Covalent and Supramolecular Helical Polymers: The Dawn of Matryoshka Materials

! TESE DE DOUTORAMENTO COVALENT AND SUPRAMOLECULAR HELICAL POLYMERS: THE DAWN OF MATRYOSHKA MATERIALS Zulema Fernández Villar ESCUELA DE DOUTORAMENTO INTERNACIONAL PROGRAMA DE DOUTORAMENTO EN CIENCIA E TECNOLOXÍA QUÍMICA SANTIAGO DE COMPOSTELA 2020 ! I Abbreviations and Acronyms ºC Celsius Degree 1,2-DCE 1,2-Dichloroethene [α] Standardized Specific Rotation α Optical Rotation αobs Observed Optical Rotation αagg Degree of Aggregation Å Angstrom Aib α-Aminoisobutiric Acid AFM Atomic Force Microscopy ap Antiperiplanar BTA Benzene-1,3,5-tricarboxamide c Concentration c-c cis-cisoid c-t cis-transoid ca. Latin expression “circa”; around calcd Calculated CBT Carbonyl-Bridged Triarylamine CD Circular Dichroism cod cis,cis-1,5-cyclooctadiene CSP Chiral Stationary Phase CyD Cyclodextrin δ Chemical Shift d Distance DCM Dicholomethane DFT Density Functional Theory ΔHelo Elongation Enthalpy ΔHnp Nucleation Penalty ΔHnuc Nucleation Enthalpy DIPEA N, N-Diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl Sulfoxide DNA Deoxyribonucleic Acid DSC Differential Scanning Calorimetry ΔSelo Elongation Entropy ΔSnuc Nucleation Entropy ΔZBip (Z)-β-(4,4’-biphenyl)- α,β-didehydropalanine ΔZPhe (Z)-α,β-didehydrophenylalanine II ε Dielectric Constant e.e. Enantiomeric Excess ECD Electronic Circular Dichroism; a.k.a. CD EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride e.g. Latin expression “exempli gratia”; for example equiv. Equivalents ESI Electrospray Ionization FT-IR ATR Fourier Transform Infrared Spectroscopy Attenuated Total Reflectance; a.k.a. IR FWHM Full Width at Half-Maximum g Grams GPC Gel Performance Chromatography HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium HBC peri-hexabenzenecoronene HOAT 1-Hydroxy-7-azabenzotriazole HOPG Highly Oriented Pyrolitic Graphite HPLC High-performance Liquid Chromatography HPMC Helical Polymer-Metal Complex HRMS High Resolution Mass Spectrometry Θ Tilting Degree i.e. Latin expression “id est”; it is IR Infrared Spectroscopy it-PMMA Isotactic Poly(methylmethacrylate) K Kelvin Degree Kelo Elongation Constant Knuc Nucleation Constant λ Wavelength l Cell Length LB Langmuir-Blodget L-CD Left-handed Cicularly Polarized Light LS Langmuir-Schaefer LSP Living Supramolecular Polymerization M Molar M Minus; Counterclockwise Helix M+ Monovalent Metal Ion M2+ Divalent Metal Ion m Multiplet MB Mass-Balance MCH Methylcyclohexane III MeOH Methanol mg Miligrams MHz Megahertz mL Mililiters MM Molecular Mechanics µM Micromolar mM Milimolar mmol Milimol Mn Number Average Molecular Weight MOF Metal-Organic Framework MPA α-Methoxyphenylacetic acid m.r.u. Monomeric Repeating Unit MTPA α-Methoxy-α-trifluoromethylphenylacetic acid Mw Weight Average Molecular Weight Mz Z Average ν Wavenumber nbd 2,5-norbadiene NMR Nuclear Magnetic Resonance nm Nanometer ODCB Ortho-dichlorobenzene OPE Oligo(phenyleneethynylene) OPV Oligo(phenylenevinylene) P Plus; Clockwise Helix PA Poly(acetylene) PBI Perylenebisimide PDI Polydispersity PLA Poly(lactic) PMMA Poly(methylmethacrylate) PPA Poly(phenylacetylene) ppm Parts Per Million POM Polarized Optical Microscopy POPEPA Poly[oligo(phenyleneethynylene)phenylacetylene] R Gas Constant R-CD Right-handed Circularly Polarized Light ROA Raman Optical Activity r.t. Room Temperature σ Cooperativity Factor s Singlet IV SC Stereocomplex SCF Self-consistent Field SEM Scanning Electron Microscopy SP Supramolecular Polymer sp Synperiplanar st-PMMA Syndiotactic Poly(methylmethacrylate) STM Scanning Tunneling Microscopy T Temperature t Triplet Tc Conflict Temperature Te Elongation Temperature Disassembly Process Te’ Elongation Temperature Assembly Process t-c trans-cisoid t-t trans-transoid TBAF Tetrabutylammonium Fluoride TD-DFT Time-Dependent Density Functional Theory TEM Transmission Electronic Microscopy TGA Thermogravimetric Analysis THF Tetrahydrofuran TMS Tetramethylsilyl Tol Toluene TrMA Triphenylmethyl Metacrylate UV-Vis Ultraviolet-Visible VCD Vibrational Circular Dichroism VT-CD Variable Temperature-Circular Dichroism VT-UV-Vis Variable Temperature-Ultraviolet-Visible ω Dihedral Angle ZINDO/S ZenerQs Intermediate Neglect of Differential Ovelap ZnP Zinc Porphyrin V Contents INTRODUCTION 1! 1.!CLASSIFICATION OF THE HELICAL POLYMERS 3! 1.1. Static Helical Polymers 3 1.2. Dynamic Helical Polymers 4 1.3. Foldamers 4 2.!POLY(ACETYLENE)S AND POLY(PHENYLACETYLENE)S 5! 3.!POLY(PHENYLACETYLENE)S’ STABILITY 7! 4.!STRUCTURAL ELUCIDATION OF A POLYMERIC HELIX: THE POLY(PHENYLACETYLENE) CASE 8! 4.1. Architecture of the Poly(phenylacetylene)s 9 4.2. Determination of the Polyene Backbone Configuration 10 4.3. Determination of the Helical Sense of the Polymer 12 4.3.1. Specific Rotation 12 4.3.2. Circular Dichroism 12 4.3.3. Theoretically Calculated Circular Dichroism 13 4.3.4. X-ray Diffraction 14 4.3.5. Atomic Force Microscopy 14 5.!PROPERTIES OF DYNAMIC HELICAL POLYMERS 21! 5.1 Helix Induction 21 5.2 Memory of Macromolecular Helicity 21 5.3 Chiral Amplification 22 5.3.1 Sergeants and Soldiers Effect 24 5.3.2 Chiral Coalition 25 5.3.3 Chiral Conflict 27 5.3.4 Majority Rules 28 5.3.5 Domino Effect 29 5.4 Helix Inversion 30 5.5 Control Over the Elongation of the Polymer Chain in PPAs 31 6.!SUPRAMOLECULAR ASSEMBLIES OF HELICAL POLYMERS 34! 6.1. Fibers and Superhelices 35 6.2. Nanoparticles Based on PPAs 38 7.!APPLICATIONS OF THE PPAS 40! 7.1. Chiral Recognition 40 VI 7.2. Sensors 41 7.3. Asymmetric Catalysis 43 8.!SUPRAMOLECULAR HELICAL POLYMERS 44! 8.1. Thermodynamic Parameters 44 8.2. Cooperative Polymerization 45 8.2.1. Thermodinamically Controlled Polymerization 46 8.2.2. Kinetically Controlled Polymerization 48 8.3. Supramolecular Helicity form Axial Chirality 51 8.4. Properties of Supramolecular Polymers 52 8.4.1. Chiral Amplification 52 8.4.2. Helix Inversion 53 OBJECTIVES 57! CHAPTER I. CHIRAL INFORMATION HARVESTING IN HELICAL POLY(ACETYLENE) DERIVATIVES USING OLIGO(p-PHENYLENEETHYNYLENE)S AS SPACERS 63 CHAPTER II. AROMATIC SUBSTITUTION PATTERN EFFECTS IN POLY-[[OLIGO(PHENYLENE ETHYNYLENE)]PHENYLACETYLENE]S: MODULATION OF THE HELICAL PERIPHERY WITHOUT AFFECTING THE FOLDING OF THE MAIN CHAIN 77 CHAPTER III. COMPLEX SUPRAMOLECULAR POLYMERIZATION PATHWAY OF AN ASYMMETRICAL AND RIGID OPE DERIVATIVE: THE ROLE OF THE SUPRAMOLECULAR POLYMERIZATION DEGREE IN THE AGGREGATE MORPHOLOGY 89 CHAPTER IV. SUPRAMOLECULAR TRIANGULAR TESSELLATION PRODUCED BY THE SELFASSEMBLY OF CHIRAL HELICAL OLIGOMERS OBTAINED FROM OPE DERIVATIVES 101 CHAPTER V. MATRYOSHKA-LIKE HELICAL POLYMERS: WHEN SUPRAMOLECULAR AND COVALENT HELICAL POLYMERS ARE MIXED UP 111 CONCLUSIONS 125 RESUMO 131 EXPERIMENTAL SECTION CHAPTER I 141 EXPERIMENTAL SECTION CHAPTER II 173 EXPERIMENTAL SECTION CHAPTER III 205 EXPERIMENTAL SECTION CHAPTER IV 215 EXPERIMENTAL SECTION CHAPTER V 239 Introduction Introduction 6 Figure 5. (a) Representative examples of the PA family. (b) Possible configurations that the polyene backbone of the PPAs can adopt. Noyori and co-workers18 developed some rhodium based catalysts —[Rh(nbd)Cl]2 (nbd: 2,5-norbornadiene), [Rh(cod)Cl]2 (cod: cis,cis-1,5-cyclooctadiene) or [Rh(cod)BF4]2 (BF4: tetrafluoroborate)— that through a stereospecific living polymerization generate polymers in high yield, with low polydispersity and high ciscontent of double bonds in the polyene skeleton. The polymerization process consists of a head-to-tail stereospecific and regioselective 2,1-insertion mechanism. This mechanism is produced by the steric repulsion between monomeric units, leading to a highly stereoregular polymer chain (Figure 6). Moreover, all Rh (I) based catalysts are tolerant to polar functional groups and solvents (organic solvents as well as water), what makes them highly versatile catalysts.19 5 (e) Liu, J.; Lam, J. W. Y.; Tang, B. Z. Chem. Rev. 2009, 109, 5799-5867. 18 (a) Hirao, K.; Ishii, Y.; Terao, T.; Kishimoto, Y.; Miyatake, T.; Ikariya, T.; Noyori, R. Macormolecules 1998, 31, 3405-3408. (b) Kishimoto, Y.; Eckerle, P.; Miyatake, T.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1994, 116, 12131-12132. 19 (a) Tan, N. S. L.; Lowe, A. B. Angew. Chem. Int. Ed. 2020, 59, 2-16. (b) Ke, Z.; Abe, S.; Ueno, T.; Morokuma, K. J. Am. Chem. Soc. 2011, 133, 7926-7941. R OR O O R O HN R O R m-17 m-18 m-19 m-20 m-21 Examples of Optically Active Acetylene Monomers H R R R R H H H H R R R R H H H R HR H H R H R R trans-cisoid trans-transoid cis-cisoid cis-transoid Promote the Helix Formation H H HR Backbone configurations in PPAs R R R H R H H H RR H R a) b) Introduction 7 Figure 6. Proposed polymerization mechanism of the PPAs catalysed by Rh (I). 3. Poly(phenylacetylene)s’ stability Some years ago, due to the potential applications of the PPAs in different fields, the necessity of knowing their stability and degradation emerged for cis-cisoidal and cis-transoidal scaffolds.20 Masuda et al. systematically studied some c-t PPAs, observing that they undergo an autooxidative degradation into oligomers, which was observed to be faster in chloroform and toluene.21 Percec and co-workers obtained similar results, confirming also the degradation in the solid state by observation of a decrease in both, the ciscontent of double bonds as well as in the molecular weight.22 However, this process could be slowed down in vacuum or under inert atmosphere, or speeded up by heating —corroborated by 1H NMR experiments—, which indicates that PPAs are thermosensitive. The degradation mechanism of PPAs consists of an intramolecular electrocyclization followed by a cleavage from the polyenic chain, obtaining a 1,3,5-trisubstituted benzene ring (Figure 7a). More recently Tabata’s group has described another isomerization process through a radical mechanism, as confirmed by electron spin resonance measurements. The 20 (a) Liu, l.; Namikoshi, T.; Zang, Y.; Aoki, T.; Hadano, S.; Abe, Y.; Wasuzu, I.; Tsutsuba, T.; Teraguchi, M.; Kaneko, T. J. Am. Chem. Soc. 2013, 135, 602-605. (c) Matsunami, S.; Watanabe, T.; Kamimura, H.; Kakuchi, T.; Ishii, F.; Tsuda, K. Polymer 1996, 37, 4853-4855. 21 (a) Deng, J.; Tabei, J.; Shiotsuki, M.; Sandra, F.; Masuda, T. Polymer 2004, 45, 7395-7400. (b) Abdul Kaim, S. M.; Nomura, R.; Masuda, T. J. Polym . Sci., Part A: Polym. Chem. 2001, 39, 3130-3136. 22 (a) Percec, V.; Rudick, J. G. Macromolecules 2005, 38, 7241-7250. (b) Percec, V.; Rudick, J.; Nomber, P.; Buchowicz, W. J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 3212-3220. (c) Simonescu, C. I.; Percec, V.; Polym. Sci., Part A: Polym. Chem. 1980, 18, 147-155. Rh L R Rh L R Rh R Rh RH Rh RH R Rh RH RRh RH RH R Rh RH RH RH cis-transoidal structure Path A Path B Rh R H R Rh R H R RH R H Rh RH R H Rh R HR H R HR Rh cis-cisoidal structure nbd RPh = = Introduction 8 isomerization from cisto transcan happen during the synthesis or by external factors (application of pressure or electric fields or by heating)23 (Figure 7b). The degradation of the PPA scaffold (poly-22) can also occur by irradiation with light. Liu et al. demonstrated that the photocyclization is possible in the solid state, yielding a 1,3,5trisubstituted benzene ring derivative (cyclotrimer).24 Interestingly, it was observed that this reaction only takes place when the polyene backbone displays a cis-cisoidal geometry, resulting in a cyclic trimer self-supported membrane (Figure 7c). Figure 7. (a) Degradation mechanism by intramolecular electrocyclization. (b) Radical-initiated degradation mechanism. (c) Degradation by photocyclization on the solid state. 4. Structural Elucidation of a Polymeric Helix: the Poly(phenylacetylene) Case In order to design and develop novel materials the structural knowledge of its secondary structure plays a key role for further applications. A detailed structure determination is essential to understand the helix formation mechanism as well as the helical structurefunction relationship. This is a challenging task that can only be overcome by the combination of different techniques. 23 (a) Huang, K.; Mawatari, Y.; Miyasaka, A.; Sadahiro, Y.; Tabata, M.; Kashiwaya, Y. Polymer 2007, 48, 6366-6373. (b) Miyasaka, A.; Mawatari, Y.; Sone, T.; Tabata, M. Polym. Degrad. Stab. 2007, 92, 253-259. (c) Tabata, M.; Tanaka, Y.; Sadahiro, Y.; Sone, T.; Yokota, K.; Miura, I. Macromolecules 1997, 30, 5200-5204. 24 (a) Liu, l.; Namikoshi, T.; Zang, Y.; Aoki, T.; Hadano, S.; Abe, Y.; Wasuzu, I.; Tsutsuba, T.; Teraguchi, M.; Kaneko, T. J. Am. Chem. Soc. 2013, 135, 602. (b) Miyata, M.; Namikoshi, T.; Liu, L.; Zang, Y.; Aoki, T.; Abe, Y.; Yoshiyuki, O.; Tsutsuba, T.; Teraguchi, M.; Kaneko, T. Polymer 2013, 54, 4431-4435. External Stimuli Radical Formation π Bond Rotation R R b) R R R R R R R R R R R R Radical Migration cisradicaltransradical R R R R c) OH OC 12 H 15 OH H n Photocyclization R RR OH OC 12 H 15 OH R= Poly-22 Cyclotrimer R R Isomerization Chain Cleveage a) Cyclization Introduction 9 4.1. Architecture of the Poly(phenylacetylene)s It is important to point out that PPAs are composed of two coaxial helices (an internal and an external one) (Figure 8). This structural feature is intrinsic to all PPAs, but is not always discussed.25,26 Most of the papers found in literature deal with changes on the internal helix, which can be easily followed by ECD, but no information related to the external helix is provided. The internal helix is the one described by the polymer backbone and is characterized by its flexibility, due to the lack of supramolecular interactions within the polyene skeleton —it is formed by conjugated double bonds—. Hence, the adoption of a preferred helical sense will depend on the conformational composition of the pendant groups and the interactions established among them. This spatial disposition will dictate the dihedral angle between the conjugated double bonds (ω1) —negative values of ω1 form an M helix, while positive values form a P helix— and, consequently, it will determine the presence of a c-c or c-t structure. The helical sense and/or elongation of the internal helix can be easily monitored by CD spectroscopy. The external helix is described by the pendant groups and is generated by the array that they describe around the inner helix. The helical sense of this helix can only be determined by AFM measurements, as well as the structural parameters (helical pitch and packing angle). It should be noticed that the inner helix and the outer helix can rotate in the same or in opposite helical sense, depending on the scaffold adopted by the polymer.27 If ω1 < 90º, the polymer presents a c-c scaffold with three residues per turn (3/1 helix, compressed structure), where the inner and outer helices rotate in the same direction —i.e., ω1 = -78º, M internal helix (negative CD) and M external helix (observed by AFM)—. On the other hand, if ω1 > 90º, the polymer presents a c-t scaffold with two residues per turn (2/1 helix, stretched structure), where the inner and outer helices rotate in opposite directions —i.e., ω1 = -140º, M internal helix (negative CD) and P external helix (observed by AFM)— (Figure 8). This clearly demonstrates that the final secondary structure cannot be elucidated only by one technique but by the combination of different ones. 25 Fernández, B.; Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. ACS Omega 2019, 4, 5233-5240. 26 Fernández, B.; Rodríguez, R.; Rizzo, A.; Quiñoá, E.; Riguera, R.; Freire, F. Angew. Chem. Int. Ed. 2018, 57, 3666-3670. 27 Leiras, S.; Freire, F.; Seco, J. M.; Quiñoá, E.; Riguera, R. Chem. Sci. 2013, 4, 2735-2743. Introduction 10 Figure 8. Schematic illustration of two possible scaffolds that a PPA helix can adopt. 4.2. Determination of the Polyene Backbone Configuration The polyene backbone in PPAs (inner helix) can adopt four possible configurations after polymerization —cis-cisoid, cis-transoid, trans-cisoid or trans-transoid—. Among these different configurations, only the cisscaffolds will promote the formation of the helix. Theoretical and experimental 1H NMR studies performed by Percec and co-workers revealed that the vinyl proton resonates differently, depending on the conformation adopted by the polyene backbone. For transpolyenes the chemical shift of the vinyl proton varies between 6.20-7.20 ppm. Moreover, the trans-cisoid scaffold can be distinguished from the trans-transoid one by carefully looking at the 1H NMR spectra. For the former the aromatic protons resonate altogether whereas, for the last one, two aromatic protons are shifted upfield. On the other hand, cispolyenes resonate around 5.60-5.80 ppm. As for the transpolyenes, the cispolyenes can be identified by the shift of the aromatic protons. For cis-cisoid scaffolds one aromatic proton is shifted upfield while, for cis-transoid scaffolds, two aromatic protons are displaced. Also, for cisscaffolds, the chemical shift of the vinyl proton will depend on the aromatic substitution pattern: 5.80 ppm for the parasubstituted (cis-cisoid), 6.85 ppm for the metasubstituted (cis-transoid) and 6.70 ppm for the orthosubstituted (cistransoid) polymers. Taking this information into account it is possible to quantify the ciscontent of double bonds in PPAs (Equation 1). %cis = [Acis/(Atotal·Htotal)]·100 Equation 1. Mathematical statement to calculate the ciscontent of double bonds in PPAs. 300 400 500 -50 -40 -30 -20 -10 0 10 20 Wavelength [nm] CD [mdeg] Negative CD 300 400 500 -50 -40 -30 -20 -10 0 10 20 Wavelength [nm] CD [mdeg] pendant “counterclockwise" backbone “counterclockwise" pendant "clockwise" backbone “counterclockwise" c-t scaffoldc-c scaffold Negative CD Oposite external Helical Senses Same Internal Helical Senses Helical Sense Described by Pendants Helical Sense Described by Pendants External Helix Rigth-Handed Internal HelixInternal Helix External Helix Left-Handed Introduction 11 Acis stands for the peak area of the vinyl proton (5.6-5.8 ppm), Atotal is the total area of the 1H NMR spectrum and Htotal is the number of the protons within the pendant. Another useful technique to elucidate the conformation of the polyene backbone is the Differential Scanning Calorimetry (DSC), which presents characteristic thermograms for c-c and c-t backbones. On the one hand, PPAs with a c-c scaffold show solely an exothermic peak (around 200 ºC-240 ºC), related to the isomerization from c-c to c-t (Figure 9b). On the contrary, c-t scaffolds display a thermogram with two exothermic peaks, arisen from the isomerization processes, from c-t to c-c (ca. 140 ºC) and from c-c to t-t (ca. 240 ºC) (Figure 9c). Figure 9. (a) Influence of the ω1 angle on the final scaffold adopted by the inner helix. Representative DSC thermograms for (b) c-c and (c) c-t scaffolds. Additionally, a different technique used to elucidate the configuration of the double bonds is the Raman spectroscopy. The polyene skeleton is active in Raman spectroscopy, where three different bands are characteristic for this family of compounds. Therefore, in polymers with cisconfiguration, these bands are C=Ccis (ca. 1530 cm-1), C-Ccis (ca. 1335 cm1) and C-Hcis (ca. 956 cm-1), while for the transconfiguration the characteristic bands are C=Ctrans (ca. 1475 cm-1) and C-Ctrans (ca. 1200 cm-1).24,28 Also, by FT-IR is possible to detect the deformation bands for C-Hcis (ca. 740 cm-1) and C-Htrans (ca. 1015 cm-1).29 Among the aforementioned structural techniques, there are other procedures involving the reactivity of the polyene backbone to elucidate the configuration of the double bonds. For instance, the isomerization by light irradiation on the solid state is used to differentiate between c-c and c-t scaffolds. As previously explained, the photocyclization is only possible for c-c scaffolds, obtaining a 1,3,5-trisubstituted benzene ring derivative and leaving the c-t scaffolds unreacted after irradiation (Figure 7c).24 UV-Vis spectroscopy is another useful technique that provides information about the elongation but not of the conformation of the helical scaffold. Comparison between different 28 (a) Palomo, L; Rodríguez, R.; Medina, S.; Quiñoá, E.; Casado, J.; Freire, F.; Ramírez, F. J. Angew. Chem. Int. Ed. 2020, 59, 90809087. (b) Misayaka, A.; Sone, T.; Mawatari, Y.; Setauesh, S.; Müllen, K.; Tabata, M. Macromole. Chem. Phys. 2006, 207, 19381944. 29 (a) Ito, T.; Shirakawa, H.; Ikeda, S. J. Polym. Sci., Part A: Polym. Chem. 1974, 12, 11-20. (b) Shirakawa, H.; Ikeda, S. Polym. J. 1971, 2, 231-244. 24 (a) Liu, l.; Namikoshi, T.; Zang, Y.; Aoki, T.; Hadano, S.; Abe, Y.; Wasuzu, I.; Tsutsuba, T.; Teraguchi, M.; Kaneko, T. J. Am. Chem. Soc. 2013, 135, 602. (b) Miyata, M.; Namikoshi, T.; Liu, L.; Zang, Y.; Aoki, T.; Abe, Y.; Yoshiyuki, O.; Tsutsuba, T.; Teraguchi, M.; Kaneko, T. Polymer 2013, 54, 4431-4435. ω1 Angle ω1< 90º c-c structure ω1> 90º c-t structure a) 125 150 175 200 225 250 T/ ºC c-t c-c t-t T1 = 135 ºC T2 = 200 ºC 175 200 225 250 275 T/ ºC T1 = 135 ºC c-c t-t b) H R H R c) Introduction 12 UV spectra gives information about which scaffold is compressed/stretched the most due to hypsochromic/batochromic shifts of the polyene backbone.30 4.3. Determination of the Helical Sense of the Polymer The most common techniques to evidence the formation of a helix with an excess of helical handedness are specific rotation and Circular Dichroism (CD). 4.3.1. Specific Rotation The optical rotation (α) measures the deviation of a polarized beam when interacting with a chiral solution —difference in velocity between left-handed circularly polarized light (L-CD) and right-handed circularly polarized light (R-CD)—. This technique is dependent on the solvent used, the temperature, the concentration and the cell length. By applying equation 2, the optical rotation can be transformed into the standardized specific rotation [α]. T indicates the temperature at which the measurement is perform, while λ indicates the wavelength; αobs stands for the observed optical rotation (degrees) that the apparatus provides, c is de concentration (g·mL-1) and l is the cell length (dm). [𝛼]! != 𝛼!"