H-bonding Motifs Research Articles

Unusual photophysics of anticancer azapodophyllotoxin: The collective effect of discrete H-bond motif spills the beans

Abstract Azapodophyllotoxin (AZP) derivatives, the alternative scaffolds to podophyllotoxins, are intriguing class of small molecules with high anti-proliferative activity against several cancer cell lines. The physicochemical factors associated with or responsible for, anticancer activity which change as a function of the intrinsic molecular nature and its interaction with environment encouraged us to study the detailed photophysics of structurally simplest AZP, 4-(2-Hydroxyethyl)-10-phenyl-3,4,6,7,8,10-hexahydro-1H-cyclopenta[g]furo[3,4-b]quinoline-1-one (HPFQ), for the first time for this class, using steady-state absorption, emission and time-resolved fluorescence (TRF) spectroscopy and TRF anisotropy in solvents of diverse polarity. HPFQ exhibits (i) primary emission originating from a mixed contribution of locally excited (LE) and pure charge transfer (CT) states and (ii) a red shifted excimer emission. The presence of more than one emitting species is confirmed by the wavelength dependent TRF studies. HPFQ shares compatible H-bonding motifs with all solvents: the H-bond acceptor solvents interact with −OH functionality while H-bond donor solvents interact with both −OH and carbonyl oxygen in cyclic ester (ring D). It is demonstrated that the H-bond interactions causes a small change in dipole moment (Δμ ∼3.52D) and directly affect the extent of HPFQ fluorescence quantum yield (ϕf). This cartel of substantial H-bond network and the weak electron acceptor nature of ring D serve as protagonist for the photophysical conduct and impressive fluorescence in all solvents, which is a very rare phenomenon and has been difficult to achieve across the entire polarity scale. Additionally, ϕf and fluorescence lifetime of CT state illustrate high sensitivity to solvent polarity, proticity and viscosity. The lower viscosity of water propels a faster deactivation and a sudden decrease in CT state lifetime in aqueous medium. The lower ϕf in water when compared to alcohols is possibly due to entrapment of water solvent molecules within the cavity formed by close proximity of flexible CH2CH2OH and phenyl (ring E) groups. Thus, the knowledge provided herein can prove momentous for decoding the fluorescence behaviour of other compounds in this category, and even the parent podophyllotoxins! Overall, the magnificent emission showcased by the antitumor HPFQ is important as it can act as a dual therapeutic and imaging agent without the use of co-staining for determining the impact of environmental factors in cancer pathophysiology in future.

Redox-Dependent Binding to an Electroactive Urea: Comparison of Ferrocene and Phenylenediamine Redox Couples with Two Different Guests

In previous work in our lab, the redox-dependent binding behavior of a phenylenediamine urea, UHH, was investigated in the presence of different guests in CH2Cl2. The urea functionality contains two good H-donors in the two urea NH bonds (a DD motif) that are capable of H-bonding with two appropriately spaced H-acceptors (AA motif). Examples are the cyclic diamide PZD (see Figure) and 1,8-naphthyridine, naph. 1H NMR studies indicated a modest Kbinding of 100 M-1 with PZD and 30 M-1 with naph in CH2Cl2. The expectation was that oxidation of the phenylenediamine couple in UHH to the radical cation would increase the acidity of one of the NH’s leading to stronger H-bonding with the guests and a negative shift in the observed redox potential upon addition of these guests. A small negative shift was observed with PZD, but further research indicated that the actual overall reaction occurring upon oxidation of UHH was not the simple 1 electron oxidation to the radical cation expected, but rather 2 electron oxidation of one UHH accompanied by proton transfer to a reduced UHH to give UH+ and HUHH+ as shown in the Figure. Addition of PZD does not change this overall reaction. An alternative explanation of the potential shift is that PZD is actually H-bonding to the protonated HUHH+, which would also be a stronger H-donor. Interestingly, similar magnitude shifts are observed upon oxidation of the ferrocene-containing urea, FcUHH. Since Fc is only capable of being oxidized by 1 electron, oxidation of the Fc also makes a +1 charge, which appears to have a similar effect on the H-bonding ability of the urea as does protonation. In contrast to the PZD, addition of naph causes the current for the oxidation of UHH to increase with little change in peak potential. This can be explained by proton transfer from the UHH radical cation to the naphthyridine. The resulting neutral radical will be immediately oxidized by a second electron leading to the increase in current. The proton transfer will change the H-bonding motif from AA-DD to AD-DA, which is inherently weaker because of unfavorable secondary interactions. In addition, because of the two electron oxidation, both binding partners in the resulting complex, (naphH+)(UH+), will be positively charged. Therefore it is not surprising that the H-bonding does not strengthen upon oxidation. It will be of interest to compare this behavior to that of FcUHH and naph. Cyclic voltammetry experiments will be run with FcUHH and naphthyridine to see if eliminating the possibility of the second electron transfer prevents proton transfer and results in the expected stronger H-bonding to the oxidized form. Figure 1

Hexaazatriphenylene-Based Hydrogen-Bonded Organic Framework with Permanent Porosity and Single-Crystallinity.

