Solid-phase synthesis of m-phenylene ethynylene heterosequence oligomers

Both homo- and heterosequence m-phenylene ethynylene oligomers are synthesized using a conceptually simple iterative solid-phase strategy. Oligomers are attached to Merrifield's resin through a known triazene-type linkage. The phenylene ethynylene molecular backbone is constructed through a series of palladium-mediated cross-coupling reactions. The strategy employs two types of monomers that bear orthogonal reactivity, one being a monoprotected bisethynyl arene and the other being a 3-bromo-5-iodo arene. The catalyst conditions are tailored to the requirements of each monomer type. The monoprotected bisethynyl arene is coupled to the growing chain in 2 h at room temperature using a Pd(I) dimer precatalyst ((t)Bu3P(Pd(mu-Cl)(mu-2-methyl allyl)Pd)P(t)Bu3) in conjunction with ZnBr2 and diisopropylamine. In alternate steps, the resin is deprotected in situ with TBAF and coupled to the 3-bromo-5-iodo arene using the iodo selective Pd(tri-2-furylphosphine)4 catalyst in conjunction with CuI and piperidine; this reaction is also completed in 2 h at room temperature. These cross-coupling events are alternated until an oligomer of the desired length is achieved. The oligomer is then cleaved from the resin using CH(2)I(2)/I(2) at 110 degrees C and purified using preparatory GPC. Using this method, a series of homo- and heterosequence oligomers up to 12 units in length in excellent yield and purity were synthesized on the 100 mg scale. Longer oligomers were attempted; however, deletion sequences were found in oligomers longer than 12 units.     

Self-assembly of folded m-phenylene ethynylene oligomers into helical columns

Circular dichroism spectroscopy has been used to study the self-assembly of two series of m-phenylene ethynylene oligomers in highly polar solvents. The helical conformation of shorter oligomer lengths was found to be stabilized in aqueous acetonitrile solutions, while longer oligomers began to interact intermolecularly. The intermolecular aggregation of the oligomers in aqueous solutions revealed a chain length dependent association that required the presence of a stable helical conformation. Evidence for intermolecular interactions is provided by Sergeants and Soldiers experiments in which the twist sense bias of a chiral oligomer is transferred to an achiral oligomer.     

Conformational ordering of apolar, chiral m-phenylene ethynylene oligomers

A series of m-phenylene ethynylene oligomers containing nonpolar, (S)-3,7-dimethyl-1-octanoxy side chains have been synthesized and studied. In apolar alkane solvents, oligomers of sufficient length (n > 10) were found to adopt a helical conformation with a large twist sense bias. In contrast, in chloroform the oligomers adopt a random coil conformation. Surprisingly, the strong twist sense bias was determined to be highly time dependent and is partially attributed to intermolecular aggregation.     

Single-site modifications and their effect on the folding stability of m-phenylene ethynylene oligomers

[reaction: see text] The folded structure of a m-phenylene ethynylene oligomer is tolerant to single-site modifications to both the backbone sequence and end groups. The helical structure is reinforced by multiple noncovalent interactions, allowing the oligomer sequence to be customized without a significant change in stability in most cases. The small changes that are observed are consistent with the expected behavior of pi-stacked systems and demonstrate subtle control over folding through single-site modifications.     

A water-soluble m-phenylene ethynylene foldamer

[reaction: see text] A water-soluble m-phenylene ethynylene (mPE) foldamer was realized by appending hexaethylene glycol side chains to the backbone repeat unit. UV spectra of the oligomer in aqueous solutions were consistent with a helical conformation. The association constant of the oligomer with (-)-alpha-pinene increased dramatically with increasing water composition, peaking at 90% water by volume in acetonitrile. The rate of the host/guest system's approach to equilibrium was found to decrease considerably with increasing water content.     

Synthesis and self-association of an imine-containing m-phenylene ethynylene macrocycle

