Exploring the Parameters Controlling Product Selectivity in Electrochemical CO2 Reduction in Competition with Hydrogen Evolution Employing Manganese Bipyridine Complexes.

Selective reduction of CO2 is an efficient solution for producing nonfossil-based chemical feedstocks and simultaneously alleviating the increasing atmospheric concentration of this greenhouse gas. With this aim, molecular electrocatalysts are being extensively studied, although selectivity remains an issue. In this work, a combined experimental-computational study explores how the molecular structure of Mn-based complexes determines the dominant product in the reduction of CO2 to HCOOH, CO, and H2. In contrast to previous Mn(bpy-R)(CO)3Br catalysts containing alkyl amines in the vicinity of the Br ligand, here, we report that bpy-based macrocycles locking these amines at the side opposite to the Br ligand change the product selectivity from HCOOH to H2. Ab initio molecular dynamics simulations of the active species showed that free rotation of the Mn(CO)3 moiety allows for the approach of the protonated amine to the reactive center yielding a Mn-hydride intermediate, which is the key in the formation of H2 and HCOOH. Additional studies with DFT methods showed that the macrocyclic moiety hinders the insertion of CO2 to the metal hydride favoring the formation of H2 over HCOOH. Further, our results suggest that the minor CO product observed experimentally is formed when CO2 adds to Mn on the side opposite to the amine ligand before protonation. These results show how product selectivity can be modulated by ligand design in Mn-based catalysts, providing atomistic details that can be leveraged in the development of a fully selective system.

Electrocatalytic Depolymerization of Self-Immolative Poly(Dithiothreitol) Derivatives.

We report the use of electrogenerated anthraquinone radical anion (AQ•-) to trigger fast catalytic depolymerization of polymers derived from poly(dithiothreitol) (pDTT)-a self-immolative polymer (SIP) with a backbone of dithiothreitols connected with disulfide bonds and end-capped via disulfide bonds to pyridyl groups. The pDTT derivatives studied include polymers with simple thiohexyl end-caps or modified with AQ or methyl groups by Steglich esterification. All polymers were shown to be depolymerized using catalytic amounts of electrons delivered by AQ•-. For pDTT, as little as 0.2 electrons per polymer chain was needed to achieve complete depolymerization. We hypothesize that the reaction proceeds with AQ•- as an electron carrier (either molecularly or as a pendant group), which transfers an electron to a disulfide bond in the polymer in a dissociative manner, generating a thiyl radical and a thiolate. The rapid and catalytic depolymerization is driven by thiyl radicals attacking other disulfide bonds internally or between pDTT chains in a chain reaction. Electrochemical triggering works as a general method for initiating depolymerization of pDTT derivatives and may likely also be used for depolymerization of other disulfide polymers.

Promoting Selective Generation of Formic Acid from CO2 Using Mn(bpy)(CO)3Br as Electrocatalyst and Triethylamine/Isopropanol as Additives.

Urgent solutions are needed to efficiently convert the greenhouse gas CO2 into higher-value products. In this work, fac-Mn(bpy)(CO)3Br (bpy = 2,2'-bipyridine) is employed as electrocatalyst in reductive CO2 conversion. It is shown that product selectivity can be shifted from CO toward HCOOH using appropriate additives, i.e., Et3N along with iPrOH. A crucial aspect of the strategy is to outrun the dimer-generating parent-child reaction involving fac-Mn(bpy)(CO)3Br and [Mn(bpy)(CO)3]- and instead produce the Mn hydride intermediate. Preferentially, this is done at the first reduction wave to enable formation of HCOOH at an overpotential as low as 260 mV and with faradaic efficiency of 59 ± 1%. The latter may be increased to 71 ± 3% at an overpotential of 560 mV, using 2 M concentrations of both Et3N and iPrOH. The nature of the amine additive is crucial for product selectivity, as the faradaic efficiency for HCOOH formation decreases to 13 ± 4% if Et3N is replaced with Et2NH. The origin of this difference lies in the ability of Et3N/iPrOH to establish an equilibrium solution of isopropyl carbonate and CO2, while with Et2NH/iPrOH, formation of the diethylcarbamic acid is favored. According to density-functional theory calculations, CO2 in the former case can take part favorably in the catalytic cycle, while this is less opportune in the latter case because of the CO2-to-carbamic acid conversion. This work presents a straightforward procedure for electrochemical reduction of CO2 to HCOOH by combining an easily synthesized manganese catalyst with commercially available additives.