Hydrogen-bonded organic frameworks (HOFs) have drawn unprecedented interest because of their high crystallinity as well as facile process for construction, deconstruction, and reassembly arising from reversible bond formation-dissociation. However, structural fragility and low stability frequently prevent formation of robust HOFs with permanent porosity. Here, we report that hexakis(4-carboxyphenyl)-hexaazatriphenylene (CPHAT) forms three dimensionally networked H-bonded framework CPHAT-1. Interestingly, the activated framework CPHAT-1 a retains not only permanent porosity but single-crystallinity, enabling precise structural characterization and property evaluation on a single crystal. Moreover, CPHAT-1 a retains its framework up to 339 °C or in hot water and in acidic aqueous solution. These results clearly show that even a simple H-bonding motif can be applied for the construction of robust HOFs, which creates a pathway to establish a new class of porous organic frameworks. We also characterize its uptake of gases and I2 , in addition to a detailed photophysical study (spectroscopy and dynamics of proton and charge transfers) of its unit in solution, and of its single crystal under fluorescence microscopy, in which we observed a marked strong anistropy and narrow distribution. The results bring new findings to the area of HOFs and their possible applications in science and technology.

Redox-Dependent Binding to an Electroactive Urea: Comparison of One and Two Electron Redox Couples

In previous work in our lab, the redox-dependent binding behavior of a phenylene-diamine urea, UHH, was investigated in the presence of different guests in CH2Cl2. The urea functionality contains two good H-donors in the two urea NH bonds (a DD motif) that are capable of H-bonding with two appropriately spaced H-acceptors (AA motif). An example is 1,8-naphthyridine, naph, which contains two pyridine-type N’s appropriately spaced and orientated to H-bond to the two NH’s in UHH. 1H NMR studies indicated a modest Kbinding of 30 M-1 in CH2Cl2 between UHH and naph. The expectation was that oxidation of the phenylenediamine couple in UHH would increase the acidity of one of the NH’s leading to stronger H-bonding and a negative shift in the observed redox potential upon addition of naph. However, instead what happened was that the current for the oxidation increased with little change in peak potential. This can be explained by proton transfer from the UHH radical cation to the naphthyridine. The resulting neutral radical will be immediately oxidized by a second electron leading to the increase in current. The proton transfer will change the H-bonding motif from AA-DD to AD-DA, which is inherently weaker because of unfavorable secondary interactions. In addition because of the two electron oxidation, both binding partners in the resulting complex, (naphH+)(UH+), will be positively charged. Therefore it is not surprising that the H-bonding does not strengthen upon oxidation. In this study the phenylenediamine couple is replaced by a ferrocene, FcUHH, which is only capable of a one electron oxidation. Cyclic voltammetry experiments will be run with FcUHH and naphthyridine to see if eliminating the possibility of the second electron transfer prevents proton transfer and results in the expected stronger H-bonding to the oxidized form.

Effect of Added Bases on the Redox-Responsive Dimerization of a 4 H-Bond Array Containing a Phenylenediamine Redox Couple

Ureidopyrimidinone (UPy) derivatives, introduced by Meijer and co-workers, are capable of forming dimers linked by four strong H-bonds. They have been widely used as polymer crosslinkers in self-healing supramolecular polymers and gels. While their donor-donor-acceptor-acceptor (DDAA) H-bond motif contributes to polymer stretchiness, their relatively high association constant of 106 also contributes to their ability to autonomously self-repair. This presentation shows the result of substituting a UPy with a N,N- dimethyl-p-phenylenediamine and therefore adding a redox reactive dimension to self-repair. In particular, this work involves the electrochemical investigation of UPyH (shown below) with a series of different bases, specifically pyridine and substituted pyridines. The focus is on finding the appropriate electroinactive base that facilitates both the dimer break up upon oxidation and proton transfer and dimer reformation by reduction and back proton transfer. Cyclic voltammetry (CV) scans of UPyH only, conducted in CH2Cl2 at slower scan rates, show two reversible redox waves. The first wave is of one electron height, corresponding to a two-electron transfer per dimer. The second oxidation wave at more positive potential is one half the height of the first and less reversible than the first. At a faster scan rate, the second wave becomes irreversible and a new reduction wave appears at a more negative potential than the reduction wave for the first electron transfer process. This type of CV return wave behavior for UPyH at faster scan rates was previously seen in another dimethylphenylurea redox active compound with only two H-bonding sites, UHH. In the UHH investigation, CV and spectroelectrochemical results pointed to the dimethylamino moiety being basic enough to abstract an N-H proton in the radical cation oxidation state and therefore allowing for a two electron transfer wave to give the quinoidal cation. A similar reduction wave negative of the first redox wave was seen in acetonitrile at all scan rates, while in CH2Cl2 this wave was seen only at faster scan rates. At slower scans the first oxidation remained reversible. Based upon the UHH study, interpretation of the UPyH second oxidation wave is that it correspond with a second e- transfer per redox center. Each urea-phenylenediamine N-H site in the dimer then becomes acidic enough to transfer its proton to the carbonyl oxygen on the UPyH isocytosine. This would then change the favorable binding motif of DDAA to a weaker binding motif of ADAD. In addition, a 2+ charge forms on each monomer in the dimer contributing to strong repulsive forces. This results in dimer break-up, where upon the protonated isocytosine carbonyl on each monomer is exposed to the more basic dimethylamino site on a fully reduced UPyH dimer. Proton transfer from the isocytosine to the dimethyl amino renders the fully reduced dimer electroinactive, explaining the half wave height. Thus, the overall reaction, shown in the accompanying scheme, corresponds to break up of the half the starting dimers, with two electron oxidation and deprotonation of each monomer to give two UPy+. However, the other half of the UPy’s remain dimerized in the protonated form as (HUPyH+)2. Further investigation focuses on the addition of a series of substituted pyridines as a base and their effect on dimer break up and reformation as the added base competes with the dimethylamino moiety on the phenylenediamine. The goal is to find an external base that will allow full oxidation and break up of all the UPyH dimers, while retaining the chemical reversibility of the process. Figure 1