The purpose of this study was to test the suitability of the imine bond as a structural unit within the backbone of phenylene ethynylene macrocycles and oligomers by determining the ability of m-phenylene ethynylene macrocycle 1 to form pi-stacked aggregates in both solution and the solid state. Macrocycle 1, with two imine bonds, was synthesized in high yield from diamine 4 and dialdehyde 5. The imine-forming macrocyclization step was carried out under a variety of conditions, with the best yield obtained simply by refluxing the reactants in methanol. The self-association behavior of 1 in various solvents was probed by (1)H NMR. The association constants (K(E)) in acetone-d(6) and tetrahydrofuran-d(8) were determined by fitting the concentration-dependent chemical shifts with indefinite self-association models. The results showed that solvophobically driven intermolecular pi-pi stacking could be preserved in the imine-containing m-phenylene ethynylene macrocycles. Interestingly, in acetone macrocycle 1 exhibited a stronger tendency to form a dimer rather than higher aggregates. We postulate that this behavior may be due to electrostatic attraction between dipolar imine groups. The solid-state packing of 1 was studied by wide- and small-angle X-ray powder diffraction (WAXD and SAXD). Bragg reflections of 1 were consistent with a hexagonal packing motif similar to our previous studies on m-phenylene ethynylene macrocycles that formed columnar liquid crystal phases.     

Hydrogen bond-stabilized helix formation of a m-phenylene ethynylene oligomer

[reaction: see text] Incorporation of a single hydrogen bonded beta-turn mimic in the backbone of a m-phenylene ethynylene oligomer is shown to affect the thermodynamic properties of the folding reaction. Oligomers 1 and 2 both undergo solvophobic helix formation, but hydrogen bonded oligomer 1 was found to form a more stable helix with a higher tolerance to solvent denaturation than isomeric, non-hydrogen bonded oligomer 2.     

Synthesis of alkoxy-substituted ortho-phenylene ethynylene oligomers

[structure: see text] This Letter describes the first published synthesis and characterization of alkoxy-substituted ortho-phenylene ethynylene (o-PE) oligomers. Sonogashira coupling was used to assemble discrete chain lengths, using a key monomer with orthogonal groups. Deprotection or activation allowed stepwise coupling to produce the dimer, trimer, and tetramer, while convergent coupling of appropriately substituted trimers produced the hexamer. The placement of alkoxy side chains renders these oligomers soluble in common organic solvents permitting solution characterization. Absorption and emission spectra of the trimer, tetramer, and hexamer are provided.     

Helical pitch of m-phenylene ethynylene foldamers by double spin labeling

To investigate the helical conformation of oligo(m-phenylene ethynylene)s, a pair of TEMPO spin labels were appended to the backbone. The two TEMPO radicals were separated by the four, five, and six repeating units. ESR spectra of the labeled oligomers were measured in chloroform and in ethyl acetate solvents in which the oligomers are disordered and folded, respectively. The measurement and analysis of ESR spectra revealed that six repeating units make one helical turn.     

Spin system assignment of homo-o-phenylene ethynylene oligomers

We previously reported the synthesis and solution characterization of short o-phenylene ethynylene (oPE) foldamers. Proton correlation techniques are not adequate for NMR assignment in these compounds as the ethynylene linkers interrupt proton connectivity. In order to facilitate structural characterization and more fully harness the power of NMR, it is necessary to know the sequence of spin systems along the molecular backbone. For example, spin system assignment is required to unambiguously assign NOE correlations for structural determination of folded forms in solution. Therefore, we developed a method to assign the aromatic spin systems in these compounds using HMBC experiments. This has been performed for tetrameric (Es4), pentameric (Es5), and hexameric (Es6) oligomers and is expected to prove useful for this class of foldamers in general. The proton assignments obtained by this technique have been useful toward confirming the previous hypotheses of helical folding in oPE systems.     

Negative differential resistance in phenylene ethynylene oligomers

The origin of the sharp peak profile (i.e., negative differential resistance, NDR) observed in the I/V curves of three-ring phenylene ethynylene oligomers is a topic of major current interest. Here, quantum-chemical calculations are performed to analyze the evolution of the one-electron structure of an unsubstituted three-ring oligomer under the influence of a static electric field (which models the driving voltage applied in the experiments). The results indicate that the rotation of the central ring of the oligomer induces resonant tunneling processes over a limited voltage range. This can thus be responsible for the NDR signature observed experimentally.     

Vibronic structures in the electronic spectra of oligo(phenylene ethynylene): effect of m-phenylene to the optical properties of poly(m-phenylene ethynylene)

At the low temperature, hidden vibronic structures are successfully resolved in the absorption and emission spectra of oligo(phenylene ethynylene)s 3-5. Identification of the hidden bands allows estimation of the vibrational energy gaps in these molecules, which appears to increase with the oligomer conjugation length. The remarkable similarity between the absorption profiles of diphenylacetylene (3) and 1,3-bis(phenylethynyl)benzene (5), especially at -198 degrees C, confirms the effectiveness of conjugation interruption at m-phenylene. The function of precise conjugation length control via m-phenylene is further demonstrated from poly(m-phenylene ethynylene) (PmPE) (6). Even though the number of recurring unit (phenylene ethynylene) increases from 2 (for 5) to 12 (for 6), the absorption and emission spectra of the latter are nearly identical to that of the former.     

