerization, the polymer will be in its protected form. The tertbutyl-group will need to be removed to finally obtain the carboxylic acid functionality that is central to the function of the material. This step should also make the polymer water soluble (or dispersible). The deprotection will be performed through ester hydrolysis, at basic or acidic conditions.. 2.5 ETHICAL CONSIDERATIONS This work does not contain animal or human test subjects. The main ethical consideration is the sustainability aspect of performing chemical synthesis. This work does strive for the use of material efficient, safer and “greener” synthesis and polymerization steps to reduce the environmental footprint. The successful synthesis of the target molecule could lead to gains in several applications that could benefit human society.. 17.

(21) 3 MATERIALS AND METHODS 3.1 THEORY OF METHODS In this work, some separation and analysis techniques have been of greater importance; thin layer chromatography (TLC), silica gel chromatography, nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), ultraviolet/visible light (UV/vis)-spectroscopy and cyclic voltammetry (CV). In the following section, a short introduction to the theory of each of the analysis techniques will be given. 3.1.1 Thin layer chromatography TLC is a fast and easy to use analytical method, commonly used to provide insight into the progression of organic synthesis and preparation of column chromatography protocols.[49] The method can be used to separate non-volatile analytes based on interaction with the stationary state and is as such suitable to this thesis work. The analyte mixture is diluted to a concentration that will give clear but not tailing spots, it is then spotted on a fluorescent TLC plate and the solvent is allowed to dry. The plate is placed in a chamber containing an eluent that will move up the plate by capillary forces and thus drive and separate the analytes by polarity and molecular weight. The plate is analysed under UV-light (254 nm), aromatic analytes will quench the florescence of the plate and show up as darker spots (see figure 13). For aliphatic impurities the plate is generally treated with iodine that will attach to the hydrophobic chains and color the spot.. Figure 13. Basic method for TLC-analysis. A plate is spotted with the analyte mixture and placed in an eluent (blue). Capillary forces will move the eluent upwards and transport the analytes along. The separation of the spots will depend on the polarity and molecular size of the analytes. TLC is limited to what information it can provide. The separation of analyte spots depends on the polarity of your eluent, a property that can change over time if one uses volatile solvents. It also depends on the solvent used, this makes it harder to compare spots from different batches, as the positions can easily be reversed between two spots if a different solvent is used. 3.1.2 Silica gel chromatography Silica gel chromatography is a common separation method in organic synthesis, used for purifying and isolating compounds.[49] The method uses a combination of a functionalized silica sand and an eluent to setup a separation column. Compounds with different chemical structures (mostly based on polarity difference) will interact to a varying extent with the stationary phase (silica gel), as such their retention time will differ. The interactions with the stationary phase can be screened to a lesser or larger extent by changing the polarity of the eluent. Analytes will therefore have a different retention time depending on their own polarity and the polarity of the solvent. By a preemptive TLC analysis, the approximate order of the bands can be decided. The eluate can then be monitored by. 18.

(22) drops on a TLC-plate to indicate when a band is starting to elute. The compound bands can be separated and collected (see figure 14).. Figure 14. Basic setup for purification with flash silica gel chromatography. Compounds are separated with regards to polarity and eluate as bands. Purification on silica gel columns have some drawbacks, it is limited in the amount of product that can be purified on a certain column size which can cause overloading and bad separation. It can be hard to know where a product band is located if it does have a visible color, this can lead to losses of product if the elution is not monitored properly. 3.1.3 Nuclear magnetic resonance NMR is a common and powerful structural analysis tool, often used to elucidate and verify chemical structures. The method analyzes atomic nuclei with a naturally occurring magnetic spin, commonly hydrogen (1H) and carbon (13C), and a magnetic field.[50] By applying a strong magnetic field, these NMR active nuclei become magnetized. When the nuclei are subjected to a broadband radio frequency pulse, their magnetization becomes disturbed. Relaxation of the disturbed magnetization from these nuclei to their initial state occurs through tumbling, and its progression to the ground state is recorded as the free-induction decay (fid). Fourier-transforming this fid gives an NMR spectrum with ppm on the x-axis and intensity on the y-axis (see figure 15 below). From an 1H-NMR spectrum, 3 basic pieces of information can be extracted: 1) The position of the peaks will depend on the chemical environment that surrounds the nuclei. Tt can be shielded from the influence of the magnetic field to a varying extent depending on the atoms that surround it. A more shielded nuclei will be less influenced by the magnetic field while a deshielded nuclei, closer to electron withdrawing groups, will give a change in peak position. The change of the peak position is known as the chemical shift and can be used to derive the chemical surrounding and groups present in a molecule. 2) Nuclei can interact with one another in a process known as coupling. In 1H-NMR, a hydrogen commonly interacts with the hydrogens on one carbon over. The coupling gives rise to a splitting of the peak. The split is n+1, where n is the number of neighboring hydrogens, this can be used to find what the surrounding of each nuclei looks like. 3) The relative number of hydrogens that have the same chemical shift can be determined by integrating the area under the peak. A larger area corresponds to more hydrogens, and the 19.