# 𝑐·𝑙 Equation 2. Equation for the calculation of the specific rotation. The main drawbacks for this technique are the low sensitivity and the large amount of sample required for the measurement. In the case of helical polymers, the specific rotation confirms the formation of a helical scaffold with a preferred handedness. The value obtained for the polymer is typically one to ten orders of magnitude bigger than the one for the corresponding monomer. 4.3.2. Circular Dichroism One of the most useful techniques for determining the presence of a preferred helical sense in macromolecules, as well as a preferential conformation in discrete chiral molecules, is the Circular Dichroism (CD). When a circularly polarized light beam interacts with a chiral molecule bearing one or more chromophores (light-absorbing groups), the light path gets altered. CD spectroscopy records this variation by measuring the difference between the absorption of left-handed circularly polarized light (L-CD) and right-handed circularly polarized light (R-CD). This technique has been widely used in the analysis of the secondary structure of peptides, as it provides not only information about the chiral content but also about the folding —there are characteristic CD spectra for the most common foldings: α-helix, 30 (a) Motoshige, A.; Mawatari, Y.; Yoshida, Y.; Matsuyama, C. S.; Tabata, M.J. Polym. Sci., Part A: Polym. Chem. 2012, 50, 30083015. (b) Percec, V.; Peterca, M.; Rudick, J. G.; Aqad, E.; Imam, M. R.; Heiney, P. A. Chem. Eur. J. 2007, 13, 9572-9581. (c) Percec, V.; Rudick, J. G.; Peterca, M.; Aqad, E.; Imam, M. R.; Heiney, P. A. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 49744987. (d) Percec, V.; Aqad, E.; Peterca, M.; Rudick, J. G.; Lemon, L.; Ronda, J. C.; De, B. B.; Heiney, P. A.; Meijer, E. W. J. Am. Chem. Soc. 2006, 128, 16365-16372. (e) V. Percec, J. G. Rudick, M. Peterca, M. Wagner, M. Obata, C. M. Mitchell, W. D. Cho, V. S. K. Balagurusamy and P. A. Heiney, J. Am. Chem. Soc. 2005, 127, 15257-15264. Introduction 13 β-sheet, β-turn or random coil—. This technique can also be employed to analyse the effect that the environmental conditions have over the studied molecule, as any conformational change will be easily detected. Hence, thermodynamic, kinetic and structural parameters can be obtained.31,32 The possibility of modifying the experiment conditions as well as the low amount of sample needed, unlike specific rotation, have turned CD into a powerful technique. For helical polymers (e.g., PPAs) it is possible to determine an excess of a single-handed helix by looking at the CD trace. The presence of a Cotton effect in the vinlylic region, in combination of an increase in the CD intensity when the traces of the monomer and the polymer are compared, is indicative of the formation of the helix. This technique provides information about the helical sense described by the internal helix, the one described by the backbone, and it has been recently reported that a positive Cotton band corresponds to a P helix, whereas a negative Cotton effect corresponds to an M helix.25 This correlation was determined by TD-DFT (Time-Dependent Density Function Theory) calculations. 4.3.3. Theoretically Calculated Circular Dichroism Theoretical calculations have merged in the last years as a useful tool for the elucidation of the helical structure. MMFF94 energy minimization together with ECD simulation, using the time-dependent self-consistent field (SCF) ZernerQs Intermediate Neglect of Differential Overlap (ZINDO/S) method, have been explored as a way to solve the secondary structure of some helical polymers. As an example, Masuda and co-workers confirmed the formation of two different helical scaffolds (different dihedral angle at the single bond along the main chain, ω1), while studying the substitution effect on a series of polymers derived from propargylamides (m-20).33 In the case of PPAs only one example has been reported and is focused on the CD bands arose by the pendant and not to those related to the polyene backbone, probably due to the complexity of the helical structure (two coaxial helices).34 Recently, Rodríguez et al. have overcome this challenge, demonstrating that is possible to determine the helical sense of the inner helix just by looking at the CD spectra. To calculate the ECD spectra, the TimeDependent Density Function Theory (TD-DFT) was employed and as base the 3-21G basis set and the rCAM-B3LYP functional were selected. The good match between the calculated ECD 25 Fernández, B.; Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. ACS Omega, 2019, 4, 5233-5240. 31 (a) Hammes, G. G. Circular Dichroism, Optical Rotatory Dispersion, and Fluorescence Polarization, In Spectroscopy for the Biological Sciences, John Wiley & Sons, Inc.: Hoboken, New Jersey, 2005, p 63. (b) Berova, N.; Nakanishi, K., Woody, R. W. Circular Dichroism: Principles and Applications, 2nd ed., Wiley-VCH: New York, 2000, p 361. (c) Nakanishi, K.; Berova, N. Circular Dichroism: Principles and Applications, 2nd ed., Wiley-VCH: New York, 2000, p 912.(d) Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy-Exciton Coupling in Organic Stereochemistry, 2nd ed., University Science Books: Mill Valley, CA, 1983. 32 (a) Suzuki, Y.; Tabei, J.; Shiotsuki, M.; Inai, Y.; Sanda, F.; Masuda, T. Macromolecules 2008, 41, 1086-1093. (b) Buffeteau, T.; Ducasse, L.; Poniman, L.; Delsuc, N.; Huc, I. Chem. Commun. 2006, 2714-2716. (c) Tang, H. Z.; Novak, B. M.; He, J.; Polavarapu, P. L. Angew. Chem. Int. Ed. 2005, 44, 7298-7301. (d) Tanatani, A.; Yokoyama, A.; Azumaya, I.; Takakura, Y.; Mitsui, C.; Shiro, M.; Uchiyama, M.; Muranaka, A.; Kobayashi, N.; Yokozawa, T. J. Am. Chem. Soc. 2005, 127, 85538561.(e) Tabei, J.; Shiotsuki, M.; Sanda, F.; Masuda, T. Macromolecules 2005, 38, 9448-9454. (f) Kaneko, T.; Umeda, Y.; Yamamoto, T.; Tereguchi, M.; Aoki, T. Macromolecules 2005, 38, 9420-9426. (g) Takei, F.; Hayashi, H.; Onitsuka, K.; Kobayashi, N.; Takahashi, S. Angew. Chem. Int. Ed. 2001, 40, 4092-4094. 33 Suzuki, Y.; Tabei, J.; Shiotsuki, M.; Inai, Y.; Sanda, F.; Masuda, T. Macromolecules 2008, 41, 1086-1093. 34 Kaneko, T.; Umeda, Y.; Yamamoto, T.; Teraguchi, M.; Aoki, T. Macromolecules 2005, 38, 9420-9426. Introduction 14 spectra for small oligomers and the experimental ECD spectra for some PPAs, with a known helical structure, allowed correlating the experimental CD with the internal helical sense of the PPA. From all the data obtained it was determined that a polymer with a positive Cotton effect in the vinylic region describes a P internal helix, whereas if a negative band is observed the polymer will be describing an M helix. Moreover, the robustness and reliability of this finding was confirmed by evaluating some PPAs taken from literature and by varying the main dihedral angles of the PPAs that can affect to the ECD spectra.25,26 4.3.4. X-ray Diffraction To get a diffraction pattern of a polymer it is necessary to prepare an oriented film, but this can only be possible if it presents a rigid rod-like structure with tendency to form liquid crystal phases. So, for lyotropic or thermotropic liquid crystals (oriented films with regular helical structure) the films can be prepared by physical shearing or by applying electric or magnetic fields to the sample.35 Notwithstanding the information that this technique provides about the secondary structure —helical pitch, helix width, helix length and the interpendant distance—, no information about the helical sense is extracted. 4.3.5. Atomic Force Microscopy Atomic Force Microscopy (AFM) is a powerful structural technique to elucidate the secondary structure of helical polymers, which provides useful information about the packing angle and the helical pitch and, what is more important, about the helical sense of the secondary structure.36 However, sample preparation is not straightforward; only well-ordered self-assembled monolayers will provide images with resolution enough to extract all the desired data. The substrate used as a support for the monolayer will also be a key factor, as it can affect the intramolecular interactions between chains as well as to the helical conformation. The different approaches developed during the last years to prepare polymer monolayers —drop casting, spin coating and Langmuir-Blodget— are discussed next. Drop Casting In a pioneering work, Yashima and co-workers analysed by AFM the helical sense of a PPA copolymer, bearing an achiral bulky C60 and an optically active amine (poly-23). They drop casted a diluted polymer solution on two different substrates, mica and highly oriented pyrolitic graphite (HOPG), observing different results.37 The AFM images on mica showed isolated particles due to the repulsive interactions between the hydrophobic C60 and the hydrophilic mica substrate, forcing the polymer to aggregate. On the contrary, the AFM images on HOPG revealed some extended and individual copolymer chains with isolated 25 Fernández, B.; Rodríguez, R.; Rizzo, A.; Quiñoá, E.; Riguera, R.; Freire, F. Angew. Chem. Int. Ed. 2018, 57, 3666-3670. 26 Fernández, B.; Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. ACS Omega 2019, 4, 5233-5240. 35 Yashima, E. Polym. J. 2010, 42, 3-16. 36 (a) Freire, F.; Quiñoá, E.; Riguera, R. Chem. Commun. 2017, 53, 481-492. (b) Kumaki, J.; Sakurai, S. I.; Yashima, E. Chem. Soc. Rev. 2009, 38, 737. 37 Nishimura, T.; Takatani, K.; Sakurai, S.; Maeda, K.;.Yashima, E. Angew. Chem. Int. Ed. 2002, 41, 3602-3604. Introduction 15 particles (Figure 10a). These studies revealed the importance that the substrate employed has over the scaffold adopted. This, combined with the selection of the pendant groups of the polymer, can be used for the formation of certain supramolecular structures.38 Similar studies carried out for poly(4-carboxyphenylacetylene) (poly-24) complexed with (R)-naphtylethylamine and also for its corresponding amide (poly-25) showing, in both cases, isolated helical chains (Figure 10b and 10c respectively). The resolution of the AFM images on mica was not good enough, therefore only the helical sense could be determined.39 The visualization of right-handed and left-handed helices by AFM on mica was feasible using a bulky chiral ruthenium complex (poly-26, Figure 10d). Although in this case the helical sense could be determined, other structural parameters such as the helical pitch and packing angle could not be obtained due to the poor quality of the images.40 Figure 10. (a) Structure and AFM images for poly-23 drop casted onto different substrates. (b) Structure and AFM image for poly-24/(R)-naphtylethylamine. (c) Structure and AFM image for poly-25. (d) Structure and AFM images for poly-26. Spin Coating Taking this information into account, Yashima et al. developed a new strategy. They decided to introduce a long alkyl chain in the pendant moiety of the PPA to promote the selfassembly and favour the monolayer formation via chain interdigitation.41 To facilitate this, a dilute solution of the sample was spin coated onto HOPG and kept under solvent vapours 38 Nishimura, T.; Maeda, K.; Ohsawa, S.; Yashima, E Chem. Eur. J. 2005, 11, 1181-1190. 39 Sakurai, S. I.; Kuroyanagi, K.; Morino, K.; Kunitake, M.; Yashima, E. Macromolecules 2003, 36, 9670-9674. 40 Sakurai, S. I.; Ohira, A.; Suzuki, Y.; Fujito, R.; Nishimura, T.; Kunitake, M.; Yashima, E. J. Polym. Sci. Part A: Polym. Chem. 2004, 42, 4621-4640. 41 Okoshi, K.; Sakurai, S. I.; Ohsawa J. K.; Yashima, E. Angew. Chem. Int. Ed. 2006, 45, 1245-1248. Drop Casting AFM Analysis a) H H r 1-r n N O O NH Mica: Aggregates HOPG: Polymer Chains b) H O OH poly-24/(R)-naphthylethylamine Complex H O NH n poly-25 H2N c) d) H n poly-26 N NRu N N N N n poly-23 Introduction 22 Before this finding, helical polymers with optical activity due to macromolecular helicity were prepared either by the polymerization of optically active monomers or by the asymmetric polymerization of achiral or prochiral monomers with chiral catalysts or initiators.56 Figure 15. Conceptual representation of the (a) helix induction and (b) memory of macromolecular helicity. 5.3 Chiral Amplification The addition of a small amount of a chiral or achiral additive to an initially axially racemic state can result into an improvement of the final chiral content, through covalent or non-covalent interactions. This process is called chiral amplification. Working in this direction, our research group has developed an axially racemic PPA —null CD signal— derived from the (R)-α-methoxy-α-phenylacetic acid (MPA) (poly-30). 57 This polymer presents two conformers in a 1:1 equilibrium, the sp conformer (synperiplanar orientation of the carbonyl and methoxy groups, dihedral angle [C=O-C-OMe] ca. 0º) and the ap conformer (antiperiplanar orientation of the carbonyl and methoxy groups, dihedral angle [C=O-C-OMe] ca. 180º) (Figure 16a). However, this conformational equilibrium can be biased. More precisely, monovalent metal ions (M+: Li+, Ag+ or Na+) will coordinate to the pendant group through the carbonyl group and also through the phenyl group (via a cation-π interaction), fixing the ap conformation (M helix). On the other hand, if divalent metal ions (M2+: Ba2+) are added, the sp conformation will be promoted due to the coordination of the metal to carbonyl and methoxy groups (P helix). Hence, depending on the valence of the metal added (only a small amount is required, < 10%), the polymer will adopt an M or P helix. The reversibility of this process was demonstrated by the addition of a metal resin scavenger to the metal-polymer complex. By employing this resin, the metal ion is removed and the original null CD trace is recovered. Arias et al. reported that the cation-π interaction that stabilizes the ap conformation in poly-30 can be selectively switched off by removing the metal ion complexed to the pendant group.47 Moreover, the addition of a cosolvent disrupts this cation-π interaction and modifies the pendant conformation from ap to sp, inducing a 56 Yashima, E.; Maeda, K.; Nishimura, T Chem. Eur. J. 2004, 10, 42-51. 57 Freire, F.; Seco, J. M.; Quiñoá, E.; Riguera, R. Angew. Chem. Int. Ed. 2011, 50, 11692-11696. 47 Arias, S.; Freire, F.; Quiñoá E.; Riguera, R. Polym. Chem. 2015, 6, 4725-4733. OH O OH O Axially Racemic Null CD H2N R1 R2 O O H3N R1 R2 Helix Induction CD Active Chiral Amine H2N R1 R2 Achiral Amine H2N R1 R2 Chiral Amine O O H3N R1 R2 Memorized Macromolecular Helicity CD Active a) b) poly-33 Introduction 23 helix inversion in the polymer. Therefore, it is possible to induce whether a left-handed or right-handed helical sense in poly-30 by the addition of a monovalent metal ion and further modification of the coordination mode by the addition of a cosolvent. Moreover, removal of the metal ion recovers the axially racemic starting material (Figure 16b). Figure 16. (a) Representation of the conformational equilibrium for poly-30 and the selective metal-mediated right- /left-handed amplification. (b) Selection of the right-/left-handed helical sense by the activation/deactivation of the cation-π interaction. Green et al. extensively studied the chiral amplification phenomena in helical poly(isocyanate)s (poly-10, Figure 3) formed by left-handed and right-handed helices and connected through helix reversals. Over the past three decades the processes described by NH OO sp conformation right-handed helix resin metal scavenger Chiral Amplification Metal delivered in a cosolvent MeOH > 100 equiv. resin metal scavenger Metal delivered in a cosolvent MeOH < 100 equiv. cosolvent Helix Inversion b) a) NH O O NH O O ap conformation sp conformation NH O O ap conformation NH OO sp conformation right-handed helix left-handed helix M + M2+ NH O O NH O O ap conformation sp conformation M + NH O O ap conformation left-handed helix M + M + M + Chiral Amplification poly-30 Introduction 24 this group have been widely studied for a wide variety of covalent and non-covalent polymeric systems. These chiral amplification processes are described next. 5.3.1 Sergeants and Soldiers Effect This chiral amplification, first described by Prof. Green in 1988, consists in the introduction of a small amount of a chiral unit (less than 1%) in a polymer chain made up by achiral units (left-handed and right-handed helices). Through a cooperative communication mechanism, the chiral unit (Sergeant) is able to command the achiral ones (Soldiers) to fold the copolymer into a preferred helical sense (Figure 17).58 Since this seminal discovery, observed in poly(isocyanate)s (poly-10, Figure 3), this effect was proven in other dynamic and static helical polymers —e.g., poly(silane)s (poly-12, Figure 3), poly(acetylene)s (poly-13, Figure 3) or poly(methacrylate)s (poly-6, Figure 2)— obtaining similar results. Figure 17. Conceptual representation of the Sergeants and Soldiers effect resulting into a chiral amplification via a (a) classical approach and a (b) metal-driven coordination approach. Despite the advantages, the main drawback of the Sergeants and Soldiers effect is that the final helical sense is determined by the chirality of the Sergeant and cannot be modified. In our research group we surpass this limitation by combining the selective chiral amplification of poly-30 (MPA, Figure 12a) and the Sergeants and Soldiers effect.59 Unlike Green’s report, in this case the Sergeant derived from MPA, although chiral, produces an 58 (a) Green, M. M.; Park, J. W.; Sato, T.; Teramoto, A.; Lifson, S.; Selinger, R. L. B.; Selinger, J. V. Angew. Chem. Int. Ed. 1999, 38, 3138-3154. (b) Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.; Lifson, S. Science 1995, 268, 1860-1886. (c) Green, M. M.; Garetz, B. A.; Munoz, B.; Chang, H. P.; Hoke, S.; Cooks, R. G. J. Am. Chem. Soc. 1995, 117, 4181-4182. (d) Green, M. M.; Reidy, M. P.; Johnson, R.D.; Darling, G.; O'Leary, D. J.; Willson, G. J. Am Chem. Soc. 1989, 111, 6452-6454. 59 Bergueiro, J.; Freire, F.; Wendler, E. P.; Seco, J. M.; Quiñoá, E.; Riguera, R. Chem. Sci. 2014, 5, 2170-2176. Sergeant Soldier Chiral Communication Chiral Amplification M Helix Chiral Conformation I Chiral Conformation II Chiral Conformation I Activated Chiral Conformation II M +/2+ Chiral Amplification a) b) M +/2+ Sergeant Soldier M Helix Sergeant Soldier Soldier Soldier Chiral Communication Sergeant Chiral Component Achiral Component The Chiral and Achiral Components Have no Helical Sense Preference Sergeant Chiral Component Achiral Component Introduction 25 axially racemic helix due to the presence of two major conformations (ap and sp) in equilibrium at the pendant moiety. Hence, the Sergeant and the Soldier will induce the formation of an axially racemic helix —mixtures of P and M helices in equal ratio—. Ulterior addition of a metal ion (M+ or M2+) to this copolymer will shift the conformational composition of the MPA moiety into a single conformer depending on the valence of the metal ion —i.e., ap/monovalent metal ion or sp/divalent metal ion—. In turn, this single conformation fixed at the pendant will command the achiral soldier to adopt a preferred conformer, which further induces a fully folded copolymer, where the helical sense is determined by the conformation fixed at the MPA moiety. Moreover, Arias et al.60 have demonstrated that the opposite helical sense can be obtained in case of using monovalent metal ions as external stimuli, by switching on/off the cation-π interaction. Thus, if Na+ is added in the presence of low amounts of a cosolvent, the MPA moiety will adopt the ap conformation due to the cation-π interaction, whereas if the metal (Na+) is added in the presence of high amount of cosolvent, the cation-π interaction is disrupted leading to an sp conformation (Figure 18). Figure 18. Conceptual representation of the total control of the helical sense of a PPA copolymer through the Sergeants and Soldiers effect and a selective tuning of the cation-π interaction mediated by the amount of cosolvent [Sergeant = (R)-MPA]. 5.3.2 Chiral Coalition Recently our research group introduced a new chiral enhancement effect, the Chiral Coalition.61 In a more complex situation than the abovementioned for the Sergeants and 60 Arias, S.; Bergueiro, J.; Freire, F.; Quiñoá, E.; Riguera, R. Small 2016, 12, 238-244. 