Electrochemical Studies of a Redox Responsive 4 H-Bond Array Capable of Self-Dimerization

Supramolecular structures can change in response to external signals, such as change in pH, temperature, or voltage of an electrode. This is important for many applications such as self-healing polymers and gels, triggered release of entrapped molecules for drug delivery, and smart material. Ureidopyrimidinone (UPy) array with an alkyl-pyridinium (RP) redox center has been synthesized for this study. This array prefers the tautomer that presents an ADAD H-bond motif in the starting oxidation state. Due to electrostatic repulsions and unfavorable secondary H-bond interactions, this motif would form a dimer with relatively weak H-bonding. Upon 2e- reduction, where 1e- is gained per R-pyridinium redox center, the H-bond strength should increase due to the loss of the repulsive charges, making the nitrogen a stronger hydrogen acceptor. Because the nitrogen is now a better hydrogen acceptor, there could be a possibility of an intermolecular proton transfer. This would encourage the tautomer to have an AADD motif that will make the H-bonding stronger by increasing the favorable secondary H-bond interactions. The UPy(RP) array is not soluble in dichloromethane using the NBu4PF6 electrolyte, but it is soluble in acetonitrile. The concentration dependent 1H NMR spectra suggest that UPy(RP) is a monomer in acetonitrile. The cyclic voltammetry scans of the UPy array in CH3CN show three reductions. The first occurs at a potential very similar to that seen with simple model compounds. The second is considerably positive of that observed for the model compounds and the third is very close to the second reduction peak of the model compounds. The first reduction is reversible if the scan direction is switched immediately after the peak, but irreversible if the scan direction is switched after the second reduction peak. As the scan rate increases, the second reduction peak disappears. An oxidation peak at far positive potentials starts to appear only after going through the second and third reduction. DFT calculations suggest the preferred tautomer changes upon reduction, and this may explain the unexpected voltammetry observed in acetonitrile where the compound is not dimerized. To improve the solubility of the UPy array in methylene chloride, TFAB was used as a counterion instead of the PF6. The CV’s of UPy/TFAB array in methylene chloride show similar behavior to that in acetonitrile with an additional fourth reduction wave observed at far negative potential. 1H NMR spectrum of UPy/TFAB at room temperature suggests the presence of two tautomeric forms in methylene chloride. However, at low temperatures, only one tautomer is observed in 1H NMR spectrum that’s believed to be the dimer. Further studies to help elucidate what is actually happening in this system will include taking CV’s at low temperatures in CH2Cl2, and conducting UV-Vis spectroelectroanalytical experiments for the system.

Microsolvation of the pyrrole cation (Py+) with nonpolar and polar ligands: infrared spectra of Py+-Ln with L = Ar, N2, and H2O (n ≤ 3).

The solvation of aromatic (bio-)molecular building blocks has a strong impact on the intermolecular interactions and function of supramolecular assemblies, proteins, and DNA. Herein we characterize the initial microsolvation process of the heterocyclic aromatic pyrrole cation (Py+) in its 2A2 ground electronic state with nonpolar, quadrupolar, and dipolar ligands (L = Ar, N2, and H2O) by infrared photodissociation (IRPD) spectroscopy of cold mass-selected Py+-Ln (n ≤ 3) clusters in a molecular beam and dispersion-corrected density functional theory calculations at the B3LYP-D3/aug-cc-pVTZ level. Size- and isomer-specific shifts in the NH stretch frequency (ΔνNH) unravel the competition between various ligand binding sites, the strength of the respective intermolecular bonds, and the cluster growth. In Py+-Ar, linear H-bonding of Ar to the acidic NH group (NHAr) is competitive with π-stacking to the aromatic ring, and both Py+-Ar(H) and Py+-Ar(π) are observed. For L = N2 and H2O, the linear NHL H-bond is much more stable than any other binding site and the only observed binding motif. For the Py+-Ar2 and Py+-(N2)2 trimers, the H/π isomer with one H-bonded and one π-bonded ligand strongly competes with a 2H isomer with two bifurcated nonlinear NHL bonds. The latter are equivalent for Ar but nonequivalent for N2. Py+-H2O exhibits a strong and linear NHO H-bond with charge-dipole configuration and C2v symmetry. IRPD spectra of cold Py+-H2O-L clusters with L = Ar and N2 reveal that Ar prefers π-stacking to the Py+ ring, while N2 forms an OHN2 H-bond to the H2O ligand. The ΔνNH frequency shifts in Py+-Ln are correlated with the strength of the NHL H-bond and the proton affinity (PA) of L, and a monotonic correlation between ΔνNH of the Py+-L(H) dimers and PA is established. Comparison with neutral Py-L dimers reveals the strong impact of the positive charge on the acidity of the NH group, the strength of the NHL H-bond, and the preferred ligand binding motif.