(23) relative ratio of each integral indicates the ratio at which hydrogens with the same chemical shift are present in the analyte.. Figure 15. The chemical environment of the nuclei will give a difference in peak position and peak splitting in the NMR spectra. The area under the peaks can be used to calculate the number of hydrogens that it corresponds to. By analyzing the chemical shift, peak splitting and the area under the peaks it is possible to derive the structure and purity of the analyte. The spectral analysis is performed in a computer program, as there are several complex calculations involved. NMR analysis of larger molecules is complex, as there are more atoms and more possible interactions present. A polymer is a large molecule in which nuclei are hindered to relax to their ground state due to reduced tumbling, that manifests itself in lower peak intensities while slightly different chemical environments of the same groups cause peak broadening. The aggregation of polymer chains makes analysis harder, as a well solubilized molecule is essential to obtaining a well-resolved spectrum.. 3.1.4 Fourier transform infrared spectroscopy FTIR is a structural analysis tool that can be used to analyze the presence of functional groups such as esters and carboxylic acids in a chemical structure.[50] The method uses the interaction between infrared light and chemical bonds to differentiate between different functional groups. Infrared light of the appropriate wavelength, corresponding to the various vibrational energies of a chemical bond, will be absorbed by the bond and give rise to a vibration. A beam of infrared light is therefore directed at or through a sample, the light will interact with the chemical bonds of the molecule if the wavelength of the light is correct. The interaction will cause a drop in intensity at the specific wavelength, this will be registered by a detector and give a peak in the spectra. By comparing peak positions to a table of known vibrational frequencies for functional groups, it is possible to determine what groups are present in the analysed material. 20.

(24) 3.1.5 Ultraviolet/visible light spectroscopy UV/vis is a simple spectroscopic analysis method for determining the optical properties of a molecule.[49] A sample is analysed by irradiation of light, with varying wavelength between UV and near IR, through a sample and recording the intensity before and after. By applying Lambert-Beers law, the absorption spectra of a molecule can be determined. The absorbance onset of a molecule is connected to the molecule’s optical bandgap, a property of interest in this project. The presence of polarons (doping) in the backbone can also be visualized from the absorption spectra.. 3.1.6 Cyclic voltammetry CV is a common technique for analyzing electrochemical properties such as reduction and oxidation potential of a conducting polymer.[51] The polymer is either coated on a working electrode or analysed in solution mixed with the electrolyte. A normal setup includes a working electrode, a counter electrode and a reference electrode in a supporting electrolyte. The voltage of the working electrode is cycled negatively, followed by positively, the current is recorded and compared to the reference electrode held at a constant voltage. The position of voltammetry peaks can be used to calculate the oxidation and reduction potential of a polymer. The shape of a cyclic voltammogram indicates the electrochemical behavior of the polymer, a Faradaic or capacitive polymer way will give a leaf shape or a box shape respectively (see figure 16). Peaks correspond to a redox reaction occurring, where an electron transfer takes place between the material and the working electrode, and can as such be used to find the reduction and oxidation potential. A capacitive material will not undergo a redox reaction, the potential in the working electrode is instead off-set by ionic charges accumulating in closest volume of the bulk electrode.. Figure 16. Cyclic voltammograms can have a variety of shapes depending on the material that was analysed. The basic 2 electrochemical behaviours are Faradaic (a) and capacitive (b). CV can be used together with UV/vis to record the optical property changes that a voltage change gives rise to, by performing a spectral analysis while a CV-measurement is running. This requires the use of an electrode that light can penetrate but can give information on the electrochromic behavior of the polymer. It can make it possible to track if a polymer is fully or partly in an oxidized or reduced state and if cycling it leads to a breakdown of the polymer.. 21.