61 (a) Arias, S.; Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. J. Am. Chem. Soc. 2018, 140, 667-674. (b) Cobos, K.; Quiñoá, E.; Riguera, R.; Freire, F. J. Am. Chem. Soc. 2018, 140, 12239-12246. Chiral Conformation I Chiral Conformation II Sergeant Chiral Component Achiral Component Chiral Conformation I Activated Chiral Conformation II Chiral Amplification P Helix Sergeant Soldier Soldier Soldier Chiral Communication Chiral Conformation I Chiral Conformation II Activated Chiral Amplification M Helix Sergeant Soldier Soldier Chiral Communication Na + Large Ammount of Cosolvent Na + Low Ammount of Cosolvent Na + Na + Switchable Helicity Addition of Cosolvent The Chiral and Achiral Components Have no Helical Sense Preference Introduction 26 Soldiers effect (chiral soldier and achiral sergeant), the copolymer in the Chiral Coalition will be composed of a Sergeant and a Soldier both chiral and with different structure. The chiral Sergeant and the chiral Soldier were chosen according to the conformational composition of the corresponding monomers, as well as the dynamic helical behaviour of their corresponding homopolymers. It was observed that, in all the copolymers evaluated, the Soldier is the one that commands the helical sense of the copolymer. The Sergeant (minor component) acts as a chiral dopant, inducing the Soldier (major component) to adopt a specific conformation (identical in all cases), which is independent of the absolute configuration of the Sergeant (R/S). For instance, if the (R)-Soldier (major component) commands a left-handed (M helix), both R and S enantiomers of the Sergeant (minor component) will adopt the same M helix, even though their intrinsic chiralities are the opposite —M helix1, [(R)-Sgtminor-co-(R)-Soldmajor]; M helix2, [(S)-Sgtminor-co-(R)-Soldmajor]—. The same effect was observed when the S enantiomer of the Soldier was used to induce a singlehanded helix (P helix) —P helix1, [(R)-Sgtminor-co-(S)-Soldmajor]; P helix2, [(S)-Sgtminor-co-(S)- Soldmajor]—. Hence, the helical sense of the copolymer (inner helix, P or M) is determined by the absolute configuration of the Sergeant (minor component; fixed conformation), while the intrinsic chirality of the Soldier (major component; two possible conformations) defines the chirality at the periphery of the helix (Figure 19). Figure 19. Conceptual representation of the Chiral Coalition. From these studies we extracted that, in order to obtain an effective chiral-to-chiral communication along the copolymer chain and, in consequence, a single-handed copolymer, the two chiral monomers forming the copolymer have to present the following characteristics: (1) both chiral monomers (Sergeant and Soldier) must promote similar helical scaffolds in their corresponding homopolymers; (2) the chiral Soldier must display a conformational equilibrium between, at least, two conformers in the corresponding homopolymer (null CD at the vinylic region); (3) the chiral Sergeant must show a preferred conformation in the corresponding homopolymer to avoid the bond rotation and therefore, the communication of NH OO HN OChiral Amplification poly-[(S)-soldier-co-(R/S)-sergeant] O (S)-Soldier No Enantiomers NH OO HN O No Enantiomers O R1 R2 (R)-Soldier R1 = Ph; R1 = H (S)-Sergeant R1 = H; R1 = Ph (R)-Sergeant poly-[(R)-soldier-co-(R/S)-sergeant] M helixP helix Chiral Amplification R1 R2 R1 = Ph; R1 = H (S)-Sergeant R1 = H; R1 = Ph (R)-Sergeant Introduction 27 orders with opposite information (e.g., one conformer induces a P helix and a second conformer induces a M helix). 5.3.3 Chiral Conflict Opposite to the Chiral Coalition effect is the Chiral Conflict. This phenomena was also described by Green and co-workers for copolymers of poly(isocyanate)s (poly-10, Figure 3), composed by two chiral monomeric units with different structure and configuration. To produce a chiral conflict effect two monomers will induce opposite helical senses within the polymer chain resulting into a non-ordered structure.62 The nature and the ratio of comonomers present in the polymer chain will play a key role in the initial helical sense as well as in the inversion temperature (Figure 20a). At a certain monomer ratio the copolymer will show, at a given temperature (Tc, conflict temperature), a null optical activity (CD = 0), which can be transformed into an optically active material by varying the temperature. Our group has reported, to our knowledge, the only practical application of this chiral conflict effect in dynamic helical copolymers.63 It was demonstrated that PPA copolymers showing chiral conflict adopt an excess of a helical sense by the addition of an appropriate external stimulus, which will act on the conformational composition of one of the constituting comonomers. In this way, it is possible to tune the excess of the helical content by playing with different stimuli (e.g., valence of the metal ion) without affecting the copolymer composition. Surprisingly, if the external stimuli acts on both of the comonomers at the same time, an axially mirror image is generated, where the global helical sense is cancelled by the two opposite helicities induced by the constituent monomers (Figure 20b). 62 (a) V. Jain, K.-S. Cheon, K. Tang, S. Jha, M. M. Green Isr. J. Chem. 2011, 51, 1067–1074. (b) Tang, K.; Green, M. M.; Cheon, K. S.; Selinger, J. V.; Garetz, B. A. J. Am. Chem. Soc. 2003, 125 ,7313-7323. 63 Alzubi, M.; Arias, S.; Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. Angew. Chem. Int. Ed. 2019, 58, 13365-13369. Introduction 28 Figure 20. (a) Conceptual representation of the Chiral Conflict described by Prof. Green. (b) Conceptual representation of the Chiral Conflict effect tuned by external stimuli. 5.3.4 Majority Rules This chiral amplification phenomena was also described by Green and co-workers for poly(isocyanate)s (poly-10, Figure 3). If two enantiomers of a molecule are mixed together in the presence of a small imbalance of one of them —a 0.12% of enantiomeric excess is enough—, the mixture will adopt a preferred helical sense. Due to a cooperative effect, the minor component will adopt the conformation commanded by the major component in order to avoid the presence of helix reversals (Figure 21a).58c,62a This effect was also observed in dynamic helical polymers involving non-covalent interactions. Prof. Yashima’s group designed a PPA bearing as pendant group a bulky aza-18crown ether (CD=0), a receptor typically involved in recognition processes.64 If a chiral aminoacid is added to the achiral PPA a supramolecular complex is formed, as confirmed by CD, obtaining a polymer with a preferred helical sense, which will be determined by the absolute configuration of the aminoacid (Figure 21b). poly-34 is one of the most sensitive and useful receptor for detecting the aminoacids chirality —the presence of 0.005% of enantiomeric excess is enough to command the helix—. 58 (c) Green, M. M.; Garetz, B. A.; Munoz, B.; Chang, H. P.; Hoke, S.; Cooks, R. G. J. Am. Chem. Soc. 1995, 117, 4181-4182. 62 (a) V. Jain, K.-S. Cheon, K. Tang, S. Jha, M. M. Green Isr. J. Chem. 2011, 51, 1067–1074. 64 Nonokawa, R.; Yashima, E. J. Am. Chem. Soc. 2003, 125, 1278-1283. m-1 (M Helix) m-2 (P Helix) External Stimulus A (acts selectively on m-2) m-1 (P Helix) m-2 (P Helix) P Helix Axially Racemic External Stimulus B (acts on m-1 and m-2) m-1 (P Helix) m-2 (M Helix) Axially Racemic Mirror Images Monomer 2 Monomer 1 + Copolymerization P helix M helix Not Fully Folded a) b) Heating Process Cooling Process T c , null CD signal Introduction 29 Figure 21. (a) Conceptual representation of the Majority Rule. (b) Majority Rule in PPA commanded by a supramolecular interaction. 5.3.5 Domino Effect This chiral amplification phenomenon consists in the introduction of a chiral residue in the terminal position of an achiral oligomer, obtaining a preferred helical sense. The introduction of the chiral residue can be accomplished via covalent 65 or non-covalent interactions66 and it was also described for polymers and oligomers (Figure 22a). Inai and co-workers reported the most representative example of the Domino Effect.67 They synthesized some optically inactive peptides (CD null), composed of fragments of αaminoisobutiric acid (Aib) and (Z)-α,β-didehydrophenylalanine (ΔzPhe) (poly-35) or Aib and (Z)-β-(4,4’-biphenyl)- α,β-didehydropalanine (ΔzBip) (poly-36), with the N-terminal position unprotected. The chiral information of the added aminoacid that covalently attaches to the Nterminus is transferred to the whole peptide chain, resulting into a fully folded helical structure (CD active) (Figure 22b). 65 (a) Obata, K.; Kira, M. Macromolecules 1998, 31, 4666-4668. (b) Maeda, K.; Matsuda, M.; Nakano, T.; Okamoto, Y. Polym. J. 1995, 27, 141-146. (c) Obata, K.; Kabuto, C.; Kira, M. J. Am. Chem. Soc. 1997, 119, 11345-11346. 66 (a) Sanji, T.; Takase, K.; Sukaria, H. J. Am. Chem. Soc. 2001, 123, 12690-12691. (b) Inai, Y.; Tagawa, K.; Takasu, A.; Hirabayashi, T.; Oshikawa, T.; Yamashita, M. J. Am. Chem. Soc. 2000, 122, 11731-11732 67 (a) Ousaka, N.; Inai, Y. J. Org. Chem. 2009, 74, 1429-1439. (b) Inai, Y.; Ousaka, N.; Okabe, T. J. Am. Chem. Soc. 2003, 125, 8151-8162. S enantiomer R enantiomer Chiral Amplification The Major Component Decides the Final Helical Sense S enantiomer R enantiomer Copolymerization (R)/(S) = 49:51 a) b) O O O O O N O O O O O O N O H 3N O OH e.e. < 0.01% N H H H Axially Racemic Helical Polymer Single-Handed Helical Polymer poly-34 Introduction 30 Figure 22. (a) Conceptual representation of the Domino Effect. (b) Some of the most representative examples of peptides that show Domino Effect. 5.4 Helix Inversion The inversion of the helical sense is an interesting and unique feature of the dynamic helical polymers. Due to the high sensitivity of the aforementioned polymers to subtle changes in the environment, the helix inversion can be easily triggered by different external stimuli such as solvent polarity, temperature, addition of metal ions, light irradiation… In our research group we have developed a dynamic helical PPA derived from the (S)- phenylglycine methyl ester (poly-37, Figure 23a).12 In low polar solvents (e.g., CHCl3) this polymer shows a negative Cotton effect, related to the less polar anti conformation adopted by the pendants —dihedral angle between carbonyl groups 180º—. However, if a metal ion (e.g., Ba2+) is added a helical inversion is observed —syn conformation, dihedral angle between carbonyl groups 0º—, due to the coordination in a bidentate fashion of the pendant group to the metal. This conformational change arranges the phenyl ring in opposite orientations, triggering the helix inversion process (Figure 23a). More recently, Feringa and co-workers have reported a PPA bearing a chiral amine (poly38) that interacts with a chiral acid molecular motor, observing a chiral amplification. The conformation of the chiral acid can be modified by light irradiation, inducing a helix inversion process due to the rearrangement in the polymer structure to optimize the supramolecular interaction between the acid and the pendant group (Figure 23b).68 12 Louzao, I.; Seco, J. M.; Quiñoá, E. Riguera, R. Angew. Chem. Int. Ed. 2010, 49, 1430-1433. 68 Van Leeuwen, T.; Heideman, G. H.; Zhao, D.; Wezenberg, S. J.; Feringa, B. L. Chem. Commun. 2017, 53, 6393-6396. H 2 N H 2 N COOH H 3 N COO Adition of a Chiral Acid Salt Bridge Formation Chiral Transmission Domino Effect N H H N O N H O OMe O 4 poly-35 poly-36 HN H H N O N H O OMe O 4 H a) b) Introduction 31 Figure 23. (a) Helix inversion in a PPA due to a change in the conformation of the pendant aroused by external stimuli. (b) Structure of poly-38 and CD spectra showing the helix inversion in a PPA at the supramolecular level mediated by light irradiation. 5.5 Control Over the Elongation of the Polymer Chain in PPAs As previously mentioned, the control over the optical and chiroptical properties of a polymer is key for the potential applications of these materials. Two structural factors determine these properties, the helical sense (P or M helix) and the elongation (compression/stretching) of the polymer backbone. The elongation of the helical scaffold depends on the nature of the pendants and the possible interactions that these may form with the external stimuli. This change can be easily recorded by UV-Vis spectroscopy and, sometimes, it can even be observed by the naked eye. A helix stretching is related to a red-shift in the UV-Vis spectra (bathochromic shift), due to an increase in the conjugation of the polymer backbone (longer wavelengths), while a helix compression corresponds to a hypsochromic shift.30a Having this information in mind, Maeda and co-workers developed different PPAs bearing several cyclodextrins (CyD) (α, β and γ-CyD) as pendant groups (linked to the backbone by ester, ether or amide connections) (poly-39).69 It was observed that the elongation and the helical sense could be tuned by external stimuli and they applied these features in the 30 (a) Motoshige, A.; Mawatari, Y.; Yoshida, Y.; Matsuyama, C. S.; Tabata, M.J. Polym. Sci., Part A: Polym. Chem. 2012, 50, 30083015. 69 (a) Maeda, K.; Mochizuki, H.; Watanabe, M.; Yashima, E. J. Am. Chem. Soc. 2006, 128, 7639-765. (b) Yashima, E.; Maeda, K.: Sato, O. J. Am. Chem. Soc. 2001, 123, 8159-8160. 300 400 500 -40 -30 -20 -10 0 10 20 Wavelength [nm] CD [mdeg] poly-37 poly-37 + Ba2+ HN O O O HN O O O M n+ M n+ O=C-NH-C-CO in anti conformation O=C-NH-C-CO in syn conformation Low Polar Solvents Polar Solvents or Metal Coordination NH O HO O HO N O HO O HO Light Driven Isomerization a) b) poly-37 poly-38 Light Responsive Molecular Motor Cl Initial After hυ Introduction 38 6.2. Nanoparticles Based on PPAs Polymer nanoparticles can be defined as nanospheres or nanocapsules made of any type of polymer and with a range size between 10 nm and 1000 nm. Nanospheres are spherical and solid and, frequently, are used to adsorb molecules on their surface. Nanocapsules are colloidal particles consisting of a hollow core surrounded by the polymeric cover. Due to their empty nature, these vesicles are usually employed for encapsulation.85 The possibility to selectively choose the size and morphology, as well as the introduction of chirality into these nanostructures, has attracted great interest into the scientific community during the last decade. The main protocols for preparing polymer nanoparticles are discussed next. Emulsification Method In this method the mixture of the corresponding polymer solution together with a surfactant produces the polymer particles as an emulsion (Figure 29). Deng et al. used this procedure for the formation of nanoparticles derived from PPAs, concluding that the nanoparticles size depends on the emulsifier concentration: the higher the concentration (more micelles in the medium), the smaller is the particle size.86 Figure 29. Schematic illustration of the emulsification method for the formation of nanonparticles. Emulsion Polymerization Unlike the emulsification method, in this process the polymerization takes place in situ, in a heterogeneous system generally formed by an aqueous phase and a non-aqueous phase (Figure 30). Hence, it requires a monomer with low solubility in water, a water-soluble initiator and a surfactant. Figure 30. Schematic illustration of the emulsification polymerization process for the formation of nanonparticles. 85 Freire, F.; Quiñoá, E.; Riguera, R. Chem. Rev. 2016, 116, 1242-1271. 86 Zhang, Y. Y.; Luo, X. F.; Deng, J. P.; Yang, W. T. Macromol. Chem. Phys. 2011, 212, 353-360. Rh (I) Catalyst Emulsifier Polymer Emulsion Rh (I) Catalyst Emulsifier Polymer Emulsion Monomer Emulsion Introduction 39 Also Deng’s group explored this method. Starting from several PAs they were able to produce optically active nanoparticles. In addition they also described the formation of smallsized (90 nm) macroscopically racemic PPAs particles.87 Metal-Driven Nanostructuration Nanoparticles based on PPAs can also be obtained by using non-covalent cross-linking agents. Our research group reported, for the first time, the formation of polymer nanoparticles by using metal cations as supramolecular cross-linking agents. For poly-30 it was observed that the addition of a metal ion produced not only a chiral amplification, but also a nanosphere.46b Moreover, the size and chiral content of this nanostructure can be controlled by the polymer/metal ratio and the solvents used to dissolve the polymer46a as well as by the metal ion valence.60,88 Hence, when a cosolvent of high boiling point is added, nanotubes are produced, while toroids are obtained if the cosolvent added reduces the solubility of the polymer and, by changing the valence of the metal ion, the chirality of the surface is modified. The encapsulation ability of these nanostructures was further demonstrated by the encapsulation of iron oxide magnetic particles, quantum dots or organic molecules such as fluorescent dyes (Figure 31).46b Figure 31. (a) Schematic illustration of the formation of nanospheres by using metal cations as cross-linking agents to obtain a helical polymer-metal complex (HPMC). (b) SEM images of nanospheres based on HPMCs. (c) SEM images of nanotubes based on HPMCs. (d) SEM images of nanotorus based on HPMCs. (e) Confocal image of HPMCs containing fluorescein. 87 (a) Chen, B.; Liu, X.; Xu, C.; Song, C.; Luo, X.; Yang, W.; Deng, J. Macromol. Chem. Phys. 2012, 213, 603-609. (b) Luo, X. F.; Kai, N. W.; Li, L.; Deng, J. P.; Yang, W. T. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 1661-1668. (c) Chen, B.; Deng, J.; Tong, L.; Yang, W. Macromolecules 2010, 43, 9613−9619. (d) Deng, J. P.; Chen, B.; Luo, X. F.; Yang, W. T. Macromolecules 2009, 42, 933-938. 46 (a) Arias, S.; Freire, F; Quiñoá, E.; Riguera, R. Angew. Chem. Int. Ed. 2014, 53, 13720-13724. (b) Freire, F.; Seco, J. M.; Quiñoá, E.; Riguera, R. J. Am. Chem. Soc. 2012, 134, 19374-19383. 88 (a) Arias, S.; Núñez-Martínez, M.; Quiñoá, E.; Riguera, R.; Freire, F. Small 2017, 13, 1602398. (b) Arias, S.; Núñez-Martínez, M.; Quiñoá, E.; Riguera, R.; Freire, F. Polym. Chem. 2017, 8, 3740-3745. 60 Arias, S.; Bergueiro, J.; Freire, F.; Quiñoá, E.; Riguera, R. Small 2016, 12, 238-244. b) a) NH O O NH O O ap conformation sp conformation NH OO sp conformation right-handed helix M2+ poly-30 N H OO M 2+ H N O O Chiral Amplification Nanostructuration e)c) d) Introduction 40 7. Applications of the PPAs 7.1. Chiral Recognition Chiral HPLC is one of the most powerful techniques for the separation of enantiomers nowadays. The development of new materials for Chiral Stationary Phases (CSPs) showing good chiral recognition ability towards the different racemates is essential for their practical use (in analytical and preparative purposes). The different chiral selectors used as CSPs for HPLC can be based either on small molecules (polysaccharides or proteins) or polymers. Although several CSPs are commercially available, not all existing racemates can be resolved yet.89 In 1979, Okamoto and co-workers reported a CSP based on an optically active poly(metacrylate) (poly-6, Figure 2) that showed, for the first time, a high chiral recognition ability.90 The chirality of poly-48 to discriminate between enantiomers, attributed to its rigid helical structure, was evaluated for two different types of CSPs —one of them was prepared by grounding the polymer into small particles while the other by coating macroporus silica with poly-48—. These CSPs showed different chiral recognition abilities for several racemates, such as 49. This is due to the different orientation of the polymer in the bulk and on the surface of the silica gel (Figure 32).91 Moreover, this milestone discovery allowed the efficient resolution of racemates with any functional group, which were difficult to resolve on other CSPs. Figure 32. (a) Structure of poly-48 and chromatogram showing the different retention times for the enantiomers of 49. PPAs have also been applied as CSPs into chiral HPLC. As an example, Maeda et al. developed an elution order switchable CSP by switching the helical sense of the polymer employed for chiral recognition. This polymer, derived from 2-2’-byphenol (axially racemic) 89 Okamoto, Y.; Ikai, T. Chem. Soc. Rev. 2008, 37, 2593-2608. 90 Okamoto,Y.; Suzuki, K.; Ohta, K.; Hatada, K.; Yuki, H. J. Am. Chem. Soc. 1979, 101, 4763-4765. 91 (a) Okamoto, Y.; Mohri, H.; Hatada, K. Polym. J. 1989, 21, 439-445. (b) Yuki, H.; Okamoto, Y.; Okamoto, I. J. Am. Chem. Soc. 1980, 102, 6356-6358. O NH O O O HN Si OEt O O Silica Particles poly-48 49 Introduction 41 (poly-50), shows a preferred helical sense upon addition of (R) or (S)-phenylethanol ((R)-51 and (S)-51) and, after the removal of the chiral alcohol, the adopted helical sense is retained. Now, the initially axially racemic (poly-50), is capable of separating the racemates (i.e., transstilbene (52)) (Figure 33).92 More recently, Maeda’s group, in collaboration with our research group, has developed a novel three-state switchable CSP based on poly-30.93 Figure 33. Structure of poly-50 and conceptual representation of the effect that the chiral amplification and the memory of macromolecular helicity have over the final enantioseparation (e.g., trans-stilbene, 52). 7.2. Sensors The possibility of tuning the helical polymers by the addition of external stimuli makes these materials suitable for their use as sensors. Different PPAs have been designed for the detection of metals,94 anions or even as thermal sensors.95 In our research group several sensors have been developed. As previously mentioned, poly-3045 can differentiate between monovalent or divalent metal ions, producing enantiomeric CD traces, while poly-3712 or poly-5396 —which is derived from a dipeptide of glycine and (R)-α-methoxy-α-phenylacetic acid— can classify the solvents according to their polarity. Moreover, in a more complex example, poly-41 will modify not only its helical sense but also its elongation, attending to the polarity and the donor/non-donor properties of the solvent.27 The aforementioned poly-39, described by Yashima et al., can act as a colorimetric sensor. Upon complexation with chiral guests molecules a helical inversion accompanied by a 12 Louzao, I.; Seco, J. M.; Quiñoá, E. Riguera, R. Angew. Chem. Int. Ed. 2010, 49, 1430-1433. 27 Leiras, S.; Freire, F.; Seco, J. M.; Quiñoá, E.; Riguera, R. Chem. Sci. 2013, 4, 2735-2743. 45 Freire, F.; Seco, J. M.; Quiñoá, E.; Riguera, R. Angew. Chem. Int. Ed. 2011, 50, 11692-11696. 92 Shimomura, K.; Ikai, T.; Kanoh, S.; Yashima, E.; Maeda, K. Nat. Chem. 2014, 6, 429-434. 93 Hirose, D.; Isobe, A.; Quiñoá, E.; Freire, F.; Maeda, K. J. Am. Chem. Soc. 2019, 141, 8592-8598. 94 Alzubi, M.; Arias, S.; Louzao, I.; Quiñoá, E.; Riguera, R.; Freire, F. Chem. Commun. 2017, 53, 8573-8576. 95 Zhou, Y.; Zhang, C.; Qiu, Y.; Liu, L.; Yang, T.; Dong, H.; Satoh, T.; Okamoto, Y. Molecules 2016, 21, 1583. 