Coexistence of ice clusters and liquid-like water clusters on the Ru(0001) surface.

The RAIRS spectra of water adsorbed on Ru(0001) at 85 K are recorded from 600 cm-1 to 4000 cm-1. Measured at water coverages from 0.13 ML to 2.0 ML, the RAIRS spectra suggest that chemisorption of water on Ru(0001) depends on coverage. Water adsorbs on a clean Ru surface as chemisorbed ice-like clusters (likely through an O-Ru bond) up to 0.33 ML. Above this coverage, the chemisorbed layer saturates. Upon more exposure, water adsorbs as a liquid-like H-bonded layer without bonding to the Ru substrate. The chemisorbed water absorbs 7 times less IR per molecule than the liquid-like structure, which indicates that the orientation of the chemisorbed water is more parallel to the surface. Additionally, the influence of water-Ru bonding on H-bonding is reflected in the OH symmetric stretching mode. Under perturbation from water-Ru bonding, a large red shift (40 cm-1) in the free OH stretching frequency is observed in the chemisorbed clusters. By deconvoluting the main H-bonded OH stretching peak into five Gaussian sub-bands at 2945 ± 5 cm-1, 3210 ± 5 cm-1, 3300 ± 15 cm-1, 3430 ± 5 cm-1 and 3570 ± 10 cm-1, changes in the H-bonding network are rationalized in terms of H-bonding motifs. The donor-acceptor-acceptor motif is significant only in the chemisorbed clusters. On the other hand, the donor-acceptor motif dominates in the liquid-like structure, which increases the disorder present in the adlayer. Although chemisorption is suppressed above 0.33 ML, no structural changes in the ice-like clusters are observed up to multilayer coverage. Therefore, ice-like and liquid-like water coexist in a meta-stable state at 85 K.

Knowledge-Based Approaches to H-Bonding Patterns in Heterocycle-1-Carbohydrazoneamides

We applied the knowledge-based approaches from the CSD-Materials to three novel heterocycle-1-carbohydrazonamides, for which molecular geometry was obtained by means of ab initio calculations, to predict the topological properties of their supramolecular motifs in the crystalline phase. Our survey suggested competition between nitrogen atoms of the heterocycle and carbohydrazonamide moieties to act as acceptors of H-bonding with the donor -NH2 group that can result in polymorphism based on various H-bonded motifs. The possibility of H-bonded polymorphism was proven for imidazole- and triazole-1-carbohydrazones with the ToposPro knowledge databases, which contain information on relations between local connectivity of molecules and topology of the whole H-bonded system. Experimental structures obtained with single crystal X-ray diffraction belong to the most abundant H-bonded motifs with proposed probabilities in the range 6–44%, thus giving evidence that the CSD-Materials and ToposPro knowledge databases c...

Cyclic Voltammetry Studies of a Redox-Responsive 4 H-Bond Ureidopyrimidinone Alkyl-Pyridinium Capable of Self-Dimerization

The design of stimuli-responsive systems in which supramolecular structure changes in response to external signals, such as the change in voltage of an electrode, is important for many applications, for example, self-healing polymers and gels, triggered release of entrapped molecules for drug delivery, and “smart” materials. In this study, a four H-bond ureidopyrimidinone (UPy) array with an alkyl-pyridinium, (RP), redox center has been synthesized, UPy(RP), shown below. This array prefers the tautomer that presents an ADAD H-bond motif in the starting oxidation state. Due to electrostatic repulsions and unfavorable secondary H-bond interactions, this motif would form a dimer with relatively weak H-bonding. Upon 2e- reduction, where 1e-is gained per R-pyridinium redox center, the H-bond strength should increase due to the loss of the repulsive charges, making the nitrogen a stronger hydrogen acceptor. Because the nitrogen is now a better hydrogen acceptor, there could be a possibility of an intermolecular proton transfer. This would encourage the tautomer to have an AADD motif that will make the H-bonding stronger by increasing the favorable secondary H-bond interactions. UPy dimers can exist in two tautomeric forms called pyrimidinol and pyrimidinone. In order to more efficiently study the electrochemistry of the two forms, two compounds, 4-acetylpyridinium (AcP) and N-methyl-4,4’-bipyridinium (MeV+), were used as model compounds. AcP resembles the pyrimidinone tautomer and MeV+ resembles the pyrimidinol tautomer. The cyclic voltammetry (CV) scans for the two model compounds in CH2Cl2 and CH3CN show two widely spaced, reversible redox waves. UPy(RP) is insoluble in CH2Cl2, but soluble in CH3CN. The concentration dependent NMR spectra suggest that UPy(RP) is a monomer in acetonitrile. The CV’s of UPy(RP) in CH3CN show three reductions. The first occurs at a potential very similar to that seen with simple model compounds. The second is considerably positive of that observed for the model compounds and the third is very close to the second reduction peak of the model compounds. The first reduction is reversible if the scan direction is switched immediately after the peak, but irreversible if the scan direction is switched after the second reduction peak. As the scan rate increases, the second and the third reduction peaks disappear and a new peak emerges in between. Going through the second and third reductions also leads to the appearance of new oxidation waves at more positive potentials. DFT calculations suggest the preferred tautomer changes upon reduction, and this may explain the unexpected voltammetry observed in acetonitrile where the compound is not dimerized. Further studies to help elucidate what is actually happening in this system will include using a new counter anion in the electrolyte to help the solubility of the compound in CH2Cl2. Figure 1