(25) 4 EXPERIMENTAL In this section, the final procedures for each synthesis step are shown. A full list of experiments and conditions is given in Appendix 1. NMR data given is representative for other compounds of the same procedure. The success of the reactions was mainly judged by yield. All chemicals were purchased from Sigma Aldrich and used as received. Risk assessments were performed for all chemicals and procedures. Reactions were performed under protective atmosphere (N2) unless otherwise stated. Flash column chromatography was performed with silica (pore size 60 Å, 35-75 µm diameter, from Sigma Aldrich). Purging of solvents to remove oxygen was done by bubbling nitrogen gas through them for 30 min.. 4.1 SYNTHETIC PROCEDURES g4T – JH001. Ullman coupling 5.31 g (47 mmol, 2.6 eq) of potassium tert-butoxide, 1.17 g (6 mmol, 0.3 eq) CuI was added to a dried 100 ml two-necked roundbottom flask along with 15 ml of anhydrous pyridine under normal atmosphere. The reaction mixture was stirred at a room temperature while 10 g (48 mmol, 2.6 eq) of tetraethylene glycol monomethylether was slowly added over 5 minutes. The mixture was stirred at room temp for 1 hour. 2.93 g (1.7 ml, 18 mmol, 1 eq) of 3-bromothiophene was added in portions and the mixture was heated to 100 °C and reacted overnight. The reaction mixture was cooled to RT and the liquid was decanted after which the remaining solids in the roundbottom flask were washed with 50 ml of diethyl ether (Et2O) in portions. The mixture was filtered through cellulose filter paper and the filter residue washed with a small portion of Et2O. The solvent was evaporated, while subsequent azeotropic distillation with 3x50 ml heptane was performed to remove residual pyridine resulting in an opaque brown oil product. The oil was dried under vacuum for 45 minutes to remove remaining heptane. The sample was purified on a silica gel column Et2O as an eluent. Fractions were collected and analysed by TLC. The fractions containing the product were combined and the solvent was evaporated resulting in a clear yellow brown oil (3,153 g, 11 mmol, 61 %). 1H NMR (500 MHz, cdcl3) δ 7.16 (dd, J = 5.2, 3.1 Hz, 1H), 6.78 (dd, J = 5.2, 1.6 Hz, 1H), 6.26 (dd, J = 3.1, 1.6 Hz, 1H), 4.12 (dd, J = 5.7, 3.9 Hz, 2H), 3.84 (dd, J = 5.5, 4.1 Hz, 2H), 3.75 – 3.59 (m, 11H), 3.55 (dd, J = 5.7, 3.7 Hz, 2H), 3.38 (s, 3H). 22.

(26) Synthesis g42T – JH002. Oxidative coupling 3.15 g (11 mmol, 1 eq) of JH001 (cf. page 22) was added to a dried 250 ml roundbottom flask along with 20 ml of anhydrous THF under argon atmosphere. The solution was cooled to 0 °C for 15 minutes before 4.4 ml (11 mmol, 1 eq) of n-butyllithium was added dropwise over 10 minutes after which the solution was stirred at 0 °C for 2 hours. 4.67 g (11 mmol, 1 eq) of Fe(acac)3 was added to a dried 250 ml roundbottom flask along with 70 ml of anhydrous THF. The solution containing JH001 was transferred into the Fe(acac)3 solution and the mixture was refluxed at 70 °C overnight resulting in a deep red brown colored suspension. The mixture was cooled to 0 °C in an ice bath to maximize the precipitation of solids. The solution was filtered, washed with 100 ml of Et2O and evaporated at 40 °C under reduced pressure. The resulting oil/solid mixture was put into the -20 °C freezer for 30 min and filtered to remove additional solids. The liquid phase was extracted with 3x50 ml of 1 M NaOH, giving poor separation, 50 ml of brine was used to break the emulsion. The water phase was further extracted with 3x50 ml of ethylacetate. The organic phases were combined and dried with sodium sulphate (Na2SO4) and magnesium sulfate (MgSO4). The mixture was filtered, giving a clear red liquid, and the solvent was evaporated giving a crude yield of 2.1 g of a red oil. The product was purified on a silica gel column and eluted using 5 % methanol in diethyl ether. The eluate was collected in fractions which were analysed on purity by TLC. The fractions containing pure product were combined and the solvent was evaporated giving a final yield of 0.7 g (1,2 mmol, 22 %). (1H NMR (500 MHz, cdcl3) δ 7.07 (d, J = 5.6 Hz, 1H), 6.85 (d, J = 5.6 Hz, 1H), 4.24 (t, J = 5.1 Hz, 2H), 3.90 (t, J = 5.1 Hz, 2H), 3.85 – 3.46 (m, 12H), 3.37 (s, 3H)).. Synthesis g42TBr2 – JH003. Bromination 0.7 g (1.2 mmol, 1 eq) of JH002 was combined with 20 ml of anhydrous THF in a 250 ml roundbottom flask and was degassed by nitrogen bubbling for 30 minutes. The flask was covered from light with aluminum foil and cooled with an ice-salt bath to -20 °C. Then, 0.43 g (2.4 mmol, 2 eq) of NBS was 23.