Achieving Near-Unity CO Selectivity for CO2 Electroreduction on an Iron-Decorated Carbon Material.

A straightforward procedure has been developed to prepare a porous carbon material decorated with iron by direct pyrolysis of a mixture of a porous polymer and iron chloride. Characterization of the material with X-ray diffraction, X-ray absorption spectroscopy, and electron microscopy indicates the presence of iron carbide nanoparticles encapsulated inside the carbon matrix, and elemental mapping and cyanide poisoning experiments demonstrate the presence of atomic Fe centers, albeit in trace amounts, which are active sites for electrochemical CO2 reduction. The encapsulated iron carbide nanoparticles are found to boost the catalytic activity of atomic Fe sites in the outer carbon layers, rendering the material highly active and selective for CO2 reduction, although these atomic Fe sites are only present in trace amounts. The target material exhibits near-unity selectivity (98 %) for CO2 -to-CO conversion at a small overpotential (410 mV) in water. Furthermore, the material holds potential for practical application, as a current density over 30 mA cm-2 and a selectivity of 93 % can be achieved in a flow cell.

Ligand-Controlled Product Selectivity in Electrochemical Carbon Dioxide Reduction Using Manganese Bipyridine Catalysts.

Electrocatalysis is a promising tool for utilizing carbon dioxide as a feedstock in the chemical industry. However, controlling the selectivity for different CO2 reduction products remains a major challenge. We report a series of manganese carbonyl complexes with elaborated bipyridine or phenanthroline ligands that can reduce CO2 to either formic acid, if the ligand structure contains strategically positioned tertiary amines, or CO, if the amine groups are absent in the ligand or are placed far from the metal center. The amine-modified complexes are benchmarked to be among the most active catalysts for reducing CO2 to formic acid, with a maximum turnover frequency of up to 5500 s-1 at an overpotential of 630 mV. The conversion even works at overpotentials as low as 300 mV, although through an alternative mechanism. Mechanistically, the formation of a Mn-hydride species aided by in situ protonated amine groups was determined to be a key intermediate by cyclic voltammetry, 1H NMR, DFT calculations, and infrared spectroelectrochemistry.

Scalable carbon dioxide electroreduction coupled to carbonylation chemistry.

Significant efforts have been devoted over the last few years to develop efficient molecular electrocatalysts for the electrochemical reduction of carbon dioxide to carbon monoxide, the latter being an industrially important feedstock for the synthesis of bulk and fine chemicals. Whereas these efforts primarily focus on this formal oxygen abstraction step, there are no reports on the exploitation of the chemistry for scalable applications in carbonylation reactions. Here we describe the design and application of an inexpensive and user-friendly electrochemical set-up combined with the two-chamber technology for performing Pd-catalysed carbonylation reactions including amino- and alkoxycarbonylations, as well as carbonylative Sonogashira and Suzuki couplings with near stoichiometric carbon monoxide. The combined two-reaction process allows for milligram to gram synthesis of pharmaceutically relevant compounds. Moreover, this technology can be adapted to the use of atmospheric carbon dioxide.Electroreduction of CO2 to CO is a potential valorisation pathway of carbon dioxide for fine chemicals production. Here, the authors show a user-friendly device that couples CO2 electroreduction with carbonylation chemistry for up to gram scale synthesis of pharmaceuticals even under atmospheric CO2.

Enhanced Catalytic Activity of Cobalt Porphyrin in CO2 Electroreduction upon Immobilization on Carbon Materials.

In a comparative study of the electrocatalytic CO2 reduction, cobalt meso-tetraphenylporphyrin (CoTPP) is used as a model molecular catalyst under both homogeneous and heterogeneous conditions. In the former case, employing N,N-dimethylformamide as solvent, CoTPP performs poorly as an electrocatalyst giving low product selectivity in a slow reaction at a high overpotential. However, upon straightforward immobilization of CoTPP onto carbon nanotubes, a remarkable enhancement of the electrocatalytic abilities is seen with CO2 becoming selectively reduced to CO (>90 %) at a low overpotential in aqueous medium. This effect is ascribed to the particular environment created by the aqueous medium at the catalytic site of the immobilized catalyst that facilitates the adsorption and further reaction of CO2 . This work highlights the significance of assessing an immobilized molecular catalyst from more than homogeneous measurements alone.