96 Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. Small 2019, 15, 1805413. H O O O O OC12H25 n O 52 poly-50 50 % e.e. [(-)-isomer rich] (-) (-) (+) (+) OH = (R)-51 OH (S)-51 = (S)-51 (R)-51 M helix, poly-50 P helix, poly-50 Introduction 42 colour change is observed, as it happens when changing the solvent composition or the temperature (Figure 34a). Additionally, poly-39 can selectively distinguish the 1phenylethylamine enantiomers and, depending on the CyD attached to the backbone, molecules with similar size and functional groups (Figure 34b).69,83 In a similar way, Kakuchi and co-workers developed some colorimetric sensors for the detection of anions in organic solvents (poly-54), as well as in aqueous media.97 The anions interact with the pendants of the polymer producing a deprotonation. Due to the proximity of the pendants within the helical scaffold this deprotonation generates electrostatic repulsions between charges, forcing the helical scaffold to adopt a stretched structure. This stretching can be easily observed not only microscopically but also macroscopically; therefore the initial yellow solution will become red after deprotonation (Figure 34c). Figure 34. (a) Structure of poly-39 and temperature dependent CD showing the stretching upon increasing the temperature. (b) Colorimetric detection by poly-39 of different alcohols. (c) Structure of poly-54. The panel on the left shows the detection ability of poly-54 towards different anions. On the right, a titration with increasing amounts of acetate anion is depicted, showing the bathochromic shift in the polyenic band. 69 (a) Maeda, K.; Mochizuki, H.; Watanabe, M.; Yashima, E. J. Am. Chem. Soc. 2006, 128, 7639-765. (b) Yashima, E.; Maeda, K.: Sato, O. J. Am. Chem. Soc. 2001, 123, 8159-8160. 83 Maeda, K.; Mochizuki, H.; Osato, K.; Yashima, E. Macromolecules 2011, 44, 3217-3226. 97 (a) Sakai, R.; Barasa, E. B.; Sakai, N.; Sato, S.-I; Satoh, T.; Kakuchi, T. Macomolecules 2012, 45, 8221-8227. (b) Sakai, R.; Sakai, N.; Satoh, T.; Li, W; Zhang, A.; Kakuchi, T. Macromoleules 2011, 44, 4249-4257.(c) Sakai, R.; Okade, S.; Barasa, E. B. Kakuchi, R. Ziabka, M.; Umeda, S.; Tsuda, K.; Satoh, T.; Kakuchi, T. Macromolecules 2010, 43, 7406-7411. (d) Qu, Y.; Hua, J.; Jiang,, Y.; Tian, H. J. Polym. Sci. Part A: Polym. Chem. 2009, 47, 1544-1552. (e) Kakuchi, R.; Nagata, S.; Tago, Y.; Sakai, R.; Otsuke, I.; Satoh, T.; Kakuchi, T. Macromolecules 2009, 42, 1476-1481. (f) Kakuchi, R.; Kodama, T.; Shimada, R.; Tago, Y.; Sakai, R.; Satoh, T.; Kakuchi, T. Macromolecules 2009, 42, 3892-3987. (g) Kakuchi, R.; Nagata, S.; Saki, R.; Otsuka, I.; Nakada, H.; Satoh, T.; Kakuchi, T. Chem. Eur. J. 2008, 14, 10259-10266. OH OH OH OH poly-40 H O HN n poly-39 c) 69 70 71 H NH n NH O F 3 C CF 3 poly-54 poly-56/CH 3 CO 268 a) Bathochromic Shift poly-72 ClO 4HSO 4N 3NO 3F - Br - Cl - CH 3 CO 2C 6 H 5 CO 2b) Introduction 43 7.3. Asymmetric Catalysis Much interest has been focused on the development of polymers based on chiral ligands for catalytic asymmetric synthesis due to their easy recovery and recyclability. The pioneering work of Regellin and coworkers reported the formation of a complex between a poly(metacrylate) —containing a bis(2-pyridyl)phenylmethyl— and palladium (poly-55), resulting into a catalytic system that promoted an asymmetric allylic alkylation. Although the novelty of this approximation, the e.e. was still moderate (60%) and a high amount of catalyst was needed (25% mol) (Figure 35a).98 Since this grounbreaking discovery, many different examples based on poly(quinoxilane)s, poly(isocyanide)s or PPAs have been described. As an example, Yashima et al. published several PPAs bearing cinchona as chiral inductor (poly-56). They observed that by modifying the connection to the backbone (i.e., ester, amide, sulphonamide…) these PPAs could be used for different asymmetric catalysis reactions, such as: the Henry reaction, enantioselective desymmetrization of prochiral cyclic anhydrides or aza-Michael additions among others (Figure 35b).99 Figure 35. Some examples on asymmetric catalysis employing helical polymers. 98 (a) Reggelin, M.; Doerr, S.; Klussmann, M.; Schultz, M.; Holbach, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5461-5466. (b) Reggelin, M.; Schultz, M.; Holbach, M. Angew. Chem. Int. Ed. 2002, 41, 1614-1617. (c) Yashima, E.; Maeda, Y.; Okamoto, Y. Polym. J. 1999, 31, 1033-1036. 99 (a) Takata, L. M. S.; Iida, H.; Shimomura, K.; Hayashi, K.; DosSantos, A. A.; Yashima, E. Macromol. Rapid Commun. 2015, 36, 2047-2054. (b) Tang, Z.; Iida, H.; Hu, H. Y.; Yashima, E. ACS Macro Lett. 2012, 1, 261-265. (d) Miyake, G. M.;Iida, H.; Hu, H. Y.; Tang, Z.; Chen, E. Y. X.; Yashima, E. J. Polym. Sci. Part A: Polym. Chem. 2011, 49, 5192. a) poly-55 X= O poly-56a X = NH poly-56b poly-46c OO NPd Cl b) n H n X N N O R H S n O N N O R O R H O +CH3NO2 R OH NO2 * Ph Ph OCOCH3 poly-55 Ph Ph CH(COCH3)2 CH2(CO2CH3)2 Introduction 44 8. Supramolecular Helical Polymers Helical polymers can be obtained by covalent or non-covalent interactions. The covalent polymerization mostly occurs under kinetic control and becomes irreversible due to the high potential barrier for depolymerisation, which is larger than the forward reaction. As a result, dilution or heating of the macromolecule will not result in a decrease of the molecular weight, due to the covalent forces established among pendants. In an opposite scenario, helical polymers obtained by supramolecular interactions are characterised by a high reversibility. This is arisen by the moderately strong non-covalent forces —e.g., hydrogen bonding, ππ stacking and Van der Waal’s forces— that bring the monomers together. Hence, the stability of these high molecular weight linear polymers will be dependent on the concentration, temperature and pressure. 8.1. Thermodynamic Parameters Considering the mechanistic viewpoint for supramolecular polymers, the polymerization process is considered to occur through a set of chemical equilibriums, each one described by its equilibrium constant (Knuc and Kelo). Attending to the mechanism through which each monomer is added, supramolecular polymers can be formed by an isodesmic or a cooperative polymerization process.100 During the isodesmic polymerization process, the non-covalent interactions established among pendants remain unaffected by increasing the length chain. As each addition is equivalent (same equilibrium constant; Knuc = Kelo), the polymer growth will be favoured by increasing the concentration of monomers in solution or by decreasing the temperature of the sample (Figure 36b). The cooperative polymerization process typically occurs under thermodynamic control and involves two phases, a less favoured nucleation stage (Knuc) followed by a favoured polymerization phase (Kelo). The formation of long polymer chains will depend on the monomer concentration as well as on the temperature or the solvent composition, resulting into a sharp transition from a regime dominated by free monomers as small aggregates to a regime composed, mostly, by large polymers (Figure 36b). The mechanism of self-assembly in organic solvents has been widely studied through temperature dependent UV-Vis and CD spectroscopy, allowing the identification of these two self-assembly processes. Plotting the variation of an intrinsic property (typically the normalized spectroscopic signal at a certain wavelength) as a function of the temperature provides the cooling curve. If the resulting curve is sigmoidal the polymerization will follow an isodesmic process, whether if a hyperbole along a slope with no angle is obtained the polymerization will follow a cooperative process (Figure 36a). In all cases the cooling curves 100 Dorca, Y.; Greciano, E. E.; Valera, J. S.; Gómez, R.: Sánchez, L. Chem. Eur. J. 2019, 25, 5848-5864. Introduction 45 need to be recorded at slow rates to avoid the possible hysteresis and ensure that the system remains in thermodynamic control. Figure 36. (a) Typical cooling curves for the isodesmic and cooperative processes. (b) Conceptual representation of the influence of the polymerization mechanism over the final outcome. The obtained cooling curves are typically fitted with the Mass-Balance (MB) mathematical model. In this case, the fraction of aggregated species at different temperatures is simulated based on Mass-Balance equations for different sets of thermodynamic parameters that describe the equilibrium in the nucleation phase (Knuc, characterized by ΔHnuc and ΔSnuc), as well as in the equilibrium in the elongation phase (Kelo, characterized by ΔHelo and ΔSelo), and both phases are separated by the characteristic temperature Te (elongation temperature). The accuracy of the obtained values is kept by fitting the cooling curve at multiple concentrations. The cooperativity is quantified by the following expression (Equation 3). 𝜎= 𝐾!!" 𝐾!"# =𝑒 !!!" !·! Equation 3. Mathematical statement to determine the degree of cooperativity of the polymerization process. In equation 3 it is assumed that ΔSelo = ΔSnuc to facilitate the fitting, therefore a new expression has to be introduced, the nucleation penalty ΔHnp —defined as ΔHelo-ΔHnuc—. The more negative ΔHnp becomes, the smaller σ is and higher is the cooperativity (σ < 0). In case ΔHelo = ΔHnuc, σ = 1 and the system will follow an isodesmic process.101 8.2. Cooperative Polymerization Usually, during the supramolecular polymerization process the monomer first aggregates into a kinetically preferred structure that depolymerizes and subsequently polymerizes into the thermodynamically stable aggregate. Self-assembled systems, particularly those governed by a cooperative mechanism, often exist as more than one single structure, suggesting that not only the parameter time but also the kinetic contributions will play a key role in the final outcome. 101 Kulkarni, C.; Meijer, E. W.; Palmans, A. R. A. Acc. Chem. Res. 2017, 50, 1928-1936. 0.0 0.2 0.4 0.6 0.8 1.0 a) b) K 1 =K 2 =K 3 =…=K n =K Isodesmic Process K 1 ≠K 2 =K 3 =…=K n =K Cooperative Process θ Temperature or concentration Supramolecular Polymer Monomer Isodesmic σ=1 Cooperative σ=10-6 Introduction 46 8.2.1. Thermodinamically Controlled Polymerization One of the most known examples of supramolecular polymers is the 1,3,5benzenetricarboxamides (BTAs) (poly-57), described by Meijer et al.102 The three amide groups present in the monomer core form a triple array of hydrogen bonds, placing the adjacent molecules one on top of the other with a rotation angle of 60º, which allows the effective π stacking of aromatic units. The VT-UV-Vis and VT-CD experiments, recorded in nheptane at dilute concentrations for a BTA bearing chiral alkyl chains, revealed a nonsigmoidal behaviour. Fitting the data to the MB model yields the cooperativity factor, σ = 5.7·10-7, confirming the cooperative nature of the polymerization process. DFT calculations based on computations of BTA oligomers indicated that the hydrogen bonds between monomers are the main forces involved in the stabilization of the assembly and that the most likely size of the nucleus is a dimer or trimer. Further monomer additions exert no effect on the stabilization of the aggregate (Figure 37a).103 The cooperative self-assembly was also observed in BTAs bearing linear and branched alkyl chains as substituents (poly-58)103,104 as well as in BTAs with inverted amide linkage (poly-59)105 or even bearing thioamides (poly-60) (Figure 37b, c and d respectively).106 Figure 37. (a) Structure and CD spectra of poly-57 in heptane (1.4·10-5 M). The inset shows the decrease of ellipticity at 223 nm when increasing the temperature. Model of the right-handed helix proposed for poly-57 based. (b) C centred BTA (poly-58). (c) N centred BTA (poly-59). (d) Thio-based BTA (poly-60). 102 (a) Smulders, M. M. J.; Filot, I. A. W.; Leenders, J. M. A.; van der Schoot, P.; Palmans, A. R. A.; Schenning, A. P. H. J.; Meijer, E. W. J. Am. Chem. Soc. 2010, 132, 611-619. (b) Smulders, M. M. J.; Stals, P. J. M.; Mes, T.; Paffen, T. F. E.; Schenning, A. P. H. J.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem. Soc. 2010, 132, 620-626. 103 Smulders, M. M. J.; Schenning, A. P. H. J.; Meijer, E. W. J. Am. Chem. Soc. 2008, 130, 606-611. 104 Stals, P. J. M.; Smulders, M. M. J.; Martín-Rapu!n, R.; Palmans, A. R. A.; Meijer, E. W. Chem. Eur. J. 2009, 15, 2071-2080. 105 Stals, P. J. M.; Everts, J. C.; de Brujin, R.; Filot, I. A. W.; Smulders, M. M. J.; Martín-Rapún, R.; Pidko, E. A.; de Greef, T. F.A.; Palmans, A. R. A., Meijer, E. W. Chem. Eur. J. 2010, 16, 810-821. 106 Mes, T.; Cantekin, S.; Balkenende, D. W. R.; Frissen, M. M. M.; Gillisen, M. A. J.; De Waal, B. F. M.; Voets, I. K.; Meijer, E. W.; Palmans, A. R. A. Chem. Eur. J. 2013, 19, 8642-8649. O HN R O H NR O NH R R = O HN C 8 H 17 O H NR 1-4 O NH C 8 H 17 R 2 = R 1 = R 3 = R 4 = α β γ δ NH HN N H O S HN R 3 S H NR 3 S NH R 3 R 3 O R 3 OR 3 C-BTA (poly-58)N-BTA (poly-59)Thio-BTA (poly-60) a) b) c) d) poly-57 Introduction 47 Inspired by these studies Sánchez et al. have also investigated the supramolecular aggregation in π extended C3-symmetric platforms bearing chiral and achiral oligo(phenyleneethynylene) (OPE) tricarboxiamides as substituents (poly-61).107 Experimental and theoretical studies for different monomers revealed that the self-assembly occurs in most of the cases via a cooperative process (Figure 38). These aggregates are stabilized by a triple array of hydrogen bonds and π-π stacking of the aromatic rings. The cooperativity factor value for poly-61 was also comparable to those obtained for the BTAs. Figure 38. Structure and CD spectra for poly-(S)-/poly-(R)-61 (MCH, 1·10-6 M) at 25 ºC and 90 ºC. Inset of the cooling curve obtained for poly-(S)-61 showing the decrease of ellipticity when increasing the temperature. Interestingly, Fernández et al. described for the fist time in 2013 the supramolecular assembly of small molecules by metal-metal interaction.108 They have demonstrated that the cooperative self-assembly of an OPE-based Pd (II) pyridyl complex (poly-62) is mainly ruled by metallophilic interactions (Figure 39a). Cooling down a molecularly dissolved solution of poly-62 —from 50 ºC (non-aggregated state) to room temperature (aggregated state)— revealed the appearance of a red-shifted band at r.t. in the UV-Vis spectra (Figure 39b). This band is ascribed to cooperative metallophilic interactions between the Pd (II) centers and the π-π interactions between OPEs. This assumption was supported by comparing this system with a metal free counterpart as well as by DFT calculations. AFM images demonstrated the formation of fibrillar aggregates (Figure 39d). More recently, they have demonstrated that by modifying the experimental conditions,109 as well as by changing the metal110 that binds the OPE units, different helical scaffolds can be obtained. 107 (a) García, F.; Korevaar, P. A.; Verlee, A, Meijer, E. W.; Palmans, A. R. A.; Sánchez, L. Chem. Commun, 2013, 49, 8674-8676. (b) García, F.; Viruela, P. M.; Matesanz, E.; Ortí, E.; Sánchez, L. Chem. Eur. J. 2011, 17, 7755-7759. 108 Mayoral, M. J.; Rest, C.; Stepanenko, V.; Schellheimer, J.; Albuquerque, R. Q.; Fernández, G. J. Am. Chem. Soc. 2013, 135, 2148-2151. 109 Langenstroer, A.; Kartha, K. K.; Dorca, Y.; Droste, J.; Stepanenko, V.; Albuquerque, R. Q.; Hansen, M. R.; Sánchez, L.; Fernández, G. J. Am. Chem. Soc. 2019, 141, 5192-5200. 110 Coelho, J. P.; Matern, J.; Albuquerque, R. Q.; Fernández, G. Chem. Eur. J. 2019, 25, 8960-8964. H N O R H NR O ONH R R = R = poly-(R)-61 poly-(S)-61 poly-(S)-61 25ºC poly-(S)-61 90ºC poly-(R)-61 25ºC poly-(R)-61 90ºC Introduction 54 bonding interactions with the two solvents and the different conformation that the chiral side chain can adopt —a gauche conformation along the C-C axis and a trans conformation along the C-O axis are favoured for the oligo(ethylene oxide) tails in water—. More recently it was demonstrated the inversion of the helical sense in a liquid crystal by light irradiation (73, Figure 47b). The initial cholesteric phase turns into a nematic phase with opposite helical sense (Figure 47c, d, e) and, after further irradiation, the fingerprint texture reappears, indicative of the recovery of the initial cholesteric phase and of the original helical sense (Figure 47f, g, h).125 Figure 46. (a) Structure for poly-72 and CD trace showing the helical inversion from THF (dashed line) to water (solid line). (b) Open and closed structure for 73 and POM (Polarized Light Microscopy) images showing the helix inversion by changes in the organization of the liquid crystal —from (c) to (e) cholesteric to nematic and from (f) to (h) nematic to cholesteric—. 125 Wang, L.; Dong, H; Li, Y.; Liu, R.; Wang Y.F.; Bisoyi, H. K.; Sun, L.-D.; Yan, C.-H.; Li, Q. Adv. Mater. 2015, 27, 2065-2069. N N O O N O RO OR OR H H n O R = poly-72 O O O O O O S S R R S S R R Open Form (S,S)-73 Closed Form (S,S)-73 O O R = UV Vis a) b) c) d) e) f) g) h) Objectives Objectives 57 Objectives Covalent and supramolecular helical polymers, although being constituted by different linking forces —non-reversible and reversible bonds—, share common properties. In both cases, the study of the secondary structure is key for further manipulation of the helix, as well as for the rational design for their possible applications. This Doctoral Thesis is focused on the study of the properties that covalent and supramolecular polymers may present, to finally encompass them into a single helical polymer creating a novel material, the matryoshka-like helical polymers. Chapter I. Chiral Information Harvesting in Helical Poly(acetylene) Derivatives Using Oligo(p-phenyleneethynylene)s as Spacers Since their discovery, dynamic helical polymers have attracted the attention of the scientific community and mastering their helical sense has emerged as an attractive task. Different mechanisms for the transmission of chiral information have been described for polymers bearing flexible spacers, although the study of this communication process employing rigid spacers remains quite unexplored. The main goal of this project is to demonstrate another remote chiral induction mechanism for polymers bearing long and rigid spacers, the chiral information harvesting process. In this communication process the chiral information is transmitted from the chiral moiety to the spacer array within the helical scaffold, which is finally harvested by the polyene backbone resulting in an effective helix induction. Publication associated with this objective: Fernández, Z.; Fernández, B.; Quiñoá, E.; Riguera, R.; Freire, F. Chem. Sci. 2020, 11, 7182-7187. Chapter II. Aromatic Substitution Pattern Effects in Poly[[oligo(phenylene ethynylene)]phenylacetylene]s: Modulation of the Helical Periphery Without Affecting the Folding of the Main Chain In dynamic helical polymers, such as poly(phenylacetyelene)s (PPAs), the aromatic substitution pattern has a significant role in the final structure adopted by the polymer chain —cis-cisoidal or cis-transoidal—, as well as on the flexibility that they may present —stretched or compressed—. This is due to the proximity between the pendant and the backbone when the former is moved from the parato the orthoposition, which results into an increasing steric hindrance. Herein, searching for novel scaffolds to overpass this problem we will describe a novel family of helical polymers, the poly[oligo(phenyleneethynylene)phenylacetylene]s — POPEPAs—, in which the chiral information will be transmitted by the aforementioned chiral harvesting mechanism. In this polymers a rigid oligo(phenyleneethynylene)n (OPE, n = 1, 2) Objectives 58 spacer will be introduced between the pendant and the backbone, aiming to reduce the congestion observed for the metaand orthoPPAs derivatives. Chapter III. Complex Supramolecular Polymerization Pathway of an Asymmetrical and Rigid OPE Derivative: The Role of the Supramolecular Polymerization Degree in the Aggregate Morphology Supramolecular helical polymers are obtained from the non-covalent interaction of building blocks. The presence of these reversible and weak interactions provide to these polymers a dynamic character, non-observed in their covalent counterparts. With this information in mind and taking advantage of the information extracted from the study of the communication process from POPEPAs (Chapters I and II), we decided to evaluate the self-assembly properties of an asymmetrical and rigid OPE. The OPE monomers will be composed by a short chiral moiety and a π conjugated core, ensuring the stabilization of the obtained aggregates by π-π and hydrogen bonding interactions mainly. Furthermore, the study of these OPE based supramolecular polymers will be interesting due to their potential applications in optoelectronics. Chapter IV. Supramolecular Triangular Tessellation Produced by the Self-Assembly of Chiral Helical Oligomers Obtained from OPE Derivatives From literature it is known that the formation of supramolecular polymers is favoured by the introduction of long alkyl chains, which improve their solubility in low-polar solvents and also promote the chain-to-chain interdigitation. Moreover, in most of the reported examples, the building blocks are usually symmetric and only few examples are found to be chiral. Prompted by this studies, we decided to evaluate the self-assembly of an asymmetric rigid OPE bearing at one of the edges a dodecyl alkyl chain. This will allow us to explore the effect that this long substituent will have over the final morphology and study the supramolecular polymerization mechanism that yields the chiral aggregate. Chapter V. Matryoshka-like Helical Polymers: When Supramolecular and Covalent Helical Polymers are Mixed Up Modelling and experimental studies for POPEPAs revealed that, as in the case of PPAs, cis-cisoidal polyene scaffolds produce the classical scaffold made-up by two coaxial helices; an internal one described by the conjugated polyene backbone and an external one outlined by the pendants. As a consequence, the OPE units will describe a large tilting degree between them. This chiral arrangement between OPE spacers, observed when analysing the communication process for POPEPAs (Chapters I and II), persuade us to study the selfassembly properties of the asymmetric OPE units (Chapters III and IV). On the other hand, computational studies also suggested that if the POPEPA adopts a stretched cis-transoidal scaffold, two additional helices —described by the OPE arrangement; Objectives 59 small tilting degree— will be found in addition to the two classical ones —described by the polyene backbone and the pendants—. Therefore, the objective of this project will be the synthesis of a cis-transoidal POPEPA, in which a non-covalent helix will be incorporated within a covalent one, producing the matryoshka-like helical polymers. To this end the monomer employed for the supramolecular studies in Chapter IV will be used, as it is known that benzamide connectors promote the formation of cis-transoidal structures. 