The modification of thioguanosine with the ferrocenyl group to prepare new redox-active coordination polymers and gels.AimsTo apply protecting group chemistry to allow for the controlled synthesis of organic nucleosides (Thioguanosine) appropriate for the addition redox active groupsTo incorporate redox active groups such as ferrocenyl groups to nucleosides synthesized to achieve new redox active polymers To analyze the new polymer gels to explore their possible structural and electrostatic properties using a range spectroscopic and electroscopic techniques Coordination Compounds and Polymers IntroductionA coordination compound consists for a central atom or ion, commonly being metals with multiple bound molecules or ions known as ligands1. Ligands generally either donate of one or more of the ligand’s electron pairs to form bonds to the metal center and as seen in figure 1 can bind in a monodentate, bidentate or polydentate fashion. The term used to describe these ligands is denticity and this refers to the number of donor groups in a single ligand that bind to the central atom in a coordination compound. A monodentate ligand only binds with one donor group with example being NH3, HO– or Cl– and an example of such a compound is shown in figure 1. A ligand that binds with two donor groups is called a bidentate ligand as seen in figure 2 with common examples being Ethylenediamine (en), phenanthroline (phen) or acetylacetonate ion (acac).  These ligands are often useful as they control the conformation of the coordination compound and restrict the rotation around bonds due to their more rigid structure and multiple binding sites. The addition of more donating groups as expected can lead to higher orders of coordinated species with polydentate ligands such as EDTA (a hexadentate ligand) having 6 donating groups available for binding. Examples of each type of coordination compound can be seen in the figure 3. Figure 2 –Bidentate coordination compound containing 2 bidentate ligandsFigure 3 – Multidentate coordination compound using polydentate ligand EDTA to coordinate to the metal center Figure 1 – Monodentate coordination compoundMetal coordination compounds can form larger more complex systems using bridging ligands which can connect two or more atoms to form polymeric systems.  These compounds consist of a metal cation center with linking ligands and there is interest in the modification of the different ligand groups attached to give them interesting and useful properties in fields such as organic and inorganic chemistry, biochemistry, materials science, electrochemistry, and pharmacology. A metal coordination compound linked by coordination bonds extending in one-dimension can be defined as a 1D coordination polymer as seen in the figure 42,3. As you add supramolecular interactions such as hydrogen bonding and ?–? stacking in two directions it can be classed as a two-dimensional (2D) coordination polymer and the structure will start to resemble a 2D sheet. When you have coordination bonds in three directions and the structure increases in complexity it can be classed as a three-dimensional (3D) coordination polymer with an example being shown in figure 5.It is possible for metals to coordinate to naturally occurring biomolecule ligands such as nucleobases, nucleosides or nucleotides, which have many accessible binding sites and form polymeric chains as seen above. An example of this4 would be the reactions of Ag(l) with the pyrimidine nucleobases; thymine (T), uracil (U), and cytosine (C).  These nucleobases can use their Oxygen and Nitrogen groups to bind to the metal cation center forming coordination compounds like the example shown in figure 6. These compounds are often stabilized by intermolecular reactions such as H-bonding (figure 7) with the nucleobase groups able to interact whilst coordinated to the metal center. These sorts of interactions can allow for more complex polymeric structures to form with a specific area of interest being the coinage metals such as copper, gold and silver. These metals are good soft acids and therefore form good soft acid/base interactions. It would therefore be conceivable to modify ligands to contain good soft basic groups that would have a high affinity for these types of coinage metals.  Figure 7 – Nucleobases interacting through Hydrogen bonding whilst coordinated to the metal center2Figure 6 – Nucleobases binding to a metal center 2Metal- Sulphur Coordination ComplexesWhen it comes to optimizing metal ligand bonding in coinage metals, metal-sulphur bonding is favored over other heteroatom options when trying to form bonds to coinage metals due to the soft base basic nature of the S and the soft acid nature of the Au, Ag or Cu metals.  