Effect of Guest Binding on a Redox Active Three Hydrogen Bond Array

Proton-coupled electron transfer (PCET) reactions are essential to many of the fundamental chemical processes of life. In the Smith group we are investigating the role of H-bonding intermediates in PCET by studying the voltammetry of compounds capable of multiple, strong H-bond interactions. In particular we have studied a p-phenylenediamine-based urea, U(H)H, which contains two H donor sites making a DD array. In this study, the phenyl group in U(H)H is replaced by an imidazole group to form a three hydrogen bond array, UImH. In this array, the two major conformers both present a DDA H-bond motif (1 and 2 in Fig 1). Therefore, AAD arrays, such as APy, are needed as guest compounds to form three intermolecular non-covalent contacts. The cyclic voltammetry of UImH has been examined in methylene chloride and acetonitrile with platinum (Pt) and glassy carbon (GC) electrodes. On both electrodes, CV’s show two, closely-spaced, reversible waves of similar height. We initially hypothesized that the first electron oxidation happens on the phenylenediamine unit, followed by rapid intramolecular proton transfer in conformer 2, Fig. 1. The second electron is removed at a slightly more positive potential due to the positive charge remaining on the array after the first oxidation. However, the voltammetry is observed to have a strong concentration dependence and this cannot be explained by this mechanism. Based on the CVs we now propose the first wave is due to loss of 2e- from UImH with an intramolecular PT to form UImH2+. Then UImH2+ undergoes an intermolecular PT with unreacted UImH to produce UIm+ and HUImH+. The second wave is due to 2e- oxidation HUImH+ to form HUImH3+ at a more positive potential. Lastly, an intermolecular PT between HUImH3+and UIm+ gives the final product UImH2+. Addition of the guest, APy, results in is a slight increase in the current of the CV waves of UImH. This could be due to preferential binding and stabilization of UImH which prevents decomposition and adsorption. Surprisingly, very little change in the potential of the CV wave is observed upon addition of the guest, indicating that oxidation does not change binding strength. Even though the H-donors in UImH2+ should be stronger than in UImH, the H-acceptor in UImH2+ is weaker than in UImH. So the two effects cancel each other. Figure 1

Investigation of a Redox-Responsive 4 H-Bond Array Capable of Strong Self-Dimerization

The design of stimuli-responsive systems in which supramolecular structure changes in response to external signals, such as the change in voltage of an electrode, is important for many applications, for example, self-healing polymers and gels, triggered release of entrapped molecules for drug delivery, and “smart” materials. In this study, a four H-bond ureidopyrimidinone (UPy) array with an alkyl-pyridinium, (RP), redox center has been synthesized, UPy(RP), shown below. This array prefers the tautomer that presents an ADAD H-bond motif in the starting oxidation state. Due to electrostatic repulsions and unfavorable secondary H bond interactions, this motif would form a dimer with relatively weak H-bonding. Upon 2e- reduction, where 1e- is gained per R-pyridinium redox center, the H-bond strength should increase due to the loss of the repulsive charges, making the nitrogen a stronger hydrogen acceptor. Because the nitrogen is now a better hydrogen acceptor, there could be a possibility of an intermolecular proton transfer. This would encourage the tautomer to have an AADD motif that will make the H-bonding stronger by increasing the favorable secondary H-bond interactions. UPy dimers can exist in two tautomeric forms called pyrimidinol and pyrimidinone. In order to more efficiently study the electrochemistry of the two forms, two compounds, 4-acetylpyridinium (AcP) and N-methyl-4,4’-bipyridinium (MeV+), were used as model compounds. AcP resembles the pyrimidinone tautomer and MeV+ resembles the pyrimidinol tautomer. The cyclic voltammetry (CV) scans for the two model compounds in CH2Cl2 and CH3CN show two widely spaced, reversible redox waves. In contrast, CV’s of UPy(RP) in these solvents show two closely spaced reductions. The first occurs at a potential very similar to that seen with simple model compounds. The second is considerably positive of that observed for the model compounds, consistent with strong stabilization of the doubly reduced form by H-bonding. However, the voltammetry is complex. The first reduction is partially reversible if the scan direction is switched immediately after the peak, but irreversible if the scan direction is switched after the second reduction peak. Going through the second reduction also leads to the appearance of new oxidation waves at more positive potentials. This behavior suggests, not surprisingly, that the second reduction induces proton transfer and tautomerization. It is possible that the new oxidation peaks are due to oxidation of a more strongly H-bonded dimer. Further studies to help elucidate what is actually happening in this system will include concentration dependent CV’s and analysis of binding strength using NMR. Figure 1