(27) added portion wise and the reaction was monitored by TLC until completion. the total reaction time was 1 h 40 min. The mixture was extracted with 1x25 ml of 1 M NaHCO3 and 3x25 ml of brine. The water phase was extracted with 3x25 ml of THF, the organic fractions were combined, and the solvent evaporated. The sample was purified using a silica gel column prepared with 1 % triethylamine and 5 % methanol in diethyl ether. The sample was collected in fractions which were analysed on purity with TLC. Fraction 1-3 and Fraction 4+5 were combined into two fractions, and the solvent evaporated giving yellow oils for both fractions. For recrystallization of the product, 2 drops of product from fraction 1-3 was mixed with a small amount of diethyl ether and cooled to -94 °C in an acetone/N2(l) bath, giving ent-crystals. The product from fraction 4+5 was dissolved in a small amount of diethyl ether and cooled to -20 °C. A small number of ent-crystals were added causing the pure product to crystallize as light-yellow fluffy needle-like crystals. Final yield was 0.7 g (88 %). 1H NMR (500 MHz, dmso) δ 7.28 (s, 1H), 4.29 – 4.20 (m, 3H), 3.82 – 3.68 (m, 3H), 3.66 – 3.56 (m, 3H), 3.53 – 3.42 (m, 6H), 3.42 – 3.38 (m, 2H), 3.22 (s, 3H). The product was stored at –20 °C.. Synthesis – JH012. Bromination 0.66 g (2.3 mmol, 1 eq) of JH008 (see appendix 1 pg. X) was combined with 15 ml anhydrous THF in a 250 ml roundbottom flask. The mixture was degassed by nitrogen bubbling for 30 minutes. The mixture was cooled to 0°C and covered with aluminum foil. 0.82 g (4.6 mmol, 2 eq) of NBS was added portion wise and the mixture was reacted overnight. The reaction mixture was extracted with 2x25 ml of 1 M NaHCO3 and 25 ml of brine. The water phase was extracted with 3x25 ml of THF, the organic phases were combined, and the solvent evaporated. The sample was purified on a silica gel column prepared with 1 % thriethylamine in diethyl ether. The product was collected and the solvent evaporated, giving a yield of 0.9 g (87 %). (1H NMR (500 MHz, cdcl3) δ 6.81 (s, 1H), 4.22 – 4.10 (m, 2H), 3.85 – 3.73 (m, 3H), 3.73 – 3.60 (m, 12H), 3.57 – 3.52 (m, 2H), 3.38 (s, 3H)).. 24.

(28) Synthesis – JH032. Ullman aryl ether synthesis 7.05 g (mmol, 7.5 eq) triethylene glycol was added to a 25 ml roundbottom flask and lowered into a 0 °C ice bath under nitrogen atmosphere. 1.03 g potassium tertbutoxide was added in portions and the mixture was stirred for 10 minutes. The vessel was transferred to a RT oil bath and stirred for 50 minutes. The bath temperature was increased to 50 °C for 10 min. 55 mg (0.61 mmol, 0.1 eq) CuI was added along with 220.4 mg 1,10-phenantroline and 0.57 ml (1 g, 6.1 mmol, 1 eq) of 3bromothiophene. The mixture was stirred at 110 °C overnight. The reaction mixture was transferred to a 500 ml roundbottom flask and the vessel was washed with some MeOH. 50 ml of silica gel was added with diethyl ether to form a slurry. The solvents were carefully evaporated, and the sample was dried in vacuo for 1.5 h. The product was purified on a silica gel column prepared with diethyl ether and eluted with 5 % MeOH in diethyl ether. Fractions containing the product were combined, the solvent evaporated, and the product was stored in the fridge. The final yield was 0,88 g (62 %). (1H NMR (500 MHz, cdcl3) δ 7.16 (dd, J = 5.3, 3.1 Hz, 1H), 6.78 (dd, J = 5.2, 1.5 Hz, 1H), 6.26 (dd, J = 3.2, 1.6 Hz, 1H), 4.12 (dd, J = 5.7, 3.8 Hz, 2H), 3.89 – 3.79 (m, 2H), 3.70 (dddd, J = 14.0, 8.3, 6.0, 4.3 Hz, 7H), 3.64 – 3.58 (m, 2H)), (13C NMR (126 MHz, cdcl3) δ 157.82, 125.02, 119.88, 97.91, 72.79, 71.09, 70.69, 70.01, 69.83, 62.07. ). Synthesis – JH039. Oxa-Michael addition 653.4 mg (2.8 mmol, 1 eq) of JH032 was combined with 451.5 mg (3.5 mmol, 1.3 eq) of tert-butyl acrylate and 8 mg of NaOH in a 10 ml roundbottom flask. The sample was covered from light and stirred at RT for 72 h. The product was purified on a silica gel column and eluted with 25 % acetone in petroleum ether. The solvent was removed and the product was dried in vacuo overnight. (1H NMR (500 MHz, cdcl3) δ 7.16 (dd, J = 5.2, 3.1 Hz, 1H), 6.77 (dd, J = 5.2, 1.6 Hz, 1H), 6.26 (dd, J = 3.1, 1.5 Hz, 1H), 4.13 – 4.09 (m, 2H), 3.87 – 3.81 (m, 2H), 3.75 – 3.57 (m, 10H), 2.50 (t, J = 6.6 Hz, 2H), 1.44 (s, 9H)), ( 13C NMR (126 MHz, cdcl3) δ 171.23, 157.95, 124.95, 119.93, 97.85, 80.83, 77.61, 77.36, 77.10, 71.14, 70.99, 70.90, 70.71, 70.03, 69.92, 67.24, 36.61, 28.43.). 25.