A review5 goes into detail about how the coinage metals Cu, Ag and AU form different structures from oligomers to coordination polymers with several varied thio-based ligands. Several oligomers can be seen where Au can act as a ?2 bridging atom to two Sulphur based ligands as seen in figure 8.  Other examples were seen where Au can form multiple bonds to several Sulphur atoms leading to more complex Au based systems.  The tetramer system seen in figure 9 shows [Au(SSi(OtBu)3)]4 which is seen to form an eight-membered Au4S4 ring with alternating Au bridging S in a ?2 bridging fashion as seen in the previous structure, however the linear coordination at the gold centres is slightly distorted.Figure 8 –Au-S based Oligomer structure with single bridging S-Au-S bonding5 Figure 9 – Au-S based Tetramer structure with a distorted eight-membered Au4S45  A 1D structure of an Au coordination compound is seen, with a polymeric structure consisting of two interpenetrated helices, where each helix is made of alternate ?2 bridging Au and S atoms. The two helical chains are thought to interact together through weak Au- Au interactions but the Au-S is the backbone to the structure. Metal-thiolate compounds do not need to bridge in a ?2 fashion with higher orders of bonding being available. ?3 bridging can be seen in several compounds of Ag & Cu with one example being a 2D layer of hexagons of Cu3S3 where each copper atom adopts a slightly distorted trigonal planar geometry coordinated with three ?3-bridging thiolates. With this increased bridging, the average length of these Cu-S ?3 thiolates bonds are 2.253 Å which is known to be longer than the average Cu-S ?2 bridging bond length of 2.181 Å. Even more complex ?4 bridging compounds can be seen but the only one reported so far is Silver Phenylselenolate compound which adopts distorted tetrahedral coordination connected through ?4 -Se-Ph ligands. Se is in group 16 like S and will have similar soft acid/ base favourability towards the coinage metals. The compound forms a sheet comprising with SePh ligands perpendicular above and below the Ag sheets and as in the previous case the bond lengths for the bridging atoms (2.737 Å) are longer than the reported average value for ?2 bridging bond length 2.493 Å. Figure 10 – Cu-S ?3 thiolates bonded coordination compound structure5 Figure 11 – Se-Ph ?4 bonded coordination compound structure5 These examples show how Au- S bonding should be used when trying to create an Au coordination polymer due to the favorable soft interactions that have shown to produce many different systems and polymers in other studies. A research paper6 looking into hyperbranched polyglycerols which are highly branched macromolecules such as dendrimers and hyperbranched polymers show how the addition of Thio based structures such as thioethers provide the coinage metal nanoparticles with long term stability and less aggregation when compared to the non-stabilized metals. This again solidifies the idea that this interaction that should be exploited when attempting to create new coordination polymers to coinage metals as it gives a good backbone that is known to be favored and relatively stable.Redox Coordination PolymersAmongst the research carried out into coordination polymers, interesting properties and consequent applications have been theorized and investigated. One key area of interest around coordination polymers is their potential ability to contain redox groups that can carry out electron transfer reactions. The very first redox polymers were investigated by Allen J Bard and Fred C Anson7,8 and their work would open the field to further interest. Their research involved using poly(vinyl ferrocene) to carry out single oxidations with the observed data showing that each oxidation was proportional to one ferrocene group as the backbone chain was understood to be electronically insulating. From these experiments it is now understood that small redox shuttles like Ferrocene undergo facile outer sphere electron transfer reactions through the process of electron tunneling. With larger structures that are not electronically insulating, it is possible to have the charge hop from one neighboring redox species to the other species through a charge diffusion process. This electron hopping (diffusion of charges) can be expressed using a simple equation as shown below:Equation 1 –electron