Triazine-Based Sequence-Defined Polymers with Side-Chain Diversity and Backbone-Backbone Interaction Motifs.

Sequence control in polymers, well‐known in nature, encodes structure and functionality. Here we introduce a new architecture, based on the nucleophilic aromatic substitution chemistry of cyanuric chloride, that creates a new class of sequence‐defined polymers dubbed TZPs. Proof of concept is demonstrated with two synthesized hexamers, having neutral and ionizable side chains. Molecular dynamics simulations show backbone–backbone interactions, including H‐bonding motifs and pi–pi interactions. This architecture is arguably biomimetic while differing from sequence‐defined polymers having peptide bonds. The synthetic methodology supports the structural diversity of side chains known in peptides, as well as backbone–backbone hydrogen‐bonding motifs, and will thus enable new macromolecules and materials with useful functions.

Supramolecular self-assembly of N-acetyl Beta3-peptide amphiphiles

Event Abstract Back to Event Supramolecular self-assembly of N-acetyl Beta3-peptide amphiphiles Nathan Habila1, Ketav P. Kulkarni1, Tzong-Hsien Lee1, Mark P. Del Borgo1 and Mibel I. Aguilar1 1 Monash University, Biochemistry and Molecular Biology, Australia Self-assembly (SA) of peptides provides a flexible approach to developing novel materials with tailored morphologies and desired functions by modulating design and engineering of monomers[1]-[3]. Natural amino acids have been frequently utilized in the design of sequences. Although promising, they still have some draw backs in terms of structural and metabolic stability as well as ease of functionalization[4]. Using peptides consisting of only β-amino acids offers the means to overcome these limitations. Recently, our group reported that N-terminal acetylated β3-peptides can self-assemble by head-to-tail into helical fibrils through a supramolecular three point H-bonding motif[5]. We have also tuned the self-assembly of β3-peptides to present a range of morphologies by the appropriate solvent medium[6]. In order to further understand the control of self-assembly and engineer new architectures, here we show a new class of β3-peptide amphiphiles consisting of alkyl chains of either C12, C14 or C16 that can self-assemble in a unique pattern. Self-assembly was investigated using atomic force microscopy and transmission electron microscopy. The alkyl chain was attached at different positions and β3-peptide amphiphiles with identical composition but with a different sequence arrangement and position of alkyl chain self-assembled into different types of nanostructures under the same conditions. We found that β3-peptide amphiphiles with the alkyl chain on the N-terminus or residue 1 self-assembled into twisted fibrous nanostructures. By comparison, when the alkyl chain is located at residue 2 or 3, self-assembly resulted in flat nanobelts. The results clearly demonstrate the significance of the position of an alkyl chain on the peptide backbone sequence in determining supramolecular architectures. These outcomes will give further insight into the design and control of β3-peptide amphiphile self-assembly.

Predicting Cocrystallization Based on Heterodimer Energies: The Case of N,N′-Diphenylureas and Triphenylphosphine Oxide

Diarylureas frequently assemble into structures with one-dimensional H-bonded chain motifs. Herein, we examine the ability of triphenylphosphine oxide (TPPO) to disrupt the H-bonding motif in 14 different meta-substituted N,N′-diphenylureas (mXPU) and form cocrystals; 1:1 mXPU:TPPO cocrystals were obtained in 9 of 14 cases examined (64% success rate). Cocrystals adopt five different lattice types, all of which show unsymmetrical H-bonded [R21(6)] dimers between the urea hydrogens and the phosphine oxygen. Heterodimer (mXPU···TPPO) and homodimer (mXPU···mXPU) interaction energies, ΔEint, calculated using density functional theory at the B3LYP/6-31G(d,p) level were used to rationalize the experimental results. A clear trend was observed in which cocrystals were experimentally realized only in cases in which the differences in heterodimer versus homodimer energy, ΔΔEint, were greater than ∼5.3–6 kcal/mol. Although calculated interaction energies are a simplified measure of the system thermodynamics, these re...

Simultaneous Interaction of Hydrophilic and Hydrophobic Solvents with Ethylamino Neurotransmitter Radical Cations: Infrared Spectra of Tryptamine(+)-(H2O)m-(N2)n Clusters (m,n ≤ 3).