Folding and duplex formation in mixed sequence recognition-encoded m-phenylene ethynylene polymers

Oligomers equipped with complementary recognition units have the potential to encode and express chemical information in the same way as nucleic acids. The supramolecular assembly properties of m-phenylene ethynylene polymers equipped with H-bond donor (D = phenol) and H-bond acceptor (A = phosphine oxide) side chains have been investigated in chloroform solution. Polymerisation of a bifunctional monomer in the presence of a monofunctional chain stopper was used for the one pot synthesis of families of m-phenylene ethynylene polymers with sequences ADnA or DAnD (n = 1–5), which were separated by chromatography. All of the oligomers self-associate due to intermolecular H-bonding interactions, but intramolecular folding of the monomeric single strands can be studied in dilute solution. NMR and fluorescence spectroscopy show that the 3-mers ADA and DAD do not fold, but there are intramolecular H-bonding interactions for all of the longer sequences. Nevertheless, 1 : 1 mixtures of sequence complementary oligomers all form stable duplexes. Duplex stability was quantified using DMSO denaturation experiments, which show that the association constant for duplex formation increases by an order of magnitude for every base-pairing interaction added to the chain, from 10³ M⁻¹ for ADA·DAD to 10⁵ M⁻¹ for ADDDA·DAAAD. Intramolecular folding is the major pathway that competes with duplex formation between recognition-encoded oligomers and limits the fidelity of sequence-selective assembly. The experimental approach described here provides a practical strategy for rapid evaluation of suitability for the development of programmable synthetic polymers.

One pot oligomerisation reactions give access to families of oligomers that allow facile analysis of folding propensity and assessment of suitability for sequence-selective duplex formation.     

Sequence-specific binding of m-phenylene ethynylene foldamers to a piperazinium dihydrochloride salt

[reaction: see text] Binding properties of a series of isomeric m-phenylene ethynylene oligomers containing short amide sequences to a piperazinium dihydrochloride salt were investigated by using circular dichroism (CD) measurements. Although these isomeric oligomers exhibited similar helical conformations, high affinity was observed only for one oligomer. This behavior is presumably controlled by the orientation of amino groups of the amide sequence and the folded conformation of the oligomer.     

Molecular packing and morphology of oligo(m-phenylene ethynylene) foldamers

Understanding and controlling solid-state morphologies and molecular conformations is the key to optimizing the properties of materials. As an example for the influence of small chemical changes on solid-state structures, we studied oligo(m-phenylene ethynylene) foldamers, where the introduction of an endo-methyl group induces a transition from an extended all-transoid to a helical all-cisoid conformation. The resulting structural changes were analyzed by X-ray diffraction (XRD), polarized optical microscopy (POM), and low-dose high-resolution electron microscopy (LD-HREM) over several length scales from the molecular to the mesoscopic level. The strong tendency of the endo-methyl oligomer 1 to form stable compact helices in solution resulted in round droplets with an ordered hexagonal columnar (Col(ho)) liquid crystalline structure, where shrinkage during the crystallization resulted in the formation of a banded texture. On the other hand, the endo-hydrogen oligomer 2 exhibited a very different morphology; its extended linear shape was maintained during crystallization and resulted in an extended lamellar structure, which was determined by a compromise between crystalline packing and minimization of the surface area. Another pronounced difference between both molecular structures was the ability of the extended lamellar "crystals" to bend, whereas the helices form either straight or disordered domains. In addition, both materials exhibit strong surface effects, which extend considerably inside the droplet and induce uniform bending of the supramolecular structures.     