(29) Synthesis – JH051. Bromination 0.5072 g (1.41 mmol, 1 eq) of JH039 was combined with 10 ml of THF, in a 25 ml roundbottom flask, under nitrogen atmosphere, and degassed for 30 minutes. The solution was allowed to cool to 0 °C for 15 minutes before 0.50 g (2.82 mmol, 2 eq) of NBS was added portion wise. The mixture was reacted for 1.5 h at 0 °C and was then allowed to react overnight at RT. After 5 h, an additional portion of NBS was added to drive the reaction to completion. The reaction was neutralized by addition of 5 ml 1 M NaHCO3 and stirred for 15 min. The solution was transferred to an extraction flask along with 140 ml of diethyl ether. The organic phase was extracted with 1x50 ml of 1 M NaHCO3 and 3x50 ml of brine. The water phase was extracted with 2x50 ml of diethyl ether. The organic phases were combined and dried with sodium sulphate and magnesium sulphate. The solvent was removed by evaporation and the product was dried in vacuo overnight. The product was purified on a silica gel column and eluted with 20 % acetone in petroleum ether. The eluate was collected in fractions and monitored by TLC. The final yield was 0.35 g (45 %) of pure product which was collected as a yellow oil. (1H NMR (500 MHz, cdcl3) δ 6.82 (s, 1H), 4.17 – 4.13 (m, 2H), 3.81 – 3.76 (m, 2H), 3.74 – 3.68 (m, 4H), 3.67 – 3.59 (m, 6H), 2.50 (t, J = 6.6 Hz, 2H), 1.44 (s, 9H)), (13C NMR (126 MHz, cdcl3) δ 171.25, 154.09, 121.85, 109.93, 72.39, 71.34, 71.02, 70.93, 70.75, 70.17, 67.26, 36.63, 28.45. ). Polymerization – JH052. Suzuki-Miyaura coupling 209.9 mg (0.40 mmol, 1 eq) of JH051 was combined with 136.1 mg (0.40 mmol, 1 eq) thiophene-2boronic acid pinacol ester, 15.0 mg (0.016 mmol, 4 mol%) of Pd2(DBA)3 catalyst and 26.6 mg (0.065 mmol, 16 mol%) Sphos co-catalyst in a 50 ml roundbottom flask along with 10 ml of toluene under nitrogen atmosphere. The mixture was stirred at 50 °C for 5 min. 1 large drop of Aliquat 336 was added to the reaction mixture and the solution was stirred for 3 minutes. 2 ml of degassed water containing 791.9 mg of cesium carbonate was added and the two phase mixture was stirred at 550 rpm for 90 h. The polymer was precipitated in heptane and filtered. The dark purple, slightly needle shaped particles were washed with heptane and petroleum ether. The product run in a Soxhlet extraction with petroleum ether and chloroform. The product was precipitated in heptane and collected by filtration. The final yield was 150 mg (71 %). (1H NMR (500 MHz, cdcl3) δ 7.20-6.83 (m, 3H), 4.39-4.22 (m, 2H), 3.97-3.85 (m, 2H), 3.80-3.40 (m, 10H), 2.55-2.35 (m, 3H), 1.49-1.28 (9H)). 26.