60 Chiral Information Harvesting in Helical Poly(acetylene) Derivatives Using Oligo(p-phenyleneethynylene)s as Spacers Chapter I 63 Chapter I. Chiral Information Harvesting in Helical Poly(acetylene) Derivatives Using Oligo(p-phenyleneethynylene)s as Spacers Adapted from: Fernández, Z.; Fernández, B.; Quiñoá, E.; Riguera, R.; Freire, F.* Chem. Sci. 2020, 11, 7182-7187 Abstract: A chiral harvesting transmission mechanism is described in poly(acetylene)s bearing oligo(p-phenyleneethynylene)s (OPEs) used as rigid achiral spacers and derivatized with chiral pendant groups. The chiral moieties induce a positive or negative tilting degree in the stacking of OPE units along the polymer structure, which is further harvested by the polyene backbone adopting either a P or M helix. Chapter I 70 Additional structural studies were carried out in poly-(S)-2 and poly-(S)-3 to obtain an approximated secondary structure of these polymers and determine their dynamic behaviour. From literature it is known that the conformational equilibrium of poly-1 can be altered in solution by the presence of metal ions. The addition of monovalent ions (e.g., Li+) stabilizes the ap conformer at the pendant group by cation-π interactions, while divalent ions (e.g., Ca2+) stabilize the sp conformations by chelation with the methoxy and carbonyl groups.36,38,39,43 As a result, both the P or M helical senses can be selectively induced in poly-1 by the action of metal ions. Therefore, we decided to add different perchlorates of monovalent and divalent metal ions to solutions of poly-(S)-2 and poly-(S)-3 with the aim of determining the conformational composition at the pendant groups. Thus, when monovalent metal ions (Li+, Ag+ and Na+) are added to a chloroform solution of poly-(S)-2, a chiral enhancement is observed (Figure 5d for Li+ and see Experimental Section Chapter I, Figure S16 for Na+ and Ag+). IR and 7Li-NMR studies show that those ions stabilize the ap conformer at the pendant group in a similar fashion to poly-1, this is by coordination to the carbonyl group of the MPA (Figure 5g) and the presence of a cation-π interaction with the aryl ring of the chiral (|Δδ| 7Li ca., 3.75 ppm) (Figure 5f and see Experimental Section Chapter I). Therefore, addition of Li+ produces a larger number of pendant groups with ap conformation among poly-2, which triggers a chiral enhancement effect through a cooperative process. On the contrary, the addition of perchlorates of divalent metal ions, such as Ca2+and Zn2+, produced an inversion of the third Cotton band —310 nm— associated to the MPA moiety and the disappearance of both first and second Cotton effects (Figure 5e for Ca2+ and see Experimental Section Chapter I, Figure S17 for Zn2+). This is a very interesting outcome because, although the conformational equilibrium at the MPA group changes from ap to sp after the addition of Ca2+, the number of pendant groups with sp conformation do not reach the number needed to trigger the helix inversion process and in fact, a mixture of P and M helices at the polyene backbone is obtained. The helical structures adopted by both polymer systems, PPAs (poly-1) and poly[oligo(pphenyleneethynylene)phenylacetylene]s (POPEPAs) (poly-2 and poly-3), are defined by two coaxial helices, one formed by the polyene backbone (internal helix, CD active) and the other constituted by the pendants (external helix, observed by AFM). 36 Freire, F.; Seco, J. M.; Quiñoá, E.; Riguera, R. J. Am. Chem. Soc. 2012, 134, 19374-19383. 38 Arias, S.; Freire, F.; Quiñoá, E.; Riguera, R. Angew. Chem. Int. Ed. 2014, 53, 13720-13724. 39 Arias, S.; Freire, F.; Quiñoá, E.; Riguera, R. Polym. Chem. 2015, 6, 4725-4733. 43 Arias, S.; Núñez-Martínez, M.; Quiñoá, E.; Riguera, R.; Freire, F. Polym. Chem. 2017, 8, 3740-3745. Chiral Information Harvesting in Helical Poly(acetylene) Derivatives Using Oligo(p-phenyleneethynylene)s as Spacers 71 Figure 5. (a) Conceptual representation of the chiral information harvesting and top view of the 3D model for poly-(S)- 2. (b) CD spectra of poly-(S)-2 (0.2 mg·mL-1) in DMSO vs calculated ECD spectra. Full Width at Half-Maximum (FWHM) equals 20 nm. (c) Low-resolution AFM image from a poly-(S)-2 monolayer and profile depicting the chain separation of the yellow highlighted area in the AFM image. (d) CD spectra showing the chiral enhancement after the addition of Li+ (50 mg·mL-1, THF) to a poly-(S)-2 solution (0.1 mg·mL-1, CHCl3). (e) CD trace of poly-(S)-2 (0.1 mg·mL-1, CHCl3) before and after the addition of a Ca2+ solution (50 mg·mL-1, THF). (f) 7Li-NMR spectra substantiating the cation-π interaction. (g) IR shifts observed for carbonyl and methoxy groups after the addition of LiClO4 and Ca(ClO4)2 (50 mg·mL-1, THF) to a poly-(S)-2 solution (3 mg·mL-1, CHCl3). The coordination modes of the MPA moiety with Li+ and Ca2+ are shown vertically in the middle of the Figure. 300 400 500 -20 0 20 Wavelength [nm] CD [mdeg] Experimental Calculated 300 400 500 -10 0 10 20 Wavelength [nm] CD [mdeg] poly-2 poly-2 + Li + 0 5 10 15 20 3.0 3.3 3.6 3.9 x [nm] y [nm] Δυ CO Δυ OMe Polymer + Li++10 -5 Polymer + Ca2+ +58 +21 300 400 500 -5 0 5 Wavelength [nm] CD [mdeg] poly-2 poly-2 + Ca 2+ P(e)/P(i) NH O O Δδ = 3.75 ppm NH OO Ca 2+ Li + ap conformation sp conformation e) f) g) Cation-π Interaction 4.3 Å Ca 2+ Ca 2+ Ca 2+ NH O O Chiral Harvesting NH O O ap conformation Li + 7 Li-NMR Ca 2+ Pendant Inversion d) poly-(S)-2 1.7 nm a) c) AFM Image of a Well Ordered Monolayer of poly-(S)-2 poly-(S)-2 poly-(S)-2 + Li + poly-(S)-2 poly-(S)-2 + Ca 2+ NH O O 1 2 backbone "clockwise" pendant "clockwise" Vinylic Band b) Chapter I 72 These two helices can rotate in either the same or the opposite sense, depending on the dihedral angle between conjugated double bonds. Thus, internal and external helices rotate in the same direction in cis-cisoidal polymers, while they rotate in opposite directions in cistransoidal ones.14,42,48,49 In order to find out an approximated helical structure for poly-(S)-2, DSC studies were performed. The thermogram shows a compressed cis-cisoidal polyene skeleton (see Experimental Section Chapter I, Figure S13a) similar to the one obtained for poly-1.42 Moreover, although AFM studies on a 2D crystal of poly-(S)-2 did not produce high-resolution AFM images, some parameters such as helical pitch (ca., 2.8 nm) and packing distance between helices of (ca., 6 nm) could be extracted from the well-ordered monolayer analyzed (Figure 5c). Previous structural studies in PPAs found that it is possible to correlate the internal helical sense with the Cotton band associated to the polyene backbone —CD (+), Pint; CD (-), Mint—.50,51 Herein, the positive Cotton effect observed for the polyene backbone [CD365 nm = (+)] in poly-(S)-2 is indicative of a P orientation of the internal helix, which correlates with a P orientation of the external helix in a cis-cisoidal polyene scaffold. To summarize, DSC, AFM and CD studies agree that poly-(S)-2 is made up of a cis-cisoidal framework with Pint and Pext helicities (Figure 5a). Computational studies [TD-DFT(CAM-B3LYP)/3-21G] were carried out on a P helix of an n = 9 oligomer of poly-(S)-2, possessing a cis-cisoidal polyene skeleton (ω1 = +50°, ω3 = -40°) and an antiperiplanar orientation of the carbonyl and methoxy groups at the pendants. The theoretical ECD spectrum obtained from these studies (Figure 5b and see Experimental Section Chapter I) is in good agreement with the experimental one, indicating that our model structure is a good approximation of the helical structure adopted by poly-(S)-2. Next, a similar set of DSC and AFM studies were carried out for poly-(S)-3, that bears an OPE spacer with n = 2. The data showed that this polymer presents a compressed cis-cisoidal polyene skeleton, similar to those obtained for poly-1 and poly-2 (see Experimental Section Chapter I, Figure S13b), with a helical pitch of 3.8 nm and a Pext helical sense (Figures 6a, c). UV studies indicate that, in poly-(S)-3, the polyene backbone absorbs at ca. 380 nm, coincident with the first Cotton effect, that is positive (see Experimental Section Chapter I, Figure S15b). Therefore, it reveals that poly-(S)-3 adopts a Pint helicity (Figure 6b). Thus, as expected for cis-cisoidal scaffolds, the orientations of the two coaxial helices are coincident. Computational studies [TD-DFT(CAM-B3LYP)/3-21G] were carried out on a P helix of an n = 9 oligomer of poly-(S)-3, possessing a cis-cisoidal polyene skeleton (ω1 = +63°, ω3 = -40°) and 14 Suárez-Picado, E.; Quiñoá, E.; Riguera, R.; Freire, F. Angew. Chem. Int. Ed. 2020, 59, 5437-4543. 42 Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. J. Am. Chem. Soc. 2016, 138, 9620-9628. 48 Palomo, L.; Rodríguez, R.; Medina, S.; Quiñoá, E.; Casado, J.; Freire, F.; Ramírez, F. J. Angew. Chem. Int. Ed. 2020, 59, 90809087. 49 Freire, F.; Quiñoá, E.; Riguera, R. Chem. Commun. 2017, 53, 481-492. 50 Fernández, B.; Rodríguez, R.; Rizzo, A.; Quiñoá, E.; Riguera, R.; Freire, F. Angew. Chem. Int. Ed. 2018, 57, 3666-3670. 51 Fernández, B.; Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. ACS Omega 2019, 4, 5233-5240. Chiral Information Harvesting in Helical Poly(acetylene) Derivatives Using Oligo(p-phenyleneethynylene)s as Spacers 73 an antiperiplanar orientation of the carbonyl and methoxy groups at the pendants. The theoretical results (Figure 6b and see Experimental Section Chapter I) match with the experimental data, indicating that our model structure is a good approximation to the helical structure adopted by poly-(S)-3. Finally, the stimuli response properties of poly-(S)-3 were explored by CD. These experiments revealed that the addition of monovalent or divalent metal ions to a chloroform solution of poly-(S)-3 does not produce any significant effect in the structural equilibrium of this polymer (see Experimental Section Chapter I, Figure S18). This fact, in addition to the previous results obtained from the interaction of poly-(S)-2 with divalent metal ions, corroborates the decrease of the dynamic character of helical PPAs when large OPEs are used as spacers. Figure 6. (a) Conceptual representation of the chiral information harvesting and top view of the 3D model for poly-(S)- 3. (b) CD spectrum of poly-(S)-3 in THF (0.2 mg·mL-1) and comparison to the calculated ECD spectra. Full Width at Half-Maximum (FWHM) equals 20 nm. (c) AFM image obtained from a poly-(S)-3 monolayer. (d) CD traces for poly-(S)- 3 in THF (0.2·mg mL-1) polymerized at different temperatures. The poor dynamic behaviour was further demonstrated by polymerizing m-(S)-3 at a lower temperature (0 °C) (Figure 6d). In this case, the region around 240-350 nm remains unaffected, indicating that the pendant is ordered in a similar manner in both batches of polymers, regardless of the temperature at which they were synthesized (20 °C and 0 °C). 250 300 350 400 450 500 -4 -2 0 2 4 6 Wavelength [nm] CD [mdeg] Experimental Calculated 300 400 500 -5 0 5 Wavelength [nm] CD [mdeg] 0 ºC 20 ºC 2.4 nm poly-(S)-3 pendant "clockwise" backbone "clockwise" P(e)/P(i) b) c) 63.3º NH O O Chiral Harvesting d) a) Pext NH O O Pext 1 2 Vinylic Band Chapter I 74 Interestingly, the magnitude of the first Cotton band is duplicated when the polymer is obtained at low temperature due to a stronger helical sense induction at the polyene backbone. This result indicates that a preorganization process may occur during polymerization, affecting the screw sense excess of the PPA. 75 Aromatic Substitution Pattern Effects in Poly[[oligo(phenyleneethynylene)]phenylacetylene]s: Modulation of the Helical Periphery Without Affecting the Folding of the Main Chain Chapter II 77 Chapter II. Aromatic Substitution Pattern Effects in Poly[[oligo(phenylene ethynylene)]phenylacetylene]s: Modulation of the Helical Periphery Without Affecting the Folding of the Main Chain Abstract: The different ortho-, metaand paraaromatic substitution pattern in poly(phenylacetylene)s (PPAs) has a large effect over the helical structure of the polymer, due to the steric repulsions between the pendant and the polyene backbone, as well as in the flexibility of the polyene backbone. Hence, the helical periphery and the helical scaffold of PPAs are largely affected by mutations in the aryl ring. This problem is surpassed by the introduction of a rigid spacer such as an oligo(p-phenyleneethynylene)n (OPE, n = 1, 2) between these two structural motifs —pendant and backbone—, resulting in a release of the congestion suffered in the metaand orthoderivatives. Additionally, this novel family of helical polymers presents, among the different aromatic substituted polymers, the same helix induction due to the presence of a chiral harvesting mechanism; generating a helical structure with a resembling scaffold —similar stretching degree and identical P or M helical sense— but with different decoration at the periphery, where the pendant groups are located in different positions at the outer helix. Aromatic Substitution Pattern Effects in Poly[[oligo(phenyleneethynylene)]phenylacetylene]s: Modulation of the Helical Periphery Without Affecting the Folding of the Main Chain 79 Biomolecules such as DNA, polysaccharides or proteins adopt helical structures that are directly related to their biological functions. Non-natural macromolecules such as helical polymers offer the possibility of creating new structures with novel functionalities with applications in different fields such as sensing,10 -10 chiral recognition,11-13 chiral stationary phases,14,15 asymmetric catalysts,16-23 chiral templates,24-26 building blocks in supramolecular chemistry,117-31 optical switches32,33 or emitting devices,34 among others. As their applicability relies on the helical structure adopted by the polymer, the elucidation of the secondary structure is an important topic that still remains challenging nowadays. The main difficultness found in the structural elucidation of these materials is the presence of a monomer repeating unit (m.r.u.) along the polymer chain, which makes classical and powerful structural techniques like Nuclear Magnetic Resonance (NMR) or X-ray useless. In general, to obtain the secondary structure of a helical polymer such as a poly(phenylacetylene) (PPA) it is necessary to combine information from different structural techniques —NMR, X-ray, Atomic Force Microscopy (AFM), Circular Dichroism (CD), UV-Vis, Time-Dependent Density Functional Theory (TD-DFT) computational studies, Vibrational Circular Dichroism (VCD), Raman Optical Activity (ROA) and so—. However, in many cases the data obtained from these studies does not fit well to solve the puzzle of the polymer helical structure. Despite this difficulty encountered when solving the secondary structure of a helical 10 Maeda, K.; Hirose, H.; Okoshi, N.; Shimomura, K.; Wada, Y.; Ikai, T.; Kanoh, S.; Yashima, E. J. Am. 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Matter. 2018, 30, 2493-2497. 34 Lam, J. W. Y.; Tang, B. Z. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 2607-2629. Complex Supramolecular Polymerization Pathway of an Asymmetrical and Rigid OPE Derivative: The Role of the Supramolecular Polymerization Degree in the Aggregate Morphology Chapter III 89 Chapter III. Complex Supramolecular Polymerization Pathway of an Asymmetrical and Rigid OPE Derivative: The Role of the Supramolecular Polymerization Degree in the Aggregate Morphology Abstract: The polymerization of a short and rigid oligo(phenyleneethynylene) (OPE, 1) produces a complex supramolecular polymerization pathway in a MCH:DCM (99:1) solvent mixture, where a kinetic —AggI— and a thermodynamic —AggII— aggregate are formed via an isodesmic process. Both aggregates show opposite axial chirality and different polymer length, which are responsible for the different aggregate morphology. Thus, while the formation of short P-twisted oligomers (offpathway, AggI) produces in-plane aggregation to generate brick-like nanostructures; the formation of large supramolecular helical polymers (on-pathway, AggII) yields M type columnar helical aggregates, which can be visualized by AFM. Interestingly, AggI (off-pathway) can be kinetically trapped by changing the solvent conditions to MCH:Tol:DCM (97:2:1), remaining stable for days. Complex Supramolecular Polymerization Pathway of an Asymmetrical and Rigid OPE Derivative: The Role of the Supramolecular Polymerization Degree in the Aggregate Morphology 91 Supramolecular polymers (SP) arise from the self-assembly of small organic molecules via non-covalent interactions. The dynamic and reversible character of these weak forces provides unique properties to these materials, revealing promising applications in fields such as pharmaceuticals,1 nanoelectronics2 or catalysis,3 among others. The inherent properties that these polymers may present are determined by the growth mechanism that binds the monomeric units together. Related to this, Meijer et al. have extensively studied several supramolecular polymers build-up by different self-assembling systems. From these studies they inferred that, according to the mechanism for aggregate formation, the polymerization process could be mainly classified either as isodesmic or as cooperative.4 Whether the polymer formation follows a mechanistic pathway or another depends on the non-covalent interactions present throughout the supramolecular structure; primarily hydrogen-bonding and π-π stacking, in combination with other non-directional forces.5 Therefore, the design of the monomeric units that build up the supramolecular scaffold is key for an effective organization. In addition to the above classification of the supramolecular polymerization mechanism, more complex SPs, in which the self-assembly process is governed by kinetics and not only by thermodynamics, have recently been described. These out-of-equilibrium states can be classified as non-dissipative non-equilibrium states —i.e., metastable and kinetically trapped states— or as dissipative non-equilibrium states —i.e., fueled aggregation and competitive or consecutive supramolecular polymerization— yielding, from the same building block, different self-assembled structures just by adjusting the experimental conditions.6 From literature it is known that within all supramolecular polymers, those formed by building blocks containing π-conjugated cores —perylenebisimides [PBIs];7 benzene-1,3,5tricarboxiamides [BTAs];8 oligo(phenyleneethynylene)s [OPEs];9 peri-hexabenzenecoronenes 1 (a) Goor, O. J. G. M.; Hendrikse, S. I. S.; Dankers, P. Y. W.; Meijer, E. W. Chem. Soc. Rev. 2017, 46, 6621-6637. (b) Bakker, M. H.; Lee, C. C.; Meijer, E. W.; Dankers, P. Y. W.; Albertazzi, L. ACS Nano 2016, 10, 1845-1852. (c) Aida, T.; Meijer, E. W.; Stupp, S. I. Science 2012, 335, 813-817. (d) Biswas, S.; Kinbara, K.; Oya, N.; Ishii, N.; Taguchi, H.; Aida, T. A. J. Am. Chem. Soc. 2009, 131, 7556-7557. 2 (a) Dumele, O.; Chen, J.; Passarelli, J. V.; Stupp, S. I. Adv. Mater. 2020, 1907247. (b) Zhang, J.; Dong, S.; Zhang,K.; Liang, A.; Yang, X.; Huang, F.; Cao, Y. Chem. Commun. 2014, 50, 8227-8230. (c) Tovar, J. D. Acc. Chem. Res. 2013, 46, 1527-1537. (d) Yamamoto, Y.; Fukushima, T.; Suna, Y.; Ishii, N.; Saeki, A.; Seki, S.; Tagawa, S.; Taniguchi, M.; Kawai, T.; Aida, T. Science 2006, 314, 1761-1764. (e) Yamaguchi, Y.; Ochi, Y.; Miyamura, S.; Tanaka, T.; Kobayashi, S.; Wakamiya, T.; Matsubara, Y.; Yoshida, Z. J. Am. Chem. Soc. 2006, 128, 4504-4505. (f) Schenning, A. P. H. J.; Meijer E. W. Chem. Commun. 2005, 3245-3258. 3 (a) Li, Y.; Hammoud, A.; Bouteiller, L.; Raynal, M. J. Am. Chem. Soc. 2020, 142, 5676-5688. (b) Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q. Science 2018, 359, 6377. (c) Desmarchelier, A.; Caumes, X.; Raynal, M.; Vidal-Ferran, A.; van Leeuwen, P. W. N. M.; Bouteiller, L. J. Am. Chem. Soc. 2016, 138, 4908-4916. (d) Huerta, E.; van Genabeek, B.; Lamers, B. A. G.; Koenigs, M. M. E.; Meijer, E. W.; Palmans, A. R. A. Chem. Eur. J. 2015, 21, 3682-3290. (e) Raynal, M.; Portier, F.; van Leeuwen, P. W. N. M.; Bouteiller, L. J. Am. Chem. Soc. 2013, 135, 17687-17690. 4 (a) Kulkarni, C.; Meijer, E. W.; Palmans, A. R. A. Acc Chem. Res. 2017, 50, 1928-1936. (b) de Greef, T. F. A.; Smulders, M. M. J.; Wolffs, M.; Schenning, A. P. H. J.; Sijbesma, R. P.; Meijer E. W. Chem. Rev. 2009, 109, 5687-5754. 5 (a) Dorca, Y.; Matern, J.; Fernández, G.; Sánchez, L. Isr. J. Chem. 2019, 59, 869-880. (b) Lübtow, M.; Helmers, I.; Stepanenko, V.; Albuquerque, R. Q.; Marder, T. B.; Fernández, G. Chem. Eur. J. 2017, 23, 6198-6205. 6 (a) Sorrenti. A.; Leira-Iglesias, J.; Markvoort, A. J.; de Greef, T. F. A.; Hermans, T. M. Chem. Soc. Rev. 2017, 46, 5476-5490. (b) Greciano, E. E.; Calbo, J.; Ortí, E.; Sánchez, L. Angew. Chem. Int. Ed. 2020, 132, 17670-17677. 7 (a) Wehner, M.; Röhr, M. I. S.; Bühler, M.; Stepanenko, V.; Wagner, W.; Würthner, F. J. Am. Chem. Soc. 2019, 141, 6092-6107. (b) Würthner, F.; Möller, C. R. S.; Fimmel, B.; Ogi, S.; Leowanawat, P.; Schmidt, D. Chem. Rev. 2016, 116, 962-1052. (c) Ogi, S.; Stepanenko, V.; Sugiyasu, K.; Takeuchi, M.; Würthner, F. J. Am. Chem. Soc. 2015, 137, 3300-3307. 8 (a) Weyandt, E.; ter Huurne, G. M.; Vantomme, G.; Markvoort, A. J.