Theoretical study of helix formation in substituted phenylene ethynylene oligomers

Theoretical investigations of the relative stabilities of helical vs extended forms of phenylene ethynylene oligomers established that MMFF molecular mechanics was more useful than AM1 or DFT for calculating helical structures and for estimating relative energies. At the level of MMFF, theory predicts that for o- or m-oligophenylene ethynylenes, helix formation is enthalpically favored for ester and ether-substituted oligomers. In contrast to simple electron-demand predictions, we predict that the position of substituents can make a substantial difference in the tendency to form helices.     

m-Phenylene ethynylene sequences joined by imine linkages: dynamic covalent oligomers

Imine metathesis between m-phenylene ethynylene oligomers of various lengths was performed in acetonitrile, a solvent in which oligomers containing eight or more repeat units adopt a compact helical conformation. The equilibrium constants and corresponding free energy change for the imine metathesis reactions were estimated. The results showed that the magnitude of equilibrium shifting measured by the free energy change for the formation of imine-containing oligomers increases linearly below a critical product chain length and grows asymptotically above it. The linear region is ascribed to the constant increase in contact area between monomer units of adjacent helical turns as the product chain grows to the 12-mer. Once the ligation product is 12 units in length, full contact is made between adjacent helical turns. On the other hand, for imine metathesis between oligomers leading to products having more than 12 units, the driving force is the difference between the folding energy of products and that of reactants. The additional stabilizing energy is roughly constant, regardless of the chain length, since the contact area between adjacent helical turns is unchanged. Consistent with the notion that the imine bond only minimally destabilizes the helical conformation, the position of the imine bond in the ligation product has been observed to have no significant effect on the folding stability. The magnitudes of equilibrium shifting are similar for ligation products of the same length but having the imine at various positions along the sequence. This suggests that the imine bond is compatible with the m-phenylene ethynylene backbone, regardless of the position in the sequence. Imine metathesis of m-phenylene ethynylene oligomers could allow a quick access to an unbiased, dynamic library of oligomer sequences joined by imine linkages.     

Synthesis and characterization of amphiphilic phenylene ethynylene oligomers and their Langmuir-Blodgett films

We report the synthesis of a series of amphiphilic molecular building blocks that can be self-assembled at the air-water interface to form two- and three-dimensional nanostructures with tunable optoelectronic properties. Compression of these molecular building blocks using the Langmuir-Blodgett method gives rise to monolayer and multilayer thin films with different packing densities and electronic properties that are tunable due to varying pi-pi (hydrophobic) interactions. Depending on the noncovalent interaction between chromophores, we observe a transition toward denser packing with increasing number of phenylene ethynylene repeat units. Additionally, we use quantum-chemical simulations to help determine the excited-state electronic structure, intermolecular interactions, and packing trends. Our results demonstrate that the interplay between dipole-dipole and pi-pi interactions dominates the formation of thin films with various packing densities and determines the associated optical properties.     

Influence of lipid composition on membrane activity of antimicrobial phenylene ethynylene oligomers

Host defense peptides (HDPs), part of the innate immune system, selectively target the membranes of bacterial cells over that of host cells. As a result, their antimicrobial properties have been under intense study. Their selectivity strongly depends on the chemical and mostly structural properties of the lipids that make up different cell membranes. The ability to synthesize HDP mimics has recently been demonstrated. To better understand how these HDP mimics interact with bilayer membranes, three homologous antimicrobial oligomers (AMOs) 1-3 with an m-phenylene ethynylene backbone and alkyl amine side chains were studied. Among them, AMO 1 is nonactive, AMO 2 is specifically active, and AMO 3 is nonspecifically active against bacteria over human red blood cells, a standard model for mammalian cells. The interactions of these three AMOs with liposomes having different lipid compositions are characterized in detail using a fluorescent dye leakage assay. AMO 2 and AMO 3 caused more leakage than AMO 1 from bacteria membrane mimic liposomes composed of PE/PG lipids. The use of E. coli lipid vesicles gave the same results. Further changes of the lipid compositions revealed that AMO 2 has selectively higher affinity toward PE/PG and E. coli lipids than PC, PC/PG or PC/PS lipids, the major components of mammalian cell membranes. In contrast, AMO 3 is devoid of this lipid selectivity and interacts with all liposomes with equal ease; AMO 1 remains inactive. These observations suggest that lipid type and structure are more important in determining membrane selectivity than lipid headgroup charges for this series of HDP mimics.     

Solution 1H NMR confirmation of folding in short o-phenylene ethynylene oligomers

Oligomers based on an o-phenylene ethynylene (oPE) backbone with polar substituents have been synthesized using Sonogashira methods. Folding of these extremely short oligomers was confirmed via 1D and 2D (NOESY) NMR methods. Utilizing electron-rich and electron-poor phenylene building blocks, variations of these oPE oligomers have been synthesized to determine the folded stability of pi-rich vs pi-poor vs pi-rich-pi-poor systems. Slight variations in temperature offer a route, aside from solvent denaturation, to probe the stability of the folded structure. This is the first report of an NMR solution characterization of folding for a PE backbone without hydrogen bonds.