(30) Deprotection – JH053. Acid catalyzed deprotection 135 mg of polymer was dissolved in 2 ml of formic acid and 1 ml of TFA. The deep purple viscous solution was stirred at RT for 1 h 45 min. The polymer was precipitated in diethyl ether, giving almost black particles that were collected by filtration. Final yield was 130 mg (97 %). Base treatment – JH054. Formation of the polyanion 122 mg KOH was dissolved in 2 ml of water and degassed. 100 mg of JH053 was added and the deep purple viscous solution was stirred at 45 °C overnight. The polymer was precipitated in acetone giving a dark purple coating in the vessel. The product was redissolved in water and precipitated in isopropanol in the filtration setup. The particles were washed with isopropanol to remove excess KOH and collected. Final yield was 120 mg (91 %).. 4.2 SOLUBILITY TESTS OF POLYMER JH050 IN BASIC AQUEOUS SOLUTIONS A small grain of polymer (around 2 mg) was added to 1 ml 1M KOH, some polymer dissolved immediately, the sample was heated to 80 °C for 2 min. The polymer dissolved completely and gave a vibrant purple solution. No re-precipitation could be observed over the next 24 h in RT. A small grain of polymer (around 2 mg) was added to 1 ml 1M K2CO3, only a light coloring could be seen upon addition, the sample was heated to 80 °C for 2 min. The polymer dissolved completely and gave a vibrant purple solution. No re-precipitation could be observed over the next 24 h in RT. A small grain of polymer was added to 1 ml of 1 M KHCO3, a very faint coloring could be observed upon addition. The sample was heated to 80 °C for 2 min, the polymer completely dissolved, giving a vibrant purple solution. No re-precipitation could be observed over the next 24 h at RT.. 27.

(31) A small grain of polymer was added to 1 ml of pure water, giving a slight coloring upon addition. The sample was heated to 80 °C for 2 min, giving a vibrant purple solution. No re-precipitation could be observed over the next 24 h at RT.. 4.3 TESTING THE FORMATION OF COMPLEX COACERVATE JH050 In a glass vial, 4 drops of 10 mg/ml JH050 (aq) was combined with 4 drops of 1,87 mg/ml polyethyleneimine x HCl (aq). The 2 solutions were mixed by carefully shaking the vial, a dark purple precipitate formed almost instantly. In another vial, 6 drops of JH050 and 6 drops of brine was combined and mixed thoroughly. 6 drops of PEIxHCl were mixed with brine in the same way. The 2 solutions were combined, no precipitation occurred. The mixture was dropped into water to see if a gel or precipitate would form, but no such gel or particles formed. JH054 A dilute water solution of JH050 was prepared. A pinch of PEIxHCl was added and mixed with the vibrant purple solution. Dark purple particles formed almost immediately, indicating the formation of a complex coacervate.. 4.4 TESTS FOR REDISSOLVING THE COMPLEX COACERVATE Particles formed when combining JH050 and polyethyleneimine hydrochloride (PEIxHCl) were split into 4 vials. Vial 1: 10 drops of 0,01 M NaCl was added and the content was mixed. Vial 2: 10 drops of 0,1 M NaCl was added and the content was mixed. Vial 3: 10 drops of 1 M NaCl was added, and the content was mixed. Vial 4: 10 drops of brine was added, and the content was mixed.. 4.5 ABSORBANCE MEASUREMENTS Solutions of JH028 (0,05 and 0,03 mg/ml) and JH050 (0,1 mg/ml) were prepared in CHCl3 and H20 respectively. The spectrum of each solution was recorded in a quartz cuvette (path length 1 mm) with an Avantas fiber optics spectrometer. Solid state measurements were done by spin coating the polymers on glass and analyzing them in the same setup with no solvent present.. 28.