hopping equation8 DE=KEX?26KEX = Rate constant for self-exchange= Distance between redox centers (separation distance)This equation is known to work for simple molecule dimer systems and redox active polymer films but for larger systems with more structural degrees of freedom it is unknown whether this simple equation is sufficient to describe the diffusion of charges. Since these original studies have been carried out theInterest in these redox active polymers has only grown with example such as …. showing.Redox active gels & alternate approaches to achieve semiconducting properties Polymers chains often can become cross linked through covalent bonding or may be linked through supramolecular interactions such as Van der waals, H bonding, ion clusters or host- guest complexing. These three-dimensional networks that are composed of macromolecules that often can retain a large amount of the solvent. when this is the case the mixture can often form insoluble systems and form a polymer gel9.  These polymer gels have elastic properties due to the large amount of solvent and the ?exibility of polymer chains themselves.  These systems often respond to different types of stimuli such a pH, temperature, magnetic & electronic fields or the presence of a bioactive species and these properties give them many uses.There are many ways polymeric gel systems can be modified to try make them undergo redox reactions10 with; Ferrocene, tetrathiafulvalene (TTF), conjugation and transition metal ions being just a few options used in different systems to achieve redox active polymeric systems. Redox active polymers can be broken down into two main categories; redox active group-embedded polymers where a polymer contains an electrochemically active backbone or redox active bearing-group polymers that contain a redox active group grafted to the nonconductive backbone and the groups described above can be applied using both methods with varying success.Ferrocene groups are commonly used redox active groups that consist of two Cp rings in a sandwich structure with a central iron and it is usually incorporated into polymer side groups or less commonly as the polymer main chain constituents as seen in Ferrocenylsilanes which possess alternating silane and ferrocene groups as repeating units (Figure 12). A study11 involving the self-assembly of ferrocene nano ladders and a nanoscale rack using Zn2+ metal centres and several different organic ligands bonded to them containing ferrocene groups showed how you can modify polymeric structures to give optimised redox potentials. The nanoscale rack and Nano ladders showed different redox potential with the ladder structures forcing the four ferrocene units into proximity, increasing their electron diffusion interaction and yielding better redox potential values.An alternate method to create redox active polymers would be to use Tetrathiafulvalene (TTF) based systems12 (Figure 13) that use charge transfer reactions through molecular stacking interactions.  These groups are incorporated into polymeric structures and spectroscopic experiments have shown how oxidation occurs at the TFF unit upon addition of an oxidation potential or Fe3+.Transition metal ions offer many possibilities when it comes to trying to produce a redox active gel with Cu, Ru and Fe being just a few useful redox active metals.  Crosslinked polymers with metal cation centers can undergo redox reactions with a change in geometry usually occurring. These coordination gels can exhibit reversible solution gel phase-transition phenomena controlled by the redox state of the transition metal. One example is the transition between Cu(I)/Cu(II) (Figure 14) with a system featuring a ligand of a 2,2 bipyridine derivative with two cholesteryl groups. When the Cu(II) complex was reduced, a gel was formed and when an oxidant was added to the Cu(I) complex the gel turned into a solution.Redox active polymers can be applied in ESS13 (Energy Storage Systems) with current options such as Li-S, Li-Si or redox flow batteries have issues around stability, safety and long-term performance. Redox active polymers are an exciting area as they can be designed to have good stability and excellent processability, with the possibly of offering a solution to current ESS’s downfalls.Studies into Coordination PolymersMany studies have been carried out into discovering how coordination polymers can be produced using a variety of different metals and ligands to give them specific properties with organic nucleosides having the potential to be used to give coordination polymers high structural organization. Guanosine was used in one study14 to try and direct a highly ordered architecture to a metal- ligand polymer system. The combination of intermolecular interactions such as hydrogen bonding, ion dipole and ?