Covalent Modification of Glassy Carbon Surfaces by Electrochemical Grafting of Aryl Iodides.

The reduction of an aryl iodide is generally believed to involve a clean-cut two-electron reduction to produce an aryl anion and iodide. This is in contradiction to what is observed if a highly efficient grafting agent, such as an aryldiazonium salt, is employed. The difference in behavior is explained by the much more extreme potentials required for reducing an aryl iodide, which facilitates the further reduction of the aryl radical formed as an intermediate. However, in this study we disclose that electrografting of aryl iodides is indeed possible upon extended voltammetric cycling. This implies that even if the number of aryl radicals left unreduced at the electrode surface is exceedingly small, a functionalization of the surface may still be promoted. In fact, the grafting efficiency is found to increase during the grafting process, which may be explained by the inhibiting effect the growing film exerts on the competing reduction of the aryl radical. The slow buildup of the organic film results in a well-ordered structure as shown by the well-defined electrochemical response from a grafted film containing ferrocenylmethyl groups. Hence, the reduction of aryl iodides allows a precisely controlled, albeit slow, growth of thin organic films.

Functionalizing Arrays of Transferred Monolayer Graphene on Insulating Surfaces by Bipolar Electrochemistry.

Development of versatile methods for graphene functionalization is necessary before use in applications such as composites or as catalyst support. In this study, bipolar electrochemistry is used as a wireless functionalization method to graft 4-bromobenzenediazonium on large (10 × 10 mm(2)) monolayer graphene sheets supported on SiO2. Using this technique, transferred graphene can be electrochemically functionalized without the need of a metal support or the deposition of physical contacts. X-ray photoelectron spectroscopy and Raman spectroscopy are used to map the chemical changes and modifications of graphene across the individual sheets. Interestingly, the defect density is similar between samples, independent of driving potential, whereas the grafting density is increased upon increasing the driving potential. It is observed that the 2D nature of the electrode influences the electrochemistry and stability of the electrode compared to conventional electrografting using a three-electrode setup. On one side, the graphene will be blocked by the attached organic film, but the conductivity is also altered upon functionalization, which makes the graphene electrode different from a normal metal electrode. Furthermore, it is shown that it is possible to simultaneously modify an array of many small graphene electrodes (1 × 1 mm(2)) on SiO2.

Controlled electropolymerisation of a carbazole-functionalised iron porphyrin electrocatalyst for CO2 reduction.

Using a one-step electropolymerisation procedure, CO2 absorbing microporous carbazole-functionalised films of iron porphyrins are prepared in a controlled manner. The electrocatalytic reduction of CO2 for these films is investigated to elucidate their efficiency and the origin of their ultimate degradation.

Synthetic heparan sulfate dodecasaccharides reveal single sulfation site interconverts CXCL8 and CXCL12 chemokine biology.

The multigram-scale synthesis of a sulfation-site programmed heparin-like dodecasaccharide is described. Evaluation alongside dodecasaccharides lacking this single glucosamine O6-sulfation, or having per-O6-sulfation, shows that site-specific modification of the terminal glucosamine dramatically interconverts regulation of in vitro and in vivo biology mediated by the two important chemokines, CXCL12 (SDF1α) or CXCL8 (IL-8).

Modular synthesis of heparin-related tetra-, hexa- and octasaccharides with differential o-6 protections: programming for regiodefined 6-o-modifications.

Heparin and heparan sulphate (H/HS) are important members of the glycosaminoglycan family of sugars that regulate a substantial number of biological processes. Such biological promiscuity is underpinned by hetereogeneity in their molecular structure. The degree of O-sulfation, particularly at the 6-position of constituent D-GlcN units, is believed to play a role in modulating the effects of such sequences. Synthetic chemistry is essential to be able to extend the diversity of HS-like fragments with defined molecular structure, and particularly to deconvolute the biological significance of modifications at O6. Here we report a synthetic approach to a small matrix of protected heparin-type oligosaccharides, containing orthogonal D-GlcN O-6 protecting groups at programmed positions along the chain, facilitating access towards programmed modifications at specific sites, relevant to sulfation or future mimetics.

Patterned Carboxylation of Graphene Using Scanning Electrochemical Microscopy.