(32) 4.6 ELECTROCHEMICAL MEASUREMENTS JH028 (protected form of pCAT) and JH050 (potassium salt of pCAT) were used for electrochemical measurements. Cyclic Voltammetry (CV) was performed with a Biologic Potentiostat SP-200, in a three-electrode electrochemical cell. Experiments were conducted at RT in H2O containing KCl (0.2 M) or acetonitrile containing tetra-n-butylammonium hexafluorophosphate (TBAPF6-, 0.2 M) as supporting electrolyte. Polymer spin coated on gold coated glass was used as the working electrode, a platinum mesh as the counter electrode and ASL co Ltd Ag/AgCl electrode as reference electrode. Electrolysis experiments of JH028 were performed with a Biologic Potentiostat SP-200, using a standard one-compartment, three-electrode electrochemical cell. Experiments were conducted at RT in CH2Cl2 containing TBAPF6- (0.1 M) as supporting electrolyte. Typically, millimolar solutions of the polymer were used for the electrochemical studies. The working and the counter electrode were a platinum wire, a Pine research Ag+jAg electrode was used as the reference. This electrode was separated from the solution by abridge compartment.. 4.7 NUCLEAR MAGNETIC RESONANCE 1. H- and 13C-NMR were performed on a Varian 500 MHz NMR. Peaks were reported relative to the residual proton signal of the deuterated solvent, 7.26 ppm for CDCl 3 and 2.50 ppm for d-DMSO. In case of known compounds, the structure was verified with 1H-NMR only.. 4.8 FT-IR FT-IR analysis was performed on a Bruker Equinox mid-IR spectrometer with a DTGS detector, using a diamond-ATR setup. The samples were analysed in solid form at wavelengths between 370 and 4000 reciprocal centimetres.. 29.

(33) 5 RESULTS AND DISCUSSION The results and discussion are presented in the following sections: • • • •. Synthesis of polar conjugated monomer Synthesis of polar conjugated polymers Deprotection of pg3CAT Investigation of material properties.. 5.1 SYNTHESIS OF POLAR CONJUGATED MONOMERS 5.1.1 Synthesis of g42TBr2 The g42TBr2 monomer was used to investigate the Suzuki-Miyaura coupling by the synthesis of p(g42T-T). In addition, performing the multistep synthesis of a known compound (g 42TBr2) was a good way to gain practical lab experience in a new lab and become familiar with new synthesis procedures, behavior of reaction intermediates and analytical methods.. Figure 17. Synthesis scheme for the g42TBr2 monomer. The monomer g42TBr2 was synthesized in 4 steps as seen in figure 17 above. First, an Ullman aryl ether coupling was performed, resulting in compound 1 which was obtained in good yield. An oxidative coupling is performed with compound 1, the resulting compound 2 was obtained in very moderate yield. Finally, bromination at low temperature and recrystallization resulted in the final monomer (compound 3) in excellent yield and purity. Compound 3 was used to test the SuzukiMiyaura polymerization to obtain the polymer p(g42T-T). The overall synthesis compared really well with previously obtained results.[45] The main losses of intermediate products came from the liquidliquid extractions during the synthesis workup of compound 2. Typical yields for this reaction are ~40-50%. 5.1.1.1 Compound 1 – g4T Compound 1 was synthesized by an Ullman coupling in anhydrous pyridine and gave a yield of 61 %. The synthesis was performed under air due to lack of nitrogen in the new lab. The yield could potentially be further improved by increasing the reaction time and ensuring that all starting material has reacted before stopping the reaction. The workup of the compound included a liquid-liquid extraction to remove residual copper salts and KBr, a step that did create some problems due to formation of emulsions. This procedure was performed in pyridine, a solvent that is not suited to upscaling due to its toxicity and the added difficulty of removing it after the synthesis is done. During this work, the pyridine was driven off by azeotropic distillation with heptane.. 30.

(34) Figure 18. NMR spectra (CDCl3) of the first intermediate, g4T. The expected peaks are present and the product was pure enough for use in the next synthesis step. NMR analysis of g4T showed that the compound was successfully synthesized and sufficiently pure (see figure 18). The expected peaks are all present, 3 in the aromatic region, 5 in the region around 4 ppm with a singlet at 3.38 ppm corresponding to the methyl terminal group. No additional peaks can be seen except for the solvent peak, a reference peak list can be found in Kroon, 2019.. 5.1.1.2 Compound 2- g42T The oxidative coupling of two g4T-molecules to form the dimer g42T was performed in a 2-step reaction, a lithiation with n-butyllithium followed by a coupling of the thiophenes facilitated by Fe(acac)3. The synthesis was followed by a liquid-liquid extraction work-up, a step that proved detrimental to the yield of the reaction. The low yield (22 %) can be explained by the formation of emulsions in the workup and by inexperience in working with this type of emulsion (see figure 19). This did lead to a change in workup procedures for synthesis of the CAT-monomer, to avoid product loss.. 31.