Solvation of biomolecules by a hydrophilic and hydrophobic environment strongly affects their structure and function. Here, the structural, vibrational, and energetic properties of size-selected clusters of the microhydrated tryptamine cation with N2 ligands, TRA(+)-(H2O)m-(N2)n (m,n ≤ 3), are characterized by infrared photodissociation spectroscopy in the 2800-3800 cm(-1) range and dispersion-corrected density functional theory calculations at the ωB97X-D/cc-pVTZ level to investigate the simultaneous solvation of this prototypical neurotransmitter by dipolar water and quadrupolar N2 ligands. In the global minimum structure of TRA(+)-H2O generated by electron ionization, H2O is strongly hydrogen-bonded (H-bonded) as proton acceptor to the acidic indolic NH group. In the TRA(+)-H2O-(N2)n clusters, the weakly bonded N2 ligands do not affect the H-bonding motif of TRA(+)-H2O and are preferentially H-bonded to the OH groups of the H2O ligand, whereas stacking to the aromatic π electron system of the pyrrole ring of TRA(+) is less favorable. The natural bond orbital analysis reveals that the H-bond between the N2 ligand and the OH group of H2O cooperatively strengthens the adjacent H-bond between the indolic NH group of TRA(+) and H2O, while π stacking is slightly noncooperative. In the larger TRA(+)-(H2O)m clusters, the H2O ligands form a H-bonded solvent network attached to the indolic NH proton, again stabilized by strong cooperative effects arising from the nearby positive charge. Comparison with the corresponding neutral TRA-(H2O)m clusters illustrates the strong impact of the excess positive charge on the structure of the microhydration network.

Vibrational dephasing in ionic liquids as a signature of hydrogen bonding.

Understanding both structure and dynamics is crucial for producing tailor-made ionic liquids (ILs). We studied the vibrational and structural dynamics of medium versus weakly hydrogen-bonded CH groups of the imidazolium ring in ILs of the type [1-alkyl-3-methylimidazolium][bis(trifluoromethanesulfonyl)imide] ([Cn mim][NTf2 ]), with n=1, 2, and 8, by time-resolved coherent anti-Stokes Raman scattering (CARS) and quantum-classical hybrid (QCH) simulations. From the time series of the CARS spectra, dephasing times were extracted by modeling the full nonlinear response. From the QCH calculations, pure dephasing times were obtained by analyzing the distribution of transition frequencies. Experiments and calculations reveal larger dephasing rates for the vibrational stretching modes of C(2)H compared with the more weakly hydrogen-bonded C(4,5)H. This finding can be understood in terms of different H-bonding motifs and the fast interconversion between them. Differences in population relaxation rates are attributed to Fermi resonance interactions.

The Effect of Intra Vs. Intermolecular Proton Transfer on the Oxidation of Phenylenediamine-Based Ureas

Recently, we have been examining the role that H-bonding intermediates play in the mechanism of proton-coupled electron transfer using an electroactive phenylene-diamine based urea, U(H)H (Clare et al., J. Am. Chem. Soc. 2013, 135, 18930-41). This compound appears to undergo a reversible one electron oxidation to the radical cation in methylene chloride that in fact corresponds to two electron oxidation of half the ureas to the quinoidal form, accompanied by proton transfer to the dimethylamino group and subsequent deactivation of the other half of the ureas, 2U(H)H = U(H)+ + H(U)H+ + 2 e-. The reaction gives chemically irreversible voltammetry in acetonitrile as would be expected given that the product quinoidal cation, U(H)+, is harder to reduce than the initially formed radical cation. However, it gives reversible voltammetry in methylene chloride because the reverse reaction can proceed through the H-bonded complex formed between U(H)+ and H(U)H+, which is easier to reduce than the quinoidal cation. In new work reported here, we have modified U(H)H by replacing the phenyl group with an imidazole group, compound 1 in Fig. 1. With 1, the two major conformers, 1a/1b, both present a donor-donor-acceptor (DDA) H-bond motif and therefore are capable of binding compounds with the opposite (AAD) motif through three H-bonds. While our plan is to investigate the electrochemistry of 1 in the presence of such guests, initial voltammetry of 1 by itself has produced interesting results that are quite different from those observed with U(H)H. CV’s of 1 in both acetonitrile and methylene chloride show two, closely-spaced, reversible waves of equal height. This contrasts with CV’s of U(H)H where only a single CV wave is seen that is reversible in methylene chloride and irreversible in acetonitrile. We hypothesize that this difference is due to rapid intramolecular proton transfer in conformer 1b, Fig. 1, after one electron oxidation. This beats out the intermolecular proton transfer that occurs with U(H)H and leads to deactivation of half of the ureas. Unlike U(H)H, with 1, complete two electron oxidation of all the ureas near the electrode is possible, although the second oxidation occurs at a slightly more positive potential due to the positive charge remaining on the molecule after the first oxidation. Interestingly, there is also a strong concentration dependence to the CV’s. When the concentration increases, the relative currents of both peaks decrease. We hypothesize that this is because the highly acidic doubly oxidized product produced at the electrode can protonate reduced 1 coming in from the bulk in a secondary intermolecular proton transfer. Since the dimethylamino group is the most basic site on 1, it gets protonated, resulting in the deactivation of incoming urea. When the concentration increases, this transfer will be faster, resulting in a smaller amount of active urea reaching the electrode. Thus, although rapid intramolecular proton transfer in 1 allows for complete oxidation of 1 near the electrode, in the bigger picture, intermolecular proton transfer still results in less than full oxidation of all the urea. Figure 1