–? stacking interactions lead to a very stable guanosine quadruplex structure that surrounds the metal cation and forms a star polymer in a self-assembled arrangement. The study shows how there are options during polymer formation as it can choose to polymerize first (arm first) and then bind to the metal or choose to self-assemble (core first) followed by the polymerization step. Both were shown to lead to rapid synthesis of the star polymer which is expected to show ion transport behavior as well as having possible applications as a vehicle for drug delivery.   One such study15, sought to investigate the properties of modified coordination polymers and how these properties differed from DNA based materials. One of the main reasons for the study was to see if they could optimise the semiconducting properties of these polymers as integration of semiconducting properties into DNA Duplex remains challenging and unsuccessful beyond lengths of a few nm. The 6-Thioguanosine ligand (figure 15) was used with Au(l) ions as the metal ion and the coordination structure was seen to spontaneously assemble into one dimensional chains extending many ?m in length in a similar fashion to DNA. The main binding mode of the chain was through the M-S (Metal – Thiol bond) in a single atom bridge.  These structures were then studied using an array of spectroscopic techniques and using Atomic force microscopy the structure was found to be highly arranged with individual strands of coordination polymer appearing periodically (figure 16). In this study the integration of the Au(l) – Thiolate semiconducting motif into DNA sequences was attempted successfully with the Au(l) – Thiolate bonding dominating over other alternate donor atom sites such as N or O. Further study is to be carried out into the modification and design of ligands which could be more favorable to bind to DNA or offer even better potential for semiconducting properties. Figure 15 – 6-Thioguanosine used in formation of Au(l) coordination polymer 15  Figure 16 – The following shows a section of the {Au(l)-Thioguanosine}n coordination polymer viewed along and onto the helical chain.15  Protecting Group ChemistryThioguanosine is an example of a nucleoside and it has potential to act as a coordination polymer ligand. The use of such a group will require some selectivity when it comes to trying to add potential redox active groups to the structure as there are multiple OH groups available for reaction (figure 17). The general structure of a nucleoside consists of a purine/ pyrimidine base linked to a sugar with OH groups that are accessible for reactions. The two OH groups alpha to each other on carbons labelled 2 & 3 and one singular branched OH on the carbon labelled 5 shown in the figure. It is possible to protect these OH groups in several different ways. One way to protect the two OH groups adjacent to each other (2, 3) would be to form an acetal and force any chemistry to go through the branched hydroxyl group16,17,18. This conversion can occur through the scheme shown:Figure 17 – 6-Thioguanosine with labelled hydroxyl groups that need protecting. To deprotect these acetal groups a simple acid will result in the reversal back to the diol form.An alternate option for the mono-protection of alcohols would be to use silyl ether groups such as TMS, TBDMS, TIPS etc. These groups are based on Si-O bonds and with their relative protecting ability being dependent on the size of the groups as shown in the table. NaH could be used to deprotonate the alcohol but it may be too strong, and a softer base may be necessary.TMSTESTBSTIPSTBDPSRelative Protecting ability in Acidic Media16420,000700,0005,000,000Relative Protecting ability in Basic Media110-10020,000100,00020,000These groups are typically deprotected with a source of fluoride ion as the Si–F bond strength is about 30 kcal/mol stronger than the Si–O bond. This is favorable as fluoride is a uncommon reagent and would not be involved in a synthesis process. However, fluoride sources such as Tetrabutylammonium fluoride (TBAF) or Hydrofluoric acid that would most likely be used are highly reactive and there is a high risk if using these in a laboratory.Orthogonality of protecting groups is a key issue for the planning and experimental execution of a given synthesis. This can be exploited when using ethers when trying to selectively protect alcohol groups with Trityl ethers, benzyl ethers and Allyl ethers all having different stabilities.  