A simple, direct, and versatile scanning electrochemical microscopy (SECM) approach for local carboxylation of multilayered graphene on nickel is demonstrated, in which carbon dioxide serves as the carboxylation agent under reductive conditions in N,N-dimethylformamide. The use of SECM gives control over both the spatial dimensions and the degree of carboxylation. While the pattern size, in general, is governed by the dimension of the SECM tip, the degree of modification, expressed as the surface coverage of carboxylate groups introduced at the graphene substrate, is found to be controlled by the electrolysis time. This is supported by electrochemical measurements, two-dimensional X-ray photoelectron spectroscopy, Raman spectroscopy mapping, and He ion microscopy. Surprisingly, intercalation of the supporting electrolyte in the multilayered graphene on nickel occurs to a relatively small extent when compared to corresponding results obtained in previously described carboxylations of this kind of multilayered graphene.

Synthesis of L-iduronic acid derivatives via [3.2.1] and [2.2.2] L-iduronic lactones from bulk glucose-derived cyanohydrin hydrolysis: a reversible conformationally switched superdisarmed/rearmed lactone route to heparin disaccharides.

L-Idofuranoside cyanohydrin 1 is converted on large scale into a mixture of L-IdoA methyl pyranosides and furanosides, which is converged to provide short 2-step routes to bicyclic [3.2.1] or [2.2.2] L-iduronate lactones. The former is obtained via a 100 g scale synthesis of 3-OBn L-IdoA. A two-step conversion of this mixture provides either pure anomer of the novel [2.2.2] l-iduronate thioglycoside lactones. Both [3.2.1] and [2.2.2] lactones are converted into GlcN-IdoA heparin precursor disaccharides. The [2.2.2] lactone enables a scalable 3-step route from 1 to a new type of highly disarmed O-4 iduronate thioglycoside, which is an effective acceptor with glucoazide thioglycoside donors. The resulting new iduronic [2.2.2] lactone disaccharides are readily rearmed by mild methanolysis to provide GlcN-IdoA thiophenyl disaccharide donors, intercepting their established utility for the assembly of both heparin- and heparan sulfate-like oligosaccharides. The [2.2.2] lactonization acts as a conformational switch to superdisarm iduronate components, reversible by lactone ring opening. In addition, the separated 2,4-diacetates also provide short access to all four anomeric and ring size isomers of l-iduronic acid methyl glycosides, including the first syntheses of the parent idofuranosides. X-ray structures are reported for a [2.2.2] iduronate lactone and examples of both methyl L-idopyranoside and novel methyl-L-idofuranoside systems.

Making the longest sugars: a chemical synthesis of heparin-related [4] n oligosaccharides from 16-mer to 40-mer.

The chemical synthesis of long oligosaccharides remains a major challenge. In particular, the synthesis of glycosaminoglycan (GAG) oligosaccharides belonging to the heparin and heparan sulfate (H/HS) family has been a high profile target, particularly with respect to the longer heparanome. Herein we describe a synthesis of the longest heparin-related oligosaccharide to date and concurrently provide an entry to the longest synthetic oligosaccharides of any type yet reported. Specifically, the iterative construction of a series of [4] n -mer heparin-backbone oligosaccharides ranging from 16-mer through to the 40-mer in length is described. This demonstrates for the first time the viability of generating long sequence heparanoids by chemical synthesis, via practical solution-phase synthesis. Pure-Shift HSQC NMR provides a dramatic improvement in anomeric signal resolution, allowing full resolution of all 12 anomeric protons and extrapolation to support anomeric integrity of the longer species. A chemically pure 6-O-desfulfated GlcNS-IdoAS icosasaccharide (20-mer) represents the longest pure synthetic heparin-like oligosaccharide.

Synthesis of a heparin-related GlcN-IdoA sulfation-site variable disaccharide library and analysis by Raman and ROA spectroscopy.

Synthesis of an array of differentially sulfated GlcN-IdoA disaccharides, accessible on good scale, directly from l-iduronate components is described. These are specifically directed to provide the sulfation variability at the key most common biologically relevant sulfation-variable l-IdoA O-2 and d-GlcN O-6 and amino sites of this heparin disaccharide. This sulfation-varied matrix has allowed the first evaluation of using Raman/ROA spectroscopy to characterize changes in spectra as a function of both site and level of sulfation with pure, defined heparin-related disaccharide species. This provides analysis of both similarities and differences to digest native heparin and this shows evidence of different types of changes in conformations and conformational freedom as a function of some specific sulfation changes at the disaccharide level. It is anticipated that this data set will open the way for applications to further site-specific sulfated saccharides and demonstrates the capability offered by Raman-ROA towards fingerprinting sulfation in heparin fragments.