Proton-Coupled Electron Transfer in an Electroactive Three Hydrogen Bond Dda Array Capable of Binding an Aad Guest

Proton-coupled electron transfer (PCET) reactions are essential to many of the fundamental chemical processes of life. In the Smith group we are investigating the role of H-bonding intermediates in PCET by studying the voltammetry of compounds capable of multiple, strong H-bond interactions. In particular we have studied a p-phenylenediamine-based urea, U(H)H, which contains two H donor sites making a DD array. This compound undergoes an apparent one electron oxidation in aprotic solvents that actually corresponds to two electron oxidation of half of the ureas to a quinoidal cation, U(H)+, accompanied by proton transfer to and deactivation of the other half of the ureas by formation of HU(H)H+. This oxidation is reversible in methylene chloride due to the stability of the H-bond complex formed between U(H)+ and HU(H)H+.1 In this study, the phenyl group in U(H)H is replaced by an imidazole group to form a three hydrogen bond array. In this array, the two major conformers both present a DDA H-bond motif (1 and 2). Therefore, AAD arrays are needed as guest compounds to form three intermolecular non-covalent contacts. The cyclic voltammetry of the three hydrogen bond DDA array has been examined in methylene chloride with platinum (Pt) and glassy carbon (GC) electrodes. On both electrodes, CV’s show two, closely-spaced, reversible waves of equal height. This contrasts with CV’s of U(H)H where only a single reversible CV wave is seen. We hypothesize that this difference is due to rapid intramolecular proton transfer in conformer 2, after one electron oxidation of the phenylenediamine unit. This out competes the intermolecular proton transfer to the dimethylamino group on another phenylenediamine that occurs with U(H)H and results in deactivation of half of the ureas. With 1 and 2, complete two electron oxidation of all the ureas near the electrode is possible, although the second oxidation occurs at a slightly more positive potential due to the positive charge remaining on the array after the first oxidation. Interestingly, there is also a strong concentration dependence to the CV’s. When the concentration increases, the relative currents of both peaks decrease. We hypothesize that this is because proton transfer also happens between the highly acidic 5, produced at the electrode, and 2 coming in from the bulk. Since the dimethylamino group is the most basic site on 2, it gets protonated, resulting in the deactivation of incoming urea. When the concentration increases, this transfer will be faster, resulting in a smaller amount of active urea reaching the electrode. In future work, the voltammetry of the electroactive DDA array will be investigated in the presence of an AAD guest to determine if and how this changes the mechanism of the oxidation. 1. Clare, L. A.; Pham A. T.; Magdaleno, F.; Acosta, J.; Woods, J. E.; Cooksy, A. L.; Smith, D. K. J. Am. Chem. Soc., 2013, 135(50), 18930–18941. 2. Andrea M. McGhee, Colin Kilner and Andrew J. Wilson. Chem. Commun., 2008, 344-346. Figure 1

Analysis of a Four H-Bond Array Using Cyclic Voltammetry: Introducing a New Redox Center to Strengthen Dimerization

Hydrogen bonding arrays are useful building blocks for supramolecular chemistry due to their strong hydrogen bond interactions that can form dimers. The strength of the H-bond interactions can be perturbed by applying an external stimuli, in this case electron transfer. Recently, our group has modified Meijer’s four H-bond ureidopyrimidinone (UPy) array1 to make it electroactive by adding a dimethylaminophenyl group. The modified structure forms strong H-bond interactions in CH2Cl2, creating a dimer that can undergo a reversible 2e-oxidation, followed by an irreversible oxidation at more positive potentials. The latter results in the break-up of the dimer due to electrostatic repulsion. For this study, we aim to modify another four H-bond Upy array by introducing a methyl pyridinium redox center as shown below. We hypothesize that this array will prefer the tautomer that presents an ADAD H-bond motif in the starting oxidation state. This motif will form a dimer with relatively weak H-bond interactions due to electrostatic repulsions and also unfavorable secondary H-bond interactions. Upon 2e- reduction, where 1e- is gained for each methyl pyridinium redox center, the H-bond strength should increase due to the loss of repulsive charges and also allows the nitrogen to become a stronger hydrogen acceptor. Since the resulting nitrogen is now a better H-acceptor, there is a possibility of intermolecular proton transfer which will induce the tautomer to have an AADD motif that will further strengthen the H-bonds by favorable secondary H-bond interactions. 1. Beijer, F.H.; Sijbesma, R.P.; Kooijman, H.; Spek, A.L.; Meijer, E.W. J. Am. Chem. Soc., 1998, 120 (27), pp 6761–6769. Figure 1