Traditionally, benzyl ethers are used for “permanent” protection and are removed during the latter stages of a synthesis. Esters and silyl ethers, however, can be used as “temporarily” protect hydroxyl groups that are removed during the synthesis. Benzyl ethers have been explored with different reactions showing that one substituted benzyl ether can be selectively removed in the presence of unsubstituted benzyl ether within the same molecule. One example of a studies benzyl ether would be 4-O-methoxy benzyl group (PMB) which has been used frequently in the synthesis of natural products since it can be cleaved oxidatively in a selective manner. Although this group is acid sensitive limiting the synthetic utility, this has allowed for the selectivity of its removal.Proposed ApproachList the objectives of your research project. What do you plan to have achieved by the end of the project?Outline your research plan, try to justify the particular approach you are taking and be specific about what experiments you intend to do.Provide a ‘project timeline’ showing specific tasks and milestones (key stages/results in the work) and by when you hope to have them completed. This should show the reader how you see the project developing/progressing over the time available.Make sure it is really clear what you intend to do!My aim in this project it to modify the nucleobase 6-Thioguanosine using several synthetic steps including protection, addition of a redox active group, esterification and deprotection to create a coordination polymer that will be redox active and be able to carry out electron transfer reactions. By the end of the project I hope to have successfully created the redox active 6-Thioguanosine and be able to carry out analysis of the coordination compound produced. Objectives –1) Modification of Nucleosides-          Protection-          Addition (Redox active groups)-          Esterification-          Deprotection2) Nanowire synthesis with modified Nucleosides3) Analysis & SpectroscopyOther Avenues (Alternate nucleosides)Synthesizing ferrocenyl-acetic acid – The first task will be to prepare the redox active target molecule Ferrocene acetic acid. Ferrocene was chosen as the redox active group due to the detailed understanding of the electron transfer reactions that occur and due to its accessibility and known hazards making it a more attractive option to use in the laboratory. The aim will be to couple the ferrocenyl group to the 6-Thioguanosine nucleoside at the single OH group that will not be protected. This means the ferrocene will need to be modified to allow it to react with the OH group and link the groups together. Ferrocenylcarboxylic acid was explored as an option but it is believed that the carboxylic acid group being directly next to the Cp ring reduces its redox potential due to its electron withdrawing nature. The aim is to therefore try synthesize Ferrocenyl-acetic-acid which contains an carbon atom that should reduce or remove this electron withdrawing effect.Method 1The synthetic route taken to yield the carboxylic acid derivative of ferrocene is as shown:Preparation of AcetylferroceneA mixture of 93 g. (0.5 mol) of Ferrocene, 250 ml. of acetic anhydride and 20 ml. of 85% phosphoric acid was heated at 100° for 10 minutes. The reaction mixture was cooled slightly and poured onto ice. After standing overnight, the mixture was neutralized with 200 g. of sodium carbonate monohydrate in 200 ml. of water. The resulting brown pasty mass was cooled in an ice-bath and filtered. The tan product was washed four times with 100-ml. portions of water and filtered. The granular product was dried in a vacuum desiccator over phosphoric anhydride. Sublimation of the crude product at 100° (1 mm.) gave 81.5 g. (71.4% yield) of an orange crystalline product, m.p. 85- 86° (lit.3 85-86°) after recrystallization from «-heptane. Acetic anhydride (250ml), Phosphonic acid (20ml, 85%) 100°, 10 mins, Yield 71.4% FerroceneAcetylferrocenePreparation of ThiomorphylamidomethylferroceneA mixture of 9.5 g. of the monoacetyl derivative, 1.9 g. of sulfur and 5.2 ml. of morpholine was heated at 130° for 2.5 hours. The viscous black reaction mixture was extracted with hot methanol, and the extracts were diluted with water to give a dark brown precipitate of thioamide. Successive recrystallizations from benzene-hexane and water-methanol mixtures gave orange