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem. Soc. 2020, 142, 6295-6303. (b) Smulders, M. M. J.; Stals, P. J. M.; Mes, T.; Paffen, T. F. E.; Schenning, A. P. H. J.; Palmans, A. R. A.; Meijer, E. W. J. Am. Chem. Soc. 2010, 132, 620-626. (c) Smulders, M. M. J.; Filot, I. A. W.; Leenders, J. M. A.; van der Schoot, P.; Palmans, A. R. A.; Schenning, A. P. H. J.; Meijer, E. W. J. Am. Chem. Soc. 2010, 132, 611-619. Chapter III 92 [HBCs]10 and so on11 — constitute a very interesting family. As previously mentioned, the supramolecular polymerization of these building blocks is triggered by π-π interactions in addition to other non-covalent forces. Moreover, the self-assembly of these molecules is favoured by the introduction of long alkyl chains, which play a twofold role: 1.- ensure a good solubility of the monomeric unit in non-polar solvents, such as heptane or cyclohexane, and 2.- trigger the formation of a preferential helicity in the supramolecular aggregates. In this regard, linear OPEs have attracted much attention, not only for their good supramolecular properties, but also due to the possibility of being used in molecular electronic devices.12 Several examples have been reported using linear achiral OPEs as building blocks for generating supramolecular scaffolds. Most representatives bear long alkyl chains at both edges of the OPE building blocks, or even in all the aromatic rings of the OPE unit13 however, scarce examples are found to be chiral.14 Herein we describe the complex aggregation pathway of a novel asymmetrical OPE endowed with a short chiral moiety at one end and a terminal alkyne group at the opposite terminus. The supramolecular forces involved in the supramolecular polymerization process —mainly hydrogen bonding and π-π interactions— of the OPE monomers lead to a complex aggregation pathway, where a thermodynamic or a kinetically trapped aggregate, showing opposite supramolecular chirality, can selectively be obtained. Moreover, microscopy studies revealed the different morphology of the chiral aggregates. To this end, a building block based on an OPE trimer was prepared bearing at one edge the anilide of the (S)-α-methoxy-α-phenylacetic acid (MPA), while at the opposite edge the alkyne remains unaltered (1, Figure 1a). Next, aggregation studies were carried out for 1. This monomer is not soluble in pristine methylcyclohexane (MCH), thus a small amount of other solvents —such as dichloromethane (DCM) or chloroform (CHCl3)— is necessary to solubilize the monomer. ECD and UV-Vis studies in different MCH:DCM solvent mixtures confirmed the formation of a chiral supramolecular aggregate at low DCM ratios —up to 4%—, achieving the best conditions for obtaining the chiral aggregate (AggI) at a 99% MCH:1% DCM solvent mixture. 9 (a) Hifsudheen, M.; Mishra, R. K.; Vedhanarayanan, B.; Praveen, V. K.; Ajayaghosh, A. Angew. Chem. Int. Ed. 2017, 56, 1263412638. (b) Buendía, J.; García, F.; Yélamos, B.; Sánchez, L. Chem. Commun. 2016, 52, 8830-8833. (c) Buendía, J.; Calbo, J.; García, F.; Aragó, J.; Viruela, P. M.; Ortí, E.; Sánchez, L. Chem.Commun. 2016, 52, 6907-6910. (d) García, F.; Korevaar, P. A.; Verlee, A.; Meijer, E. W.; Palmans, A. R. A.; Sánchez, L. Chem.Commun. 2013, 49, 8674-8676. (e) Aparicio, F.; García, F.; Fernández, G.; Matesanz, E.; Sánchez, L. Chem. Eur. J. 2011, 17, 2769-2776. (f) Fernández, G.; García, F.; Aparicio, F.; Matesanz, E.; Sánchez, L. Chem. Commun. 2009, 7155-7157. (g) García, F.; Fernández, G.; Sánchez, L. Chem. Eur. J. 2009, 15, 6740-6747. 10 (a) Zhang, W.; Jin, W.; Fukushima, T.; Ishii, N.; Aida, T. J. Am. Chem. Soc. 2013, 135, 114-117. (b) Zhang, W.; Jin, W.; Fukushima, T.; Ishii, N.; Aida, T. Angew. Chem. Int. Ed. 2009, 48, 4747-4750. (c) Jin, W.; Fukushima, T.; Niki, M.; Kosaka, A.; Ishii, N.; Aida, T. Proc. Natl. Acad. Sci., U.S.A. 2005, 102, 10801-10806. 11 Dorca, Y.; Greciano, E. E.; Valera, J. S.; Gómez, R.; Sánchez, L. Chem. Eur. J. 2019, 25, 5848-5864. 12 (a) Jagtap, S. P.; Mukhopadhyay, S.; Coropceanu, V.; Brizius, G. L.; Brédas, J.-L.; Collard, D. M. J. Am. Chem. Soc. 2012, 134, 7176-7185. (b) Xiao, X.; Nagahara, L. A.; Rawlett, A. M.; Tao, N. J. Am. Chem. Soc. 2005, 127, 9235-9240. 13 (a) Philips, D. S.; Kartha, K. K.; Politi, A. T.; Krügger, T.; Albuquerque, R. Q.; Fernández, G. Angew. Chem. Int. Ed. 2019, 58, 4732-4736. (b) Albert, S. K.; Golla, M.; Thelu, H. V. P.; Krishnan, N.; Varghese, R. Chem. Eur. J. 2017, 23, 8348-8352. (c) Rudolph, T.; Allampally, N. K.; Fernández, G.; Schacher, F. H. Chem. Eur. J. 2014, 20, 13871-13875. (d) Mayoral, M. J.; Rest, C.; Schellheimer, J.; Stepanenko, V.; Fernández, G. Chem. Eur. J. 2012, 18, 15607-15611. 14 (a) Langenstroer, A.; Kartha, K. K.; Dorca, Y.; Dröste, J.; Stepanenko, V.; Albuquerque, R. Q.; Hansen, M. R.; Sanchez, L.: Fernández, G. J. Am. Chem. Soc. 2019, 141, 5192-5200. (b) Hifsudheen, M.; Mishra, R. K.; Vedhanarayanan, B.; Praveen, V. K.; Ajayaghosh, A. Angew. Chem. Int. Ed. 2017, 56, 12634-12638. Complex Supramolecular Polymerization Pathway of an Asymmetrical and Rigid OPE Derivative: The Role of the Supramolecular Polymerization Degree in the Aggregate Morphology 93 Increasing the amount of DCM results in a null ECD spectrum, whereas a magnification is observed in the UV-Vis trace, associated to the molecularly dissolved monomer state (Figure 1b, c). Figure 1. (a) Chemical structure of compound 1. ECD spectra and UV-Vis traces of the disassembly process for AggI upon increasing the polarity (b, c) of the solvent mixture —99% MCH:1% DCM to 96% MCH:4% DCM and 100% DCM—. ECD and UV measurements were performed in a 1mm quartz cuvette for [1] = 100 µM. Similar results are obtained when a MCH:DCM (99:1) solution of 1, is heated up to 353 K (Figure 2a, b). Increasing the temperature of the polymer solution produces the disassembly of the aggregate due to the breaking of all the supramolecular interactions —mainly hydrogen bonds and π-π interactions—, resulting into a null CD. This CD vanishing is concomitant with a magnification in the UV-Vis spectra, related to the molecularly dissolved state (Figure 2a, b). Time dependent CD studies for AggI —[1] = 100 µM in 99% MCH:1% DCM— showed the formation of a metastable aggregate (Figure 2c, d). The CD trace obtained for a freshly prepared sample of AggI becomes null with time, indicating the formation of a kinetic aggregate that evolves towards another species, as also observed by UV-Vis spectroscopy. 250 300 350 400 450 -20 0 20 Wavelength [nm] CD [mdeg] 99% MCH:1% DCM 98% MCH:2% DCM 97% MCH:3% DCM 96% MCH:4% DCM 100% DCM N π Conjugated OPE O O H a) b) Supramolecular Aggregate Molecularly Dissolved 250 300 350 400 450 0.0 0.5 1.0 1.5 Wavelength [nm] Abs c) Molecularly Dissolved Supramolecular Aggregate Increasing Polarity Chiral Moiety (Agg I ) (Agg I ) (S)-1 (S)-1 (S)-1 H Chapter III 94 Figure 2. (a, b) ECD spectra and UV-Vis traces of the disassembly process for AggI by increasing the temperature. Time dependent (c) ECD and (d) UV-Vis for AggI. ECD and UV measurements were performed in a 1mm quartz cuvette for [1] = 100 µM. In order to study the aggregation mechanism, a freshly prepared solution of AggI —[1] = 100 µM in 99% MCH:1% DCM— was heated up to 353 K and slowly cooled down to 273 K at 1 K·min-1. At 353 K AggI is disassembled (molecularly dissolved) and cooling to 293 K produces no changes in the CD and UV-Vis spectra but, once reached 273 K, a novel aggregate is formed (Figure 3a, b). Interestingly, this aggregate, AggII, shows opposite chirality when compared to AggI and it was found to be stable over time at room temperature —thermodynamic aggregate— (see Experimental Section Chapter III, Figure S1). The same thermal study was performed for other MCH:DCM (99:1) solutions of 1 (AggI) at different concentrations —[1] = 80 µM and 60 µM—. By plotting the degree of aggregation (αagg) at λ = 274 nm versus the temperature, an isodesmic supramolecular polymerization mechanism is observed (Figure 3c).15 The difference between the disassembly (heating curves) and the assembly (cooling curves) processes (thermal hysteresis) is indicative of a complex supramolecular polymerization mechanism, due to the presence of a kinetic (AggI) and a thermodynamic (AggII) aggregate. 15 Smulders, M. M. J.; Nieuwenhuizen, M. M. L.; de Greef, T. F. A.; van der Schoot, P.; Schenning, A. P. H. J.; Meijer, E. W. Chem. Eur. J. 2010, 16, 362-367. 250 300 350 400 450 -20 0 20 Wavelength [nm] CD [mdeg] Agg I after 3 days Agg I 250 300 350 400 450 -20 -10 0 10 20 Wavelength [nm] CD [mdeg] Increasing Temperature 293 K 353 K a) 250 300 350 400 450 0.0 0.5 1.0 Wavelength [nm] Abs b) 293 K 353 K 250 300 350 400 450 0.0 0.2 0.4 0.6 0.8 Wavelength [nm] Abs c) d) Complex Supramolecular Polymerization Pathway of an Asymmetrical and Rigid OPE Derivative: The Role of the Supramolecular Polymerization Degree in the Aggregate Morphology 95 Figure 3. (a) ECD and (b) UV-Vis cooling from 353 K to 273 K. [1] = 100 µM in MCH:DCM (99:1). (c) Thermal analysis of the aggregation behaviour for [1] = 60, 80 and 100 mM in MCH:DCM (99:1) —solid line: heating cycle; dashed line: cooling cycle—. ECD and UV measurements were performed in a 1mm quartz cuvette. Next, the morphology of the different aggregates (AggI and AggII) was analyzed by AFM. Thus, a solution of 1 ([1] = 100 µM, 99% MCH:1% DCM) was spin coated onto HOPG before (AggI) and after (AggII) the thermal treatment. AFM studies revealed the different morphology of the two aggregates, which is also indicative of their different stability. The AFM images obtained for the kinetic aggregate —AggI— show the presence of large sheet-like nanomaterials. The arrangement of these structures can be explained by the formation of short oligomers of 1 —AggI—, where the absence of a macromolecular helix, in combination with a large hydrophobic surface, produced the transformation from the in-plane aggregation towards extended and slightly twisted sheet-like nanostructures (Figure 4a). Moreover, these aggregates can evolve generating more complex brick-like nanostructures. Theoretical ECD studies —TD-DFT(CAM-B3LYP)/3-21G—16 were carried out on a short supramolecular oligomer of 1 (octamer) to explain the chirality of these twisted sheets (see Experimental Section Chapter III for detailed information). This oligomer was built using a rotation angle within the adjacent monomeric units (Θ) of ca. 11º, a distance (dπ-π) between OPE units of 3.1 Å and a N-H···O=C distance (dH) of 2.0 Å, which produces a columnar 16 (a) Runge, E.; Gross, E. K. U. Phys. Rev. Lett. 1984, 52, 997-1000. (b) Yanai, Y.; Tew, D. P.; Handy, N. C. Chem. Phys. Lett. 2005, 393, 51-57. (c) Binkley, J. S.; Pople, J. A.; Hehre, W. J. J. Am. Chem. Soc. 1980, 102, 939-947. 280 290 300 0.0 0.5 1.0 T/ K α agg at 274 nm 60 µM 250 300 350 400 450 -50 0 50 Wavelength [nm] CD [mdeg] 353 K Agg I (293 K) cooling Agg II (273 K) 250 300 350 400 450 0.0 0.5 1.0 Wavelength [nm] Abs 280 290 300 T/ K 100 µM 280 290 300 T/ K 80 µM 300 K 283 K 301 K 290 K 304 K 296 K b) a) c) Supramolecular Triangular Tessellation Produced by the Self-Assembly of Chiral Helical Oligomers Obtained from OPE Derivatives 103 Supramolecular interactions are found in nature in hierarchically structured helical materials, such as DNA, collagen, chitin or cellulose, whose supramolecular helical structures are directly related to the function developed by the biomaterial.1 These findings have inspired the scientific community to pursuit novel helical structures, made up by the non-covalent bonding of monomeric species, to explore the generation of innovative materials with new functionalities.2-10 Notwithstanding, creating sophisticated scaffolds inspired in biomolecules remains as a challenging task, since the phenomena observed at the molecular level has to be conveyed to larger scales (2D structures). In case of supramolecular helical polymers, the chiral information of the monomeric unit has to be transferred into the supramolecular assemblies and finally into the macroscopic superstructures by a self-assembly process.11,12 However, this ideal aggregation process can be altered by the presence of kinetic effects, which may lead to the formation of complex aggregation pathways.13 In this line, our group reported the complex aggregation pathway of an asymmetrical OPE [oligo(phenyleneethynylene)] bearing a short chiral moiety on one of the rims (Figure 1).14 It was found that by controlling the experimental conditions of the supramolecular polymerization process, it is possible to selectively obtain either a kinetic or a thermodynamic aggregate, with opposite axial chirality and different polymer length. Thus, by activation of the kinetic process (off-pathway, AggI) P twisted oligomers are produced —which converge into sheet-like nanostructures—, whereas activation of the thermodynamic conditions (on-pathway, AggII) results in the formation of M type long helical aggregates. These studies revealed that AggI is a metastable state that disaggregates over time; nevertheless, we succeed in the preparation of the kinetically trapped aggregate (off pathway) by modifying the polarity of the solvent (i.e., addition of a small amount of toluene). In this work, besides studying the supramolecular polymerization mechanism of the OPE derivative, we also analyzed in great detail the 3D-structure of the supramolecular aggregates. 1 Chung, W.-J.; Oh, J.-W.; Kwak, K.; Lee, B. Y.; Meyer, J.; Wang, E.; Hexemer, A.; Lee, S.-W. Nature 2011, 478, 364-368. 2 Morgese, G.; de Waal, B.F.M.; Varela-Aramburu, S.; Palmans, A. R. A.; Albertazzi, L.; Meijer, E. W. Angew. Chem. Int. Ed. 2020, 21, 17229-17233. 3 Salikolimi, K.; Praveen, V. K.; Sudhakar, A. A.; Yamada, K.; Horimoto, N. N.; Ishida, Y. Nat. Commun. 2020, 11, 2311. 4 Dumele, O.; Chen, J.; Passarelli, J. V.; Stupp, S. I. Adv. Mater. 2020, 1907247. 5 Goor, O. J. G. M.; Hendrikse, S. I. S.; Dankers, P. Y. W.; Meijer, E. W. Chem. Soc. Rev. 2017, 46, 6621-6637. 6 Yashima, E.; Ousaka, N.; Taura, D.; Shimomura, K.; Ikai, T.; Maeda, K. Chem Rev. 2016, 116, 13752-13990. 7 Leiras, S.; Freire, F.; Quiñoá, E; Riguera, R. Chem. Sci. 2015, 6, 246-253. 8 Korevaar, P. A.; de Greef, T. F. A.; Meijer, E. W. Chem. Mater. 2014, 26, 576-586. 9 Aida, T.; Meijer, E. W.; Stupp, S. I. Science 2012, 335, 813-817. 10 Whitesides, G. M.; Grzybowski, B. Science 2002, 295, 2418-2421. 11 Greciano, E. E.; Rodríguez, R.; Maeda, K.; Sánchez, L. Chem. Commun. 2020, 56, 2244-2247. 12 Dorca, Y.; Greciano, E. E.; Valera, J. S.; Gómez, R. Sánchez, L. Chem. Eur. J. 2019, 25, 5848-5864. 13 (a) Wehner, M.; Würthner, F. Nat. Rev. Chem. 2020, 4, 38-53. (b) Matern, J.; Dorca, Y.; Sánchez, L.; Fernández, G. Angew. Chem. Int. Ed. 2019, 58, 16730-16740. 14 See Chapter III. Chapter IV 104 Figure 1. Conceptual representation of the pathway complexity in asymmetrical OPEs. In literature it is found that supramolecular polymers can lead to the formation of large hierarchical structures, which produce materials with different morphologies.15 An example of this is the formation of non-covalent 2D structures displaying regular patterns, such as Archimedean or Kagomé tiling scaffolds.16 Usually these intriguing structures are produced by the aggregation of highly symmetrical molecules bearing long alkyl chains or from the selfassembly of metallosupramolecular structures.17 For instance, Sugiyasu et al.18 have recently reported a porphyrinato zinc derivative that forms a 1D supramolecular polymer (SP) that, depending on the concentration employed and the interactions established between monomers, can evolve into a 2D nanosheet or produce more complex Archimedean spirals. Encouraged by these results, we decide to explore the effect of the introduction of a long alkyl chain in an asymmetrical OPE, analyzing not only the changes in the morphology of the aggregate but also variations in the supramolecular polymerization mechanism. To this end, a π-conjugated chiral OPE trimer was designed, introducing at one of the OPE edges a chiral moiety derived from the decyl-(L)-alaninate, and keeping the alkyne unaltered at the other end [(L)-1] (Figure 2a). This design ensures the stabilization of the aggregate by means of π-π interactions and hydrogen bonding, whereas the dodecyl alkyl chain promotes the solubility in low-polar solvents, as well as the chain-to-chain interdigitation. Monomer (L)-1 was synthesized according to common organic synthetic procedures (see Experimental Section Chapter IV) and aggregation studies were carried out in 15 (a) Zeng, X.; Khan, S. B.; Mahmooda, A.; Lee, S.-L. Nanoscale 2020, 12, 15072-15080. (b) Danila, I.; Pop, F.; Escudero, C.; Feldborg, L. N.; Puigmartí-Luis, J.; Riobé, F.; Avarvari, N.; Amabilino, D. B. Chem. Commun. 2012, 48, 4552-4554. 16 (a) Furukawa, S.; Uji-i, H.; Tahara, K.; Ichikawa, T.; Sonoda, M.; De Schryver, F. C.; Tobe, Y.; De Feyter, S. J. Am. Chem. Soc. 2006, 128, 3502-3503. (b) Stepanenko, V.; Kandanelli, R.; Uemura, S.; Würthner, F.; Fernández, G. Chem. Sci. 2015, 6, 58535858. (c) Chen, T.; Chen, Q.; Zhang, X.; Wang, D.; Wan, L.-J. J. Am. Chem. Soc. 2010, 132, 5598-5599. (d) Mo, Y.-P.; Liu, X.-H.; Wang, D. ACS Nano 2017, 11, 11694-11700. (e) Fujita, D.; Ueda, Y.; Sato, S.; Mizuno, N.; Kumasaka, T.; Fujita, M. Selfassembly of Tetravalent Goldberg Polyhedral From 144 Small Components. Nature 2016, 540, 563-566. 17 Zhang, Z.; Li, Y.; Son, B.; Zhang, Y.; Jiang, X.; Wang, M.; Trumbleson, R.; Liu, C.; Wang, P.; Hao, X.-Q.; Rojas, T.; Ngo, A. T.; Sessler, J. L.; Newkome, G. R.; Hla, S. W.; Li, X. Nat. Chem. 2020, 12, 468-474. 18 C Sasaki, N.; Mabesoone, M. F. J.; Kikkawa, J.; Fukui, T.; Shioya, N.; Shimoaka, T.; Hasegawa, T.; Takagi, H.; Haruki, R.; Shimizu, N.; Adachi, S.-I.; Meijer, E. W.; Takeuchi, M.; Sugiyasu, K. Nat Commun. 2020, 11, 3578. Supramolecular Triangular Tessellation Produced by the Self-Assembly of Chiral Helical Oligomers Obtained from OPE Derivatives 105 methylclyclohexane (MCH) —[(L)-1] = 147 µM—. First, variable temperature CD (VT-CD) measurements were performed by slowly cooling (10 K·min-1) the (L)-1 solution from a molecularly dissolved state —353 K to 293 K—, revealing the formation of a chiral aggregate when the solution temperature reaches 293 K (negative exciton band centered at 286 nm, CD286 < 0; Figure 2b). Additionally, variable temperature UV-Vis (VT-UV-Vis) studies registered the formation of a novel band at ca. 286 nm (Figure 2b) for 293 K, coincident with the UV band observed for other long helical OPE aggregates.14 In order to gain insight into the supramolecular polymerization mechanism that rules the formation of the helical structure, VT-CD experiments —T = 353 K to 293 K, at 1 K·min-1— were carried out for (L)-1 in MCH at different concentrations —[(L)-1] = 147 µM, 166 µM and 184 µM—. Registering the variation of the degree of aggregation (αagg) at λ = 280 nm versus the temperature, reveals that the self-assembly of (L)-1 follows a cooperative mechanism (Figure 2c). It should be pointed out that the elongation temperatures obtained for the heating (Te) and cooling (Te’) processes differ. This thermal hysteresis between the heating and cooling cycles during temperature dependent measurements indicates the presence of kinetically trapped states in the cooling cycle, since the structural changes required in the molecules for an effective supramolecular polymerization are too slow. 13a,14,19 13 (a) Wehner, M.; Würthner, F. Nat. Rev. Chem. 2020, 4, 38-53. 14 See Chapter III. 19 Greciano, E. E.; Sánchez, L. Chem. Eur. J. 2016, 22, 13724-13730. 293 313 T (K) α agg at 295 nm 184 µM 293 313 T (K) 166 µM 293 313 T (K) 147 µM 250 300 350 400 -50 0 50 Wavelength [nm] CD [mdeg] 250 300 350 400 0.0 0.5 1.0 1.5 Wavelength [nm] Abs HN O O O 353 K a) b) c) (L)-1 303 K Monomeric State Aggregated State 293 K 293 K 303 K 353 K 318 K 300 K317 K 299 K 318 K 301 K Chapter IV 106 Figure 2. (a) Chemical structure for (L)-1. (b) VT-CD and VT-UV-Vis cooling 10 K·min-1 from 353 K to 293 K —[(L)-1] = 147 µM —. (c) Heating and cooling curves (dashed and solid lines, respectively) ––1 K·min-1; 293 K to 393 K and reverse— recorded for different concentrations of 1. Experiments performed in a 1 mm quartz cuvette. Fitting the obtained cooling curves to the mass balance (MB) model20 allows the calculation of the different thermodynamic parameters. The enthalpy of elongation (∆He = - 149.9 kJ·mol-1), the entropy of elongation (∆Se = -424.4 J·mol-1 K-1) and the nucleation penalty (∆Hnp = -29.3 kJ·mol-1) extracted from this fitting are used to determine the nucleation factor (σ = 6.0·10-6; calculated at 293 K), which quantifies the cooperativity of the supramolecular polymerization process —the smaller the σ-value becomes, the higher is the cooperativity in the system; this indicates that if σ = 1 the self-assembly follows an isodesmic mechanism—. The value obtained for the nucleation factor of (L)-1 in MCH approximates the ones obtained for other well-known family of building blocks, such as the symmetrically substituted BTAs (benzene-1,3,5-tricarboxiamides).2110 Next, the helical structure of the supramolecular polymer and the morphology of the aggregate were analyzed by theoretical ECD studies and AFM measurements. In a previous work it was found that theoretical ECD calculations —TD-DFT(CAM-B3LYP)/3-21G— on a supramolecular oligomer of an unsubstituted OPE (dodecamer) leads to a bisignate (-/+), which corresponds to a M orientation of the SP.14 Herein, the same bisignated (-/+) ECD trace is obtained for (L)-1 in MCH at 293K —[(L)-1 = 147 µM], indicating that the obtained SP adopts a M rotation sense. To confirm the M orientation of the supramolecular polymer, AFM measurements were carried out. A solution of the (L)-1 in MCH (368 µM) was drop casted into a HOPG substrate and submitted to AFM studies, generating high-resolution AFM images. By analyzing the different AFM images obtained it is possible to observe the formation of isolated helical polymer chains and extract different helical parameters from them, such as the helix width — ca., 2.6 nm—, the packing angle —ca., 33°—, the helical pitch —ca., 15 nm— and the M orientation of the supramolecular helix (Figure 3a), coincident with the one suggested by ECD calculations.14 By using these experimental data an approximated columnar M oriented SP was built, possessing a rotation angle within the adjacent monomeric units (Θ) of ca. 8°, a distance between OPE units (dπ-π) of 3.3 Å and a N-H···O=C distance (dH) of 1.7 Å. The resulting 3D-model comprises the π-π interactions and the hydrogen bonds necessary to form the SP (Figure 3a). Remarkably, during the AFM studies a triangular shaped lattice, which appears in several regions of the AFM substrate, is also observed (Figure 3f). Some areas of the HOPG substrate show a complete triangular shaped lattice, while in other regions of the substrate this triangular lattice is partially generated (see Experimental Section Chapter IV, Figure S10b). 