(35) Figure 19. The liquid-liquid extraction workup was a main loss of product for the oxidative coupling step due to the formation of emulsions. The formation of emulsions in the workup steps were the motivation for exploring workup without liquid-liquid extractions for the synthesis of the CATmonomer. The chemical structure and purity of compound 2 were confirmed with NMR-analysis. As can be seen in the spectra, the hydrogen signal for the 2-position in the aromatic region is lacking (see figure 20) when compared to that of uncoupled g4T (figure 18). The expected peaks are present, 2 in the aromatic region and 4 peaks around 4 ppm. This, combined with peak positions from literature, indicates that the correctly coupled product was obtained. There are some residual impurities present, likely some uncoupled material, as indicated by the small extra peak in the aromatic region.. Figure 20. NMR-spectra (CDCl3) for intermediate 2, after oxidative coupling. All expected peaks were present. Some impurities can be seen, likely some uncoupled material remained. The product was deemed sufficiently pure for use in the next synthesis step.. 32.

(36) 5.1.1.3 Compound 3 – g42TBr2 The final monomer synthesis step was the bromination of the g42T dimer. The bromination was performed with n-bromosuccinimide at -20 °C. The reaction is performed cold to suppress any possible side reactions. The bromination step was performed according to literature with no significant changes to the synthesis, workup or purification. Polymerizations need precise molar ratios between monomers to ensure a good molecular weight, therefore the monomers need to be very pure. The product was recrystallized from Et2O to purify it further. NMR analysis showed that the desired dibrominated product had been obtained in sufficient purity to proceed to the polymerization trials (see figure 21). 1 proton remains in the aromatic region, corresponding to the 4 position. The peak pattern of the tetra ethylene glycol sidechain remains. No extra peaks can be seen in the spectra, indicating good purity after recrystallization.. Figure 21. NMR-spectra (d-DMSO) of the di-brominated monomer. Only 1 aromatic proton remains, as is expected after bromination of the 2 and 5 positions on the thiophene. 5.1.1.4 Compound 4 - g4TBr2 To increase the efficiency of the optimization of the polymerization conditions, a simpler version of the training monomer was also synthesized. This monomer was made by directly brominating compound 1, instead of performing the oxidative coupling (see figure 20). The oxidative coupling had proven to give a substantial loss of material and required work up, purification and verification, all of which would consume time. This approach provided an easy-to-make monomer that could be used to focus on the optimization of the polymerization.. 33.

(37) Figure 22. Structure of the g4TBr2-monomer. This was used to provide a faster and easier synthesis of the monomer to enable more efficient optimization of the polymerization. g4T was synthesized according to the previously used Ullman coupling procedure (cf. page 30). The product was brominated by treatment with NBS and the product was used as monomer for the optimization trials of the Suzuki Miyaura coupling. The final amount of product was improved when compared to the synthesis of g42TBr2, as was the use of synthesis time.. Figure 23. NMR-spectra (CDCl3) of the g4TBr2-monomer. The expected peaks were present, and the compound was of excellent purity. NMR-spectra of the g4TBr2 monomer variant showed that it had been successfully brominated and the correct structure was obtained (see figure 23). The peak positions were compared to literature values. Only one aromatic proton remains, indicating that the product was dibrominated in the 2 and 5 positions. It was deemed pure enough for use in the polymerization.. 34.

(38) 5.1.2. Synthesis of the protected CAT-monomer - g3T-CATtBu-Br2. Figure 24. Synthesis route of the CAT-monomer g3T-CATtBu-Br2 and the resulting intermediate compounds. The protected CAT-monomer was synthesized in 3 steps (see figure 24). An Ullman aryl ether coupling was used to connect the triethylene glycol (TEG) side chain to the thiophene. The protected form of the carboxylic acid functionality was installed via an oxa-Michael addition. Di-bromination gives the monomer that can be used for polymerization. 5.1.2.1 Compound I - g3T The Ullman coupling was optimized over several experiments (see table 1). The reaction was performed neat (with one reactant also acting as the solvent) in all but one case. Toluene was used once in an attempt to improve the compatibility of the TEG with the 3-bromothiophene. Several changes were made to improve the final yield. Solvent, excess of TEG, the use of 1-10-phenantroline, what base was used and the headspace volume were all explored.[46, 47] The main improvements consisted of the addition of 1,10-phenantroline as a ligand, an increase of reaction temperature and performing the reaction in 2 steps (indicated with * in table 1 below). The yield was increased to around 60 % - a good number for this reaction. Typical yield of this reaction, when performed in pyridine, is 70-80 %. The main side reaction is thiophene di-substitution of a single TEG chain. This reaction is much more likely when not protecting 1 side of the TEG, but it seems to be sufficiently suppressed by the excess of TEG.. 35.

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