needles, m.p. 128.5-129°, yield 4.5 g. (30%) Sulphur 1.9g, Morpholine (5.2ml)130°, 2.5 hours, Yield 30%Acetylferrocene ThiomorphylamidomethylferrocenePreparation of ferrocene-acetic acidA solution of 5.0 g. of the thioamide in 50 ml. of 10% methanolic potassium hydroxide was refluxed 17 hours. The reaction mixture was poured into 800 ml. of cold water and was thoroughly extracted with ether. Neutralization of the aqueous layer with concentrated hydrochloric acid gave a fine yellow precipitate. Recrystallization from deoxygenated methanol gave light yellow needles, m.p. 150- 152°,11 yield 2.5 g. (60%)  Methanolic potassium hydroxide (50ml,10%)Reflux, 17 hours, Yield 60%Ferrocene-acetic acidThiomorphylamidomethylferroceneSome Acyl Ferrocenes and their Reactions By. J. Graham, R. V. Lindsey, G. W. Parshall, M. L. Peterson and G. M. WhitmanMethod 2An alternate route that produces ferroceneacetic acid from acetyl ferrocene is described below:Stage 1 – To a 500 mL three-necked flask equipped with a mechanical stirrer and a spherical condenser were added 0.01 mol of acetyl ferrocene, 0.1 mol morpholine, 0.05 mol of sulfur and 0.001 mol of Na2S · 9H2O, Oil bath was heated to 128°, Reflux 7h, TLC monitoring. The mixture was cooled to room temperatureStage 2 – Then, 10 mL of ethanol and 25 mL of 2 mol/L sodium hydroxide aqueous solution were added there to, Stirring temperature, Reflux 4h, TLC monitoring. The reaction is completed, cool down, adjust the pH value with hydrochloric acid to between 7 and 8, Filter cleaning, the filtrate was then adjusted to pH 1 with hydrochloric acid, placed overnight, filter, washed. A yellow-brown solid, ferrocenyl acetic acid, the yield is 79% 1)      morpholine (0.1mol), Sulphur (0.05mol), Na2S · 9H2O (0.001mol) 128°, Reflux 7h2)      ethanol (10ml), NaOH (25ml, 2mol/L) Reflux, 4 hours, Yield 79%Shaanxi University of Science and Technology; Liu, Yuting; Song, Simeng; Yin, Dawei; Jiang, Shanshan; Liu, Beibei; Yang, Aning; Wang, Jinyu; Lyu, Bo – CN104231004, 2017, BNucleoside protectionTo allow the addition of the redox active group the 1,2 Diol of the Thioguanosine needs to be protected to ensure it does not react to form side products. Although silyl and ether methods of protection may offer high selectivity the fact that the acetal protection method ties up the desired diol group whilst leaving the branched OH group free for reaction makes this a good option for the synthesis process that would be carried out.  Acetal protection has been used to selectively protect 1,2-diequatorial diols in sugars, in the presence of other hydroxyl group combinations. Silyl Acetal protection is an option and are usually deprotected with fluoride sources. Acetals are stable under basic and reductive conditions and unstable toward acids with a tolerance toward iodination, reduction, oxidation, Wittig, silylation, and glycosidation reactions.The proposed acetal protection of the 1,2 diol would be as shown below:  Diol Protection Selective Protection of 1,2-Diols – https://pubs.acs.org/doi/pdf/10.1021/cr990101jSchmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6Ferro, V.; Mocerino, M.; Stick, R. V.; Tilbrook, D. M. G. Aust. J. Chem. 1988, 41, 813.Diol Protection – https://pubs.rsc.org/en/content/articlelanding/1997/p1/a605851e#!divAbstract Acid/ alcohol reaction (Connection) – Fischer Esterification/ condensationTo connect the two groups produced an esterification reaction will need to be carried out giving H2O as a condensation side product. Esters are produced when carboxylic acids are heated with alcohols in the presence of an acid catalyst (Conc Sulphuric acid). https://chem.libretexts.org/Textbook_Maps/Organic_Chemistry/Supplemental_Modules_(Organic_Chemistry)/Carboxylic_Acids/Reactivity_of_Carboxylic_Acids/Fischer_Esterificationhttps://www.organic-chemistry.org/namedreactions/fischer-esterification.shtm DeprotectionThe final step will be the deprotection of the acetal group which is carried out under acidic conditions.  The scheme below shows the nucleobase product with R being the Ferrocenyl group.Andrew Nickel, Toru Maruyama, Haifeng Tang, Prescott D. Murphy, Blake Greene, Naeem Yusuff, and John L. Wood, J. Am. Chem. Soc., 2004, 126 (50), pp 16300–16301Haifeng Tang, Naeem Yusuff, and John L. Wood Org. Lett., 2001, 3 (10), pp 1563–1566 Au Coordination Polymer FormationWhen we have obtained the modified 6-Thioguanosine group with the redox active ferrocenyl group attached the aim will be to add it to the Au to form a redox active polymer capable of carrying out electron transfer reactions.