14 See Chapter III. 20 ten Eikelder, H. M. M.; Markvoort, A. J.; de Greef, T. F. A.; Hilbers, P. J. A. J. Phys. Chem. B 2012, 116, 5291-5301. 21 Kulkarni, C.; Meijer, E. W.; Palmans, A. R. A. Acc. Chem. Res. 2017, 50, 1928-1936. Supramolecular Triangular Tessellation Produced by the Self-Assembly of Chiral Helical Oligomers Obtained from OPE Derivatives 107 These results may indicate a crystallization process during the drop casting and solvent evaporation of the sample, where short oligomers of (L)-1 self-assemble creating this triangular lattice. The triangles observed in the different AFM images show a regular structure with a side length of ca. 65 nm and a height of around 1 nm (Figure 3f). This thickness of the triangular tessellation (1 nm) indicates that each polygon should be composed by short oligomers constructed from the self-assembly of only four monomers. A closer look to these regular structures reveals a honeycomb-like aggregate made up by regular hexagons (Figure 3e). These hexagonal gaps found within the triangles present an internal diameter of ca. 15.4 nm and a side length of ca. 7.8 nm (Figure 3d). This side length of the hexagon is coincident with two (L)-1 oligomers (monomer length ca. 3.7 nm) non-covalently connected and interacting by interdigitation of the alkyl chains. Figure 3. (a) 3D model and AFM image depicting the single-stranded helix obtained from the self-assembly of 1. (b)-(f) Proposed hierarchical process for the crystallization of the short oligomers (b) to yield the triangular tessellation (f). The AFM images show the intermediate honeycomb-like scaffold (e) as well as the final geometric pattern (f). To explain this large hierarchical structure, the asymmetric structure of (L)-1 has to be taken into account, as within this molecule there are two different structural motifs —one rigid (OPE) and one flexible (long alkyl chain)— (Figure 3). Oligomerization of (L)-1 orients all the OPE units at one side of the aggregate, while the alkyl chains stabilize the aggregate due to weak London forces at the other end (Figure 3b). During the drop-casting and solvent evaporation, short oligomers interact through the interdigitation of alkyl chains, which 60º 33º 15 nm Helix Formation M helix 3.7 nm 2.6 nm 2.6 nm 15 nm Supramolecular Polymer 7.8 nm 15.5 nm 60º 65 nm 1 nm Oligomer Triangular Planar Triangular Tessellation a) b) Monomer Honeycomb Scaffold c) d) e) Hexagonal Gap e) f) Oligomers Aggregation Chapter IV 108 generates one side of the hexagonal structure. These dimers interact head to head —OPE moieties— through electron poor terminal alkyne-π interactions2211generating an unexpected geometric pattern, in this case a triangular planar structure (Figure 3c) which, by expansion of this structure, produces a regular hexagon (Figure 3d). This triangular planar structure can continuously grow until reach a honeycomb regular structure made by five fused rings (Figure 3e), or interact with another planar triangular structure, producing a linear tetramer of short oligomers with a side length of 15.4 nm. This structure is extended along the HOPG substrate to form the final triangle lattice (Figure 3f). The defects found in some areas of the HOPG substrate where this triangle lattice is observed are due to the fast solvent evaporation, avoiding the tessellation of the AFM substrate. 22 Li, Q.; Han, C.; Horton, S. R.; Fuentes-Cabrera,M.; Sumpter, B. G.; Lu, W.; Bernholc, J.; Maksymovych, P.; Pan, M. ACS Nano 2012, 6, 566-572. Matryoshka-like Helical Polymers: When Supramolecular and Covalent Helical Polymers are Mixed Up Chapter V 111 Chapter V. Matryoshka-like Helical Polymers: When Supramolecular and Covalent Helical Polymers are Mixed Up Abstract: Supramolecular and covalent helical polymers share multiple structural features such as chiral amplification, helix inversion, Sergeants and Soldiers or Majority Rules among others. These properties are determined by the axial helical structure presented in both materials. Herein, a novel material obtained through the combination of information from both fields, covalent [poly(acetylene) (PA)] and supramolecular [oligo(phenyleneethynylene) (OPE)] helical polymers, is presented. To achieve this goal, the polyacetylene has to adopt a dihedral angle between conjugated double bonds (ω1) larger than 165º. In such cases, the tilting degree (Θ) between OPE units is 11º, similar to the one observed in supramolecular helical arrays of these molecules. Polymerization of oligo[(pphenyleneethynylene)n]phenylacetylene monomers (n = 1, 2) bearing the (L)-decyl alaninate as pendant group yielded the desired scaffolds. The corresponding polymers adopt a stretched almost planar polyene helix, where the OPE units are arranged describing a helical structure. As a result, a novel multi-helical material was prepared —the matryoshka helix—, where the ECD spectra is dominated by the OPE axial array. Chapter V 118 Interestingly, when poly-2 is dissolved in low-polar solvents such as CCl4 or Toluene, a yellow to red color change is produced, indicative of a helical stretching. UV-Vis studies confirm the elongation of the polyene chain due to a 100 nm bathochromic shift of the polyene band, from 425 (CHCl3) to 525 nm (Toluene) (Figure 4c). Moreover, the solubility of the polymer decreases in these solvents due to the presence of a highly stretched, almost planar, helix. ECD studies of poly-2 in these solvents revealed the disappearance of the classical ECD trace with three alternating Cotton effects, depicting a large bisignated (-/+) signal centered at 323 nm (Figure 4d). Interestingly, the ECD trace obtained for poly-2 in CCl4 or Toluene is coincident with the CD signature of an OPE supramolecular helix, where the -/+ sign of the CD trace is indicative of an M helical array of the OPE units within the POPEPA scaffold.49,50 8 Figure 4. (a) Chemical structure for poly-2 and ECD spectra recorded in different solvents compared to the simulated ECD (FWHM = 20 nm). (b) High-resolution AFM images and 3D-model of poly-2 in polar solvents. (c) Comparison of the UV-Vis spectra obtained for poly-2 in CHCl3 and Toluene. (d) ECD spectra of poly-2 in CCl4 and Toluene. 49 See Chapter III. 50 See Chapter IV. 300 400 500 600 0.0 0.5 1.0 1.5 Wavelength [nm] Abs CHCl3 Tolue n e 300 400 500 -20 -10 0 10 20 Wavelength [nm] CD [mdeg] THF CHCl 3 DCM DMF Calculated 300 400 500 -20 0 20 Wavelength [nm] CD [mdeg] Tol u e n e CCl 4 9 poly-2 pendant “anticlockwise" backbone "clockwise" M ext /P int 80º a) b) c) d) 4.6 nm n OPE helix: M helix helix 3 and heilx 4 O HN O O H Matryoshka-like Helical Polymers: When Supramolecular and Covalent Helical Polymers are Mixed Up 119 By using this information, a molecular model was built up for poly-2 in low polar solvents using a large value for ω1 (ca., 175º), which corresponds to an almost planar structure (Figure 5). By looking at this 3D-model, it is possible to visualize the two coaxial helices of a PPA; the first one described by the polyene backbone —Pint helix 1 (ω 1 = + 175º)— and the second one by the pendant groups —Mext helix 2—. As expected, the presence of a cis-transoidal polyene skeleton makes that the internal and the external helices rotate in opposite directions (Pint/Mext). In addition to these two coaxial helices, another two helices can be observed in this 3D-model structure. These latter helices are described by the OPE units used as spacers between the chiral pendant groups and the polyene backbone (Θ = 11º) —helix 3 and 4— and show a helical sense coincident with that described by the external helix —M helix—. Interestingly although this structure is formed by four helices —P1/M2/M3/M4— the resulting ECD spectrum is governed by the helical array of the OPE units and the chiroptical information of the polyene chain becomes negligible in the ECD spectrum [ECD null at ca. 525 nm but UVVis active] (Figure 4c, d). Figure 5. 3D-model for poly-2 adopting a matryoshka-like helix. poly-2 Matryoshka-like Helix P int helix 1 M ext helix 2 P int helix 1 M helix OPE helix 3 M helix OPE helix 4 Chapter V 120 Among the discovery of a matryoshka-like helical material, where four different helices coexist within the same material, another important finding was done during these studies. It was demonstrated that a supramolecular helix, such as an OPE supramolecular helical polymer can be stabilized within a covalent helical polymer. To show the versatility and robustness of our hypothesis and results, similar studies to those above were performed for poly-3, which has an extra OPE unit in the spacer (n = 2). To this end, solutions of poly-3 ([poly-3] = 0.72 mM) were prepared in different solvents such as CCl4, CHCl3, THF, Toluene, ODCB, DCM or 1,2-DCE (Figure 6a and see Experimental Section Chapter V, Figure S7a and b). All these poly-3 solutions showed a deep red color and a poor solubility, indicative of the presence of a highly stretched helix with a large hydrophobic surface and a high aggregation tendency.25 UV-Vis studies of these poly-3 solutions corroborate the presence of a stretched helix due to the presence of the polyene band at ca. 565 nm (Figure 6c and see Experimental Section Chapter V, Figure S7d). 9 In addition, ECD studies for poly-3 do not show a Cotton band in the polyene region in all the tested solvents (Figure 6b and see Figure S7a and b), but a strong bisignated signal at shorter wavelengths (ca., 315 nm). The obtained CD trace resembles the one recorded for the supramolecular polymer helical arrangement (SP-3) of the monomer m-3 (Figure 6d).50 The bathochromic shift of the OPE band, observed in the CD spectrum when poly-3 is compared to SP-3, is ascribed to the conjugation with the polyene backbone. These data indicate that poly-3 describes a matryoshka-like helix, where two novel helices show up due to the chiral arrangement of the OPE units. In this polymer four helical structures coexist; the internal helix, described by the polyene backbone (helix 1), the external helix, described by the pendant groups (helix 2), and the helical structures described by the OPE (n = 2) units employed as spacers (helix 3 and helix 4). These helices are interconnected and, by knowing the orientation of one of them it is possible to extract the orientation of the other helices (Figure 6e). Therefore, if poly-3 shows a P orientation for helices 3 and 4 in DCM [CD (+/-)], then helix 2 rotates in the same P direction, whereas the internal helix 1 has to rotate in the opposite sense (M), according to the cis-transoidal configuration adopted by the polyene. Computational studies [TD-DFT(CAM-B3LYP)/3-21G]57-59 have been performed on a Mext helix (with 20 monomer units) for poly-3 —cis-transoidal skeleton (ω1 = 170º)— and, to reduce the computational demands, the chiral moiety has been removed from the pendants, keeping only the achiral spacer. This model simplification allowed us to create a 3D structure describing half a helix turn, necessary to observe the external helices described by the OPEs (helix 3 and helix 4). The calculated ECD spectrum is in full agreement with the experimental 25 Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire F. J. Am. Chem. Soc. 2016, 138, 9620-9628. 50 See Chapter IV. 57 Runge, E.; Gross, E. K. U. Density-Functional Theory for Time-Dependent Systems. Phys. Rev. Lett. 1984, 52, 997-1000. 58 Yanai, Y.; Tew, D. P.; Handy, N. C. Chem. Phys. Lett. 2005, 393, 51-57. 59 Binkley, J. S.; Pople, J. A.; Hehre, W. J. J. Am. Chem. Soc. 1980, 102, 939-947. Matryoshka-like Helical Polymers: When Supramolecular and Covalent Helical Polymers are Mixed Up 121 one obtained for DCM (Figure 6b), indicating that the proposed model is a good approximation to the cis-transoidal and highly stretched structure adopted in this solvent. Figure 6. (a) Chemical structure for poly-3. (b) ECD spectra of poly-3 in DCM and THF and comparison with the theoretically obtained ECD. Full Width at Half-Maximum (FWHM) equals 20 nm. (c) UV-Vis spectrum of poly-3 in DCM. (d) Comparison of the ECD spectra obtained for poly-3 and SP-3. (e) 3D-model for poly-3 describing a matryoshka-like helix. Moreover, CD studies indicate that the helical sense described by the OPE array in poly-3 depends on the dielectric constant of the solvent (ε-1)/(ε+1). Therefore, poly-3 is a dynamic helical polymer that can act as a chiroptical switch triggered by subtle variations of the polarity. On the one hand solvents with (ε-1)/(ε+1) > 0.8 (i.e., ODCB, DCM or 1,2-DCE) show a bisignated (+/-) CD signature, that corresponds to a P helix of the OPE array (helix 3 and 4) — M1/P2/P3/P4 matryoshka helix—. On the other hand, solvents with (ε-1)/(ε+1) < 0.8 (i.e., CCl4, CHCl3, THF or Toluene) produce an M orientation of the OPE helical array (helix 3 and 4) yielding a P1/M2/M3/M4 matryoshka helix (see Experimental Section Chapter V, Figure S7a-c). 400 600 800 0.0 0.5 1.0 Wavelength [nm] Abs 300 400 500 -50 0 50 Wavelength [nm] CD [mdeg] poly-3, THF Supramolecular Polymer, SP-3 vinyl region 300 400 500 -10 0 10 20 Wavelength [nm] CD [mdeg] THF DCM Calculated poly-3 a) b) c) 9 O HN O O n H d) e) poly-3 Matryoshka-like Helix Pint helix 1 Mext helix 2 Pint helix 1 Mhelix OPE helix 3 Mhelix OPE helix 4 Conclusions Conclusions 125 Conclusions The main conclusions obtained in the different chapters are summarized next. Chapter I. Chiral Information Harvesting in Helical Poly(acetylene) Derivatives Using Oligo(p-phenyleneethynylene)s as Spacers Herein, a novel chiral harvesting transmission mechanism has been described in poly(acetylene)s bearing oligo(p-phenylenethynylene)s as rigid spacers that place the chiral pendant group away from the polyene backbone, at a distance around 1.7 nm for poly-2, and 2.4 nm for poly-3. Hence, the disposition of the chiral moiety affects the stacking of the OPE units within the helical structure, inducing a specific positive or negative tilting degree, which is further harvested by the polyene backbone inducing either a P or M internal helix. We believe that these results open new horizons in the development of novel helical structures by combining information from the helical polymers and supramolecular helical polymers fields, which leads to the formation of novel materials with applications in important fields such as asymmetric synthesis, chiral recognition or chiral stationary phases among others. Chapter II. Aromatic Substitution Pattern Effects in Poly-[[oligo(phenylene ethynylene)]phenylacetylene]s: Modulation of the Helical Periphery Without Affecting the Folding of the Main Chain In this chapter it has been demonstrated that while in PPAs the different aromatic substitution pattern affects largely to the elongation of the helical scaffold, in POPEPAs the modifications on the stretching of the polymer backbone are drastically reduced when the size of the achiral rigid OPE (n = 1, 2) spacer is increased. Therefore, for POPEPAS bearing an OPE spacer with n = 1, a variation in the helical elongation is still observed for the different aromatic substituted polymers. However, in the case of n = 2, no variation on the elongation of the internal helix is noticed. The synthesized POPEPAs —derivatized at the ortho-, metaand parapositions of the external aryl group with the anilide of a chiral acid [(S)-MPA]— produce helical scaffolds with resembling internal helix but different external one, although the molecular structure or conformational composition of the chiral group remains unaffected. These studies open a new horizon for helical polymers with potential applications in fields such as chiral recognition, asymmetric synthesis or sensing, among others. By using these systems it is possible to explore the effect that the variations on the helical periphery can have over the efficiency of these smart materials. Conclusions 126 Chapter III. Complex Supramolecular Polymerization Pathway of an Asymmetrical and Rigid OPE Derivative: The Role of the Supramolecular Polymerization Degree in the Aggregate Morphology A complex aggregation pathway was demonstrated for a rigid chiral OPE derivative [(S)-1]. Dissolving this monomer into a MCH:DCM (99:1) solvent mixture results in an isodesmic offpathway aggregation mechanism, which yields to the formation of a metastable aggregate (AggI). In this way, a short P twisted oligomer is obtained and self-assembles producing an inplane aggregation that provides extended and slightly twisted sheets. Heating and cooling this sample (AggI) to 273 K results in an isodesmic on-pathway aggregation mechanism, generating the thermodynamic AggII aggregate. In this case, a supramolecular M helical polymer is obtained where the monomers self-assemble into a columnar helical aggregate. Furthermore, the metastable aggregate (AggI) can be kinetically trapped (isodesmic, offpathway) if the sample preparation conditions are modified —MCH:Tol:DCM (97:2:1)—, observing that the obtained aggregate becomes stable over time. These results constitute a significant example of a complex supramolecular polymerization pathway, where onand off-aggregation pathways are described, being possible to trap the kinetic aggregate by changing the solvent mixture. Moreover, these studies also reveal how the size of the supramolecular aggregate affects the aggregate morphology. Thus, while the formation of short oligomers (off-pathway) produces in-plane aggregation to generate twisted sheets, the formation of large supramolecular helical polymers (on-pathway) provides the formation of columnar helical aggregates. Chapter IV. Supramolecular Triangular Tessellation Produced by the SelfAssembly of Chiral Helical Oligomers Obtained from OPE Derivatives In this project, we have been able to demonstrate the role of the long alkyl chain in the supramolecular polymerization process of asymmetric OPE derivatives. It was previously found that a complex isodesmic pathway governs the supramolecular polymerization of an OPE lacking the alkyl chain. Herein, we have shown how an OPE derivative bearing this structural motif follows a cooperative supramolecular polymerization process, with thermodynamic parameters similar to those found in BTAs. The helical structure of this SP was elucidated by ECD theoretical calculations and AFM studies. Moreover, the use of an asymmetric OPE in combination with two different flexible ends —one rigid (OPE), one bendable (alkyl chain)—, produces the tessellation of the HOPG by second order supramolecular self-assembly of OPE oligomers during the drop casting and solvent evaporation of the sample. As a result, a novel regular triangular lattice is obtained. This work opens a new way in the creation of extended and regular 2D-supramolecular nanostructures based on supramolecular helical polymers or oligomers which can further Conclusions 127 aggregate to form regular 3D structures, similar to those found in other materials such as MOFs or nanomaterials. Chapter V. Matryoshka-like Helical Polymers: When Supramolecular and Covalent Helical Polymers are Mixed Up We have proven that it is possible to stabilize a supramolecular helix embedded within a covalent helical polymer through two different examples —poly-2 and poly-3—. To perform these studies, we have chosen as covalent polymer a poly(acetylene) derivative, while as supramolecular polymer an oligo(p-phenyleneethynylene) has been selected. From previous studies in both fields —covalent and supramolecular polymers— we know that both structures can fit in proper matryoshka helical scaffolds. In this special case —PA/OPE system—, the polyene should adopt an almost planar yet twisted helical structure (i.e., a cis-transoidal helix with ω1 > 165º). This fact makes the pendant groups of the PA, in this case OPE derivatives, display a tilting degree between OPE units (Θ) close to 11º, similar to the one present in OPE supramolecular polymers. Thus, if we are able to induce an ω1 > 165º in the PA, the matryoshka helix can be prepared, stabilizing a SP helix within a covalent helix. A perfect example is poly-2 that bears an OPE with n = 1. This polymer in THF adopts a helical structure with ω1 ca. 165º, which shows a CD signature with three alternating Cotton effects, as a classical PPA helix. On the other hand, in Toluene or CCl4 poly-2 adopts a helical scaffold with ω1 > 170º, which produces a CD signature governed by the axial orientation of the OPE units, instead of being commanded by the helical orientation of the PPA chain. As a result, two novel helices emerge within this helical novel scaffold, where four different helices coexist in the helical material: the two coaxial helices —internal (helix 1) and external (helix 2)— and the two helices described by the OPE axial arrays (helices 3 and 4). These four helices are interconnected and, by identifying the orientation of one of them, it is possible to obtain the helical sense of the others. In this case two scenarios are possible M1/P2/P3/P4 or P1/M2/M3/M4. In the second design, poly-3 always generates a matryoshka-like helix with an axial array of the OPE units and the presence of four helices within a single polymer. These results open a new horizon in helical polymer design, where the stabilization of supramolecular helices within covalent polymers will allow to use these structures in applications that were limited before, due to the difficulty of generate SP polymers in polar solvents. Resumo 134 Para poder comprender o mecanismo de formación dos agregados os polímeros supramoleculares son analizados a través do rexistro dunha medida espectroscópica — Dicroísmo Circular (CD), UV-Vis ou fluorescencia— dependente da temperatura. O sinal espectroscópico obtido a unha lonxitude de onda determinada é normalizado e representado en función da temperatura, obtendo unha curva que permitirá determinar se a polimerización segue un proceso isodésmico ou cooperativo. Para levalo a cabo, a disolución de polímero quécese ata alcanzar unha temperatura na que se asegura a rotura dos enlaces non covalentes, quedando presentes en disolución só os monómeros sen agregar, isto tradúcese nunha linealidade na curva. Este quecemento vai seguido dun arrefriamento controlado que permita a formación do produto termodinámicamente máis favorable, obtendo así a curva de arrefriamento. Neste traballo descríbese o mecanismo de polimerización supramolecular dun oligo(pfenilenoetinileno) asimétrico, no cal un dos extremos está funcionalizado cun monómero derivado do ácido (S)-α-metoxi-α-fenilacético (MPA), mentres que no outro lado o alquino permanece inalterado. Os estudos revelan que cando este monómero se disolve nunha mestura MCH:DCM (99:1) fórmase un agregado metaestable (AggI) que evoluciona co tempo. Imaxes de AFM, en conxunto con cálculos computacionais, revelan que o monómero produce pequenos oligómeros con xiro a dereitas que agregan para dar nano-follas lixeiramente rotadas unhas sobre as outras. Para poder determinar o mecanismo de agregación, tal e como se indicou con anterioridade, o polímero someteuse a un proceso de quecemento/arrefriamento e, a partir da curva de arrefriamento obtida, determinouse que a polimerización que segue é de tipo isodésmica. De xeito curioso, estudos de UV-Vis suxiren a formación dunha nova especie, debido á aparición dunha nova banda de absorción, e medidas de CD revelan a formación dunha nova estrutura (AggII) cun sentido de xiro oposto ó de AggI. O descubrimento deste novo agregado, AggII, foi confirmado mediante AFM en cálculos computacionais, o que desvelou a formación de longas cadeas helicoidais con sentido de xiro á esquerda. Adicionalmente, mediante unha lixeira modificación na polaridade do disolvente — MCH:Tolueno:DCM (97:2:1)—, fomos capaces de illar o agregado metaestable (AggI) e convertelo nun produto termodinámico e estable no tempo durante días. Desta maneira puidemos describir o complexo mecanismo de polimerización supramolecular dun OPE asimétrico. Capítulo IV. Teselado Triangular Supramolecular Producido Mediante o Autoensamblaxe de Oligómeros Helicoidais Quirais Obtidos de Derivados de OPE Estudos feitos con anterioridade revelaron que a introdución de cadeas alquílicas nos bloques de construción dos polímeros supramoleculares favorecen a agregación dos mesmos, ademais de incrementar a solubilidade en disolventes pouco polares. Animados polos Resumo 135 resultados recollidos no Capítulo III e tendo en conta os datos atopados na bibliografía, decidimos estudar o mecanismo de agregación dun OPE asimétrico substituído nun dos dous extremos cun monómero de decil-(L)-alaninato. O monómero disolveuse en MCH e someteuse a un proceso de quecemento/arrefriamento, monitorizado os cambios mediante CD a unha lonxitude de onda fixa, o que revelou que a formación do agregado segue un proceso cooperativo. As curvas de quecemento e arrefriamento obtidas presentan histérese entre elas, o que é indicativo da presenza de estados cinéticamente atrapados no proceso de arrefriamento polo que, ademais da estrutura termodinámicamente máis estable xerada, en disolución tamén haberá pequenos oligómeros. Co fin de poder observar o polímero supramolecular formado depositouse unha mostra do mesmo nun substrato de HOPG (grafito pirolítico altamente ordenado) e analizouse mediante AFM. Mediante esta técnica obtivéronse imaxes de alta resolución que indican que a hélice xira á esquerda, o que está en total acordo co observado mediante CD —onde se obtén un bisignato (-/+)— e cos cálculos computacionais levados a cabo sobre un oligómero de doce unidades monoméricas. Ademais, de forma sorprendente, na mesma placa de HOPG onde se observaron as hélices supramoleculares, rexistráronse tamén zonas nas que aparece un teselado triangular. Este teselado non é regular e nalgúns puntos os triángulos presentan defectos ou non están formados de todo, posiblemente debido o proceso de evaporación da mostra que non permite a perfecta cristalización. Para poder explicar esta intrigante formación débese ter en conta a estrutura do monómero empregado, a cal está constituída por dous motivos de diferente flexibilidade, por un lado o OPE que é totalmente ríxido mentres que no outro atópase a cadea alquílica, a cal se pode pregar con gran facilidade. A partir de estudos computacionais sábese que durante a oligomerización do monómero todas as unidades OPE orientaranse dun lado, mentres que as cadeas alquílicas disporanse no outro para estabilizar o agregado. Así ó depositala mostra e evaporarse o disolvente producirase a interacción entre os pequenos oligómeros xerados no proceso de arrefriamento. A partir dos datos extraídos de AFM sábese que os devanditos oligómeros estarán formados pola unión de catro monómeros. Estes oligómeros interactuarán entre eles a través da cadea alquílica e a través dos OPE mediante interaccións alquino-π, xerando unha estrutura plano triangular. O crecemento desta estrutura plano triangular producirá, mediante interaccións non covalentes, un hexágono que pode continuar medrando ata a formación dunha estrutura composta pola fusión de cinco polígonos regulares e que recorda aos paneis das abellas. Cada unidade de cinco hexágonos describe un triángulo e a repetición desta estrutura leva á formación do teselado triangular observado mediante AFM. Os datos extraídos das imaxes de alta resolución, tales como o espesor ou a lonxitude dos motivos xeométricos, coinciden co modelo proposto para a formación deste entramado. Resumo 136 Capítulo V. Polímeros Helicoidais Tipo Matrioshka: a Mezcla dos Polímeros Supramoleculares e Covalentes Os polímeros supramoleculares e covalentes posúen diversas características comúns, diferenciándose principalmente no tipo de enlaces que manteñen as unidades monoméricas que os conforman xuntas. En ambos os dous casos obsérvanse propiedades como a amplificación da quiralidade, a inversión da helicidade, o efecto Sarxento e Soldado ou o fenómeno da Regra da Maioría. Como se mencionou con anterioridade, coñecer a estrutura secundaria destes polímeros é clave á hora de poder manipular a hélice polimérica. No caso dos polímeros supramoleculares a hélice está definida pola disposición non simétrica dos monómeros, polo que as unidades que conforman o polímero non covalente poden ou non ser quirais. Pola contra nos polímeros helicoidais covalentes (i.e., PPAs) sábese que a estrutura secundaria está conformada por dúas hélices coaxiais, a hélice interna (hélice 1), conformada polos dobres enlaces conxugados do polieno, e a hélice externa (hélice 2), descrita polos “pendant”. Estas hélices poden rotar na mesma dirección, xerando unha estrutura cis-cisoide (ω1 < 90º), ou en sentidos opostos, dando lugar á formación dunha estrutura cis-transoide (ω1 > 90º). Este escenario dáse tamén no caso dos POPEPAs, sen embargo a análise dos modelos tridimensionais para un destes polímero con ω1 > 165º (cis-transoide) revelou que, ademais das dúas hélices clásicas (hélices 1 e 2), existen dúas hélices adicionais descritas polos espazadores (hélices 3 e 4). Isto é debido a que ó aumentar o ángulo da hélice interna (hélice 1) os espazadores derivados de OPE, localizados entre o centro quiral e o polieno, aproxímanse no espazo reducindo así o ángulo de desfase entre eles e describindo unha hélice similar á descrita nun polímero supramolecular. Tendo en conta esta información e os resultados obtidos nos capítulos anteriores, decidimos ir na procura dun novo material que combine ambos polímeros, o covalente e o supramolecular. Para levar a cabo esta idea empregamos o monómero descrito no Capítulo IV, onde demostramos que forma un agregado supramolecular de tipo helicoidal e porque é sabido que os compostos con conexión benzamida inducen a adopción dunha estrutura cis-transoide. Polo tanto sintetizamos dous polímeros co espazador de oligo(p-fenilenoetinileno)n (OPE) de diferente lonxitude (n = 1 e 2). Estudos de CD para o POPEPA con n = 1 demostran que o polímero ó ser disolto en disolventes polares (e.g., DCM ou THF) presenta unha traza clásica con tres efectos Cotton alternantes. Imaxes de AFM para unha disolución do polímero indican que nestas condicións a hélice adopta unha estrutura cis-transoide con xiro a esquerdas. Esta conformación foi asegurada mediante estudos computacionais, no que os datos teóricos concordan cos experimentais. De xeito interesante no caso en que este POPEPA se solubilice en disolventes pouco polares obsérvase un claro estiramento helicoidal no UV-Vis que se da tamén a nivel macroscópico, puidendo visualizar un claro cambio de cor, de amarela a vermella. De estudos anteriores sábese que esta cor vermella é indicativa da adopción dunha Resumo 137 hélice estirada e case plana. O cambio na elongación da estrutura helioidal dáse tamén no CD, onde desaparece o espectro clásico e a traza pasa a ser un bisignato (-/+). Este CD alternante, no que o primeiro efecto Cotton é negativo, indica que a hélice presenta un xiro a esquerdas. Con esta información na mente modelamos unha estrutura tridimensional con unha hélice interna (hélice 1) positiva (ω1 = 175º) e unha hélice externa (hélice 2) negativa, de acordo con a conformación cis-transoide adoptada polo polímero. Desta maneira é posible visualizar as hélices descritas polos espazadores (hélices 3 e 4), que xirarán no mesmo sentido que o descrito pola hélice externa (hélice 2). No caso do POPEPA con n = 2 o polímero adopta unha estrutura moi estirada —cistransoide—, o que se corrobora mediante medidas de UV-Vis e, ademais, todas as disolucións adoptan unha cor vermella escura. Este estiramento vese tamén nos estudos de CD, onde o bisignato (-/+) é coincidente coa traza de CD obtida para o polímero supramolecular do Capítulo IV, o que suxire a formación dunha hélice de xiro á esquerda. Esta hipótese foi confirmada mediante cálculos computacionais para un oligómero de 20 unidades xirando á esquerda, reproducindo desta maneira os datos obtidos experimentalmente. Así mesmo o sentido de xiro deste polímero é determinado pola constante dieléctrica do disolvente, polo que o devandito polímero actuará como un sensor quiroóptico da polaridade do medio. Así, no caso en que os disolventes presenten (ε-1)/(ε+1) > 0.8, na traza de CD observarase un bisignato (+/-) mentres que se (ε-1)/(ε+1) < 0.8, o espectro de CD será unha imaxe especular do anterior cun bisignato (-/+). 138 Chapter I Experimental Section Experimental Section Chapter I 141 1. Materials and Methods CD measurements were done in a Jasco-720 and UV spectra were registered in a Jasco V-630. The amount of polymer used is indicated in the corresponding section. Measurements were performed in a 1mm quartz cell. The concentration of perchlorate salts used in the studies was 50 mg·mL-1 in THF. VT-CD measurements were performed in a Jasco-1100. IR spectra were recorded in a Perkin Elmer FT-IR ATR Spectrum Two. The optical rotation was measured in a Jasco P-2000. Raman spectra were carried out in a Renishaw confocal Raman spectrometer (Invia Reflex model) equipped with a 785 nm diode laser and a 514 nm Ar laser. DSC traces were obtained in a DSC Q200 Tzero Technology (TA Instruments, New Castle, UK) equipped with a refrigerated cooling system RCS90 (TA Instruments, New Castle, UK), using a Tzero low-mass aluminium pan. TGA traces were obtained in a TGA Q5000 (TA Instruments, New Castle, UK) using a platinum pan. Chiral HPLC experiments were carried out in a Waters System equipped with a Phenomenex Lux 5mm i-Amilose-1 column. The amount of monomer used was 0.5 mg·mL-1 and the mixture hexane:isopropanol (8:2) was used as eluent (flow rate: 0.5 mL·min-1). GPC studies were carried out in a Waters Alliance equipped with Phenomenex GPC columns (103 Å, 104 Å and 105 Å). The amount of polymer used was 0.5 mg·mL-1. THF was used as eluent (flow rate: 1 mL·min-1) and as inner standard, polystyrene narrow standards (PSS) were used. AFM measurements were performed in a Multimode V Scanning Probe Microscope (Veeco Instruments) in air at r.t., with standard silicon cantilevers and supersharp cantilevers in tapping mode using 12 mm and 1 mm scanners. Nanoscope processing software and WSxM 4.0 Beta 1.0 [4] (Nanotec Electrónica, S.L.) was used for image analysis. All measurements were performed at CACTI (Vigo University, Spain). The monolayers were prepared by the Langmuir-Schaefer method in a rectangular shallow trough made of poly(tetrafluoroethylene) (36 cm x 11 cm x 1 cm). A Wilhelmy balance provided with a 20 mm wide filter paper was used as a plate to measure the surface pressure. The polymer solution [250 µL (0.1 mg·mL-1)] was spread drop by drop on the MilliQ water surface. After fifteen minutes, time needed to allow the CHCl3 evaporation as well as for the stabilization of the system, the barriers were gradually closed until reaching the target pressure (1 mN·m-1), indicative for the formation of a compact monolayer. This monolayer was recollected onto a freshly cleaved HOPG substrate (Telstar Instrumat, ZYH grade), with a dipper speed of 1mm·s-1. Spartan 10 (MMFF94) was used for molecular modelling. PyMOL was used as a molecular visualization system. Experimental Section Chapter I 142 2. Synthesis of Monomers m-(S)-1 and m-(R)-1 were prepared according to the previously reported procedure.S1 S1 F. Freire, J. M. Seco, E. Quin!oá and R. Riguera, Angew. Chem. Int. Ed. 2011, 50, 11692-11696. NH O O NH O O m-(S)-2m-(S)-3 NH O O m-(S)-1 NH O O NH O O m-(R)-2m-(R)-3 NH O O m-(R)-1 Experimental Section Chapter I 143 Synthesis of 4-((4-((trimethylsilyl)ethynyl)phenyl)ethynyl)aniline (1) ((4-iodophenyl)ethynyl)trimethylsilane (0.80 g, 2.66 mmol 1.00 equiv.), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2, 0.04 g, 0.05 mmol, 0.02 equiv.) and copper iodide (CuI, 0.01 g, 0.05 mmol, 0.02 equiv.) were dissolved in dry THF (30 mL). Next triethylamine (Et3N, 15 mL) and 4-ethynylaniline (0.31 g, 2.66 mmol, 1 equiv.) were added and the mixture was stirred for three hours. After removing the solvent, the crude product was chromatographed on silica gel (70-230 mesh) with hexane/ethyl acetate (80:20) as eluent obtaining, after solvent removal, a pale-yellow solid (0.65 g, 84% of yield). 1H NMR (300 MHz, CDCl3) δH (ppm): 7.42 (s, 4H), 7.33 (d, 2H), 6.62 (d, 2H), 3.84 (s, 2H), 0.27 (s, 9H). 13C NMR (75 MHz, CDCl3) δC (ppm): 146.9, 133.0, 131.8, 131.1, 124.1, 122.1, 114.7, 112.2, 104.9, 95.9, 92.3, 87.1, 0.0. + Pd(PPh3)2Cl2, CuI, Et3N THF INH2 TMS NH2 TMS 1 Experimental Section Chapter V 246 6.2 Studies for poly-3 To prepare the polymer samples, due to the difficulty of solubilizing the polymer, small ammounts of poly-3 are weighted and dissolved into the corresponding solvent at the desired concentration. The resulting mixture is heated overnight at 40 ºC while being magnetically stirred. Depending on the dielectric constant of the solvent in which poly-3 is dissolved, the polymer will adopt a M or P helix. The change in the conformation of the chiral moiety is produced when (ε-1)/(ε+1) > 0.8. Figure S7. CD spectra (a) and magnification of the same (b) for poly-3 (0.2 mg·mL-1) evaluated in different solvents. (c) Plot of the CD intensity of poly-3 at 380 nm as a function of the dielectric constant of the different solvents. (d) UV-Vis trace for poly-3 in diferent solvents where a large absorption in the 600 nm region is recorded due to the large stretching of the helical scaffold. 0.4 0.6 0.8 1.0 -2 -1 0 1 2 (ε-1)/(ε+1) CD@380 nm [mdeg] ODCB DCM 1,2-DCE CCl 4 TOL CHCl 3 THF 400 600 800 0.0 0.5 1.0 Wavelength [nm] Abs 400 600 800 -5 0 5 10 Wavelength [nm] CD [mdeg] DCM CHCl 3 CCl 4 ODCB THF TOL 1,2-DCE 300 350 400 450 500 -5 0 5 10 Wavelength [nm] CD [mdeg] a) b) d)c) Experimental Section Chapter V 247 7. Atomic Force Microscopy (AFM) Measurements AFM images for poly-2. Figure S8. (a) AFM image for poly-2, from large scale image to magnification of the highlighted area. (b) Graphics depicting the chain distribution and the helical pitch measured in the indicated zones. Profile 1 Profile 2 Profile 1 Profile 2 Average Chain Separation Helical Pitch a) b) Experimental Section Chapter V 248 8. Theoretical Calculations Considering the difficulties to carry out ECD theoretical calculations on large polymers, representative oligomers were used. On the one hand, in the case of poly-2 an oligomer with n = 8 —where n denotes the number of monomer repeating units (m.r.u.)— was employed and, in order to reduce the computational demands, the long alkyl chains were replaced by methyl groups. The number of monomer units was selected considering the results of previous studies,S4-S6 where we evaluated the spectra for a series of poly(phenylacetylene) oligomers obtained through systematic increase of monomer units, and concluded that 8-10 monomers were enough to describe the n+2 polymer ECD spectra. The starting structure of poly-2 was built through adjustment to the experimental data obtained from structural techniques, such as AFM and UV-Vis spectroscopy, defining the four different dihedral angles needed to build up the helical scaffold (ω1, ω2, ω3 and ω4; see Figure S9). Additionally, the pendant groups were introduced in the most stable conformation (ap). The oligomer geometry was optimized using the DFT methodS7 together with the B3LYP-D3 functionalS8 and the 6-31G** basis set.S9 Figure S9. Main dihedral angles involved in the helical structure for poly(phenylacetilene)s and derivatives. On the other hand, for poly-3 the chiral moiety was removed from the pendant units in order to achieve a longer oligomer (n = 20, 504 atoms). In this case the length of the oligomer is essential to visualize the helices described by the OPE pendants (helix 3 and helix 4). S4 Fernández, B.; Rodríguez, R.; Rizzo, A.; Quiñoá, E.; Riguera, R.; Freire, F. Angew. Chem. Int. Ed. 2018, 57, 3666-3670. S5 Fernández, B.; Rodríguez, R.; Quiñoá, E.; Riguera, R.; Freire, F. ACS Omega 2019, 4, 5233-5240. S6 Fernández, Z.; Fernández, B.; Quiñoá, E.; Riguera, R.; Freire, F. Chem. Commun. 2020, 11, 7182-7187. S7 Hohenberg, P.; Walter, K. Physical Review 1964, 136, B864-B871. S8 Grimme, S. WIREs Computational Molecular Science 2011, 1, 211-228. S9 (a) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213-222. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257-2261. R H H R H R’ R m.r.u. ω1 = 50º ω2 = 0º ω3 = -40º ω4 = 60º Experimental Section Chapter V 249 The ECD computational methodology was selected according to the size of polymers under investigation. Taking this into account, to evaluate the theoretical spectra time dependent density functional theory (TD-DFT),S10 in combination with the CAM-B3LYP functionalS11 and the 3-21G basis set,S12 have been used. The ECD calculations were performed with the ORCA program (including 80 excitations).S13 The GabeditS14 code was used to plot the spectra and the density differences were displayed with Avogadro.S15 Furthermore, the full width at half height (FWHM) was fixed to 20.0 nm and the ECD were plotted with Gaussian curves. For an efficient comparison and taking into account the tendency of the TD-DFT method to overestimate the excitation energies, the wavelength and intensity at the maximum/minimum Cotton effect correspondent to the polyene backbone in the theoretical spectra were adjusted to the experimental spectra. Employing the same correction factors, the lambdas were shifted and the intensities rescaled. The resulting ECD spectra are in good agreement with the experimental ones. Poly-2 (ω1 ca. 165º) displays a classical ECD trace with a positive Cotton effect at ca. 405 nm, dominated by the S0 to S1 excitation and ascribed to the polyenic backbone. It is observed that the excited states mostly contribute to the first Cotton bands (Figure S10). Figure S10. TD-DFT (CAM-B3LYP)/3-21G ECD poly-2 spectra evaluated at the DFT(B3LYP-D3)/6-31G** geometries showing the excited states that most contribute to the first Cotton bands. S10 Runge, E.; Gross, E. K. U. Phys. Rev. Lett. 1984, 52, 997-1000. S11 Yanai, Y.; Tew, D. P.; Handy, N. C. A. Chem. Phys. Lett. 2005, 393, 51-57. S12 Binkley, J. S.; Pople, J. A.; Hehre, W. J. J. Am. Chem. Soc. 1980, 102, 939-947. S13 Neese, F. WIREs Comput Mol Sci. 2012, 2, 73-78. S14 Allouche, A. R. J. Comput. Chem. 2011, 32, 174-182. S15 Hanwell, M. D.; Curtis, D. E.; Lonie, D. C.; Vandermeersch, T.; Zurek, E.; Hutchison, G. R. Journal of Cheminformatics 2012, 4,17. Experimental Section Chapter V 250 To get more insight into these spectral bands, the electron density differences for the corresponding transitions were evaluated at the same level of theory (Figure S11). Figure S11. Poly-2 electron density differences with respect to the ground state for the states shown in Figure S10: (a) S0 to S1, (b) S0 to S4, (c) S0 to S5, (d) S0 to S8, (e) S0 to S9, (f) S0 to S11, (g) S0 to S15 and (h) S0 to S16. An isovalue of 0.0005 was selected. a) b) c) d) e) f) g) h) Experimental Section Chapter V 251 Poly-3 (ω1 ca. 170º) ECD shows a highly intense positive Cotton effect at ca. 340 nm, dominated by the S0 to S1 excitation and ascribed to the polyenic backbone. The excited states mostly contribute to the Cotton bands (Figure S11). Figure S11. TD-DFT (CAM-B3LYP)/3-21G ECD poly-3 spectrum evaluated at the DFT(B3LYP-D3)/6-31G** geometries showing the excited states that most contribute to the first Cotton bands.