The development of anti-angiogenic heparan sulfate oligosaccharides.

Angiogenesis has emerged as a novel target for anti-cancer therapies through randomized clinical trials that tested the benefit of adding vascular endothelial growth factor (VEGF) inhibitors to conventional cytotoxic therapies. However, despite improvements in the progression-free survival, the benefit in overall survival is modest. Tumour angiogenesis is regulated by a number of angiogenic cytokines. Thus innate or acquired resistance to VEGF inhibitors can be caused, at least in part, through expression of other angiogenic cytokines, including fibroblast growth factor 2 (FGF2), interleukin 8 (IL-8) and stromal-cell-derived factor 1α (SDF-1α), which make tumours insensitive to VEGF signalling pathway inhibition. The majority of angiogenic cytokines, including VEGF-A, FGF2, IL-8 and SDF-1α, manifest an obligate dependence on heparan sulfate (HS) for their biological activity. This mandatory requirement of angiogenic cytokines for HS identifies HS as a potential target for novel anti-angiogenic therapy. Targeting multiple angiogenic cytokines with HS mimetics may represent an opportunity to inhibit tumour angiogenesis more efficiently. Our published studies and unpublished work have demonstrated the feasibility of generating synthetic HS fragments of defined structure with biological activity against a number of angiogenic cytokines.

Controlled electrochemical carboxylation of graphene to create a versatile chemical platform for further functionalization.

An electrochemical approach is introduced for the versatile carboxylation of multi-layered graphene in 0.1 M Bu4NBF4/MeCN. First, the graphene substrate (i.e., graphene chemically vapor-deposited on Ni) is negatively charged at -1.9 V versus Ag/AgI in a degassed solution to allow for intercalation of Bu4N(+) and, thereby, separation of the individual graphene sheets. In the next step, the strongly activated and nucleophilic graphene is allowed to react with added carbon dioxide in an addition reaction, introducing carboxylate groups stabilized by Bu4N(+) already present. This procedure may be carried out repetitively to further enhance the carboxylation degree under controlled conditions. Encouragingly, the same degree of control is even attainable, if the intercalation and carboxylation is carried out simultaneously in a one-step procedure, consisting of simply electrolyzing in a CO2-saturated solution at the graphene electrode for a given time. The same functionalization degree is obtained for all multi-layered regions, independent of the number of graphene sheets, which is due to the fact that the entire graphene structure is opened in response to the intercalation of Bu4N(+). Hence, this electrochemical method offers a versatile procedure to make all graphene sheets in a multi-layered but expanded structure accessible for functionalization. On a more general level, this approach will provide a versatile way of forming new hybrid materials based on intimate bond coupling to graphene via carboxylate groups.

High- versus low-quality graphene: a mechanistic investigation of electrografted diazonium-based films for growth of polymer brushes.

Electrografting using aryldiazonium salts provides a fast and efficient technique to functionalize commercially available 3-5 layered graphene (vapour-deposited) on nickel. In this study, Raman spectroscopy is used to quantify the grafting efficiency of cyclic voltammetry which is one of the most versatile, yet simple, electrochemical techniques available. To a large extent the number of defects/substituents introduced to the basal plane of high-quality graphene by this procedure can be controlled through the sweeping conditions employed. After extended electrografting the defect density reaches a saturation level ( ∼ 10(13) cm(-2)) which is independent of the quality of the graphene expressed through its initial content of defects. However, it is reached within fewer voltammetric cycles for low-quality graphene. Based on these results it is suggested that the grafting occurs (a) directly at defect sites for, in particular, low-quality graphene, (b) directly at the basal plane for, in particular, high-quality graphene, and/or (c) at already grafted molecules to give a mushroom-like film growth for all films. Moreover, it is shown that a tertiary alkyl bromide can be introduced at a given surface density to serve as radical initiator for surface-initiated atom transfer radical polymerization (SI-ATRP). Brushes of poly(methyl methacrylate) are grown from these substrates, and the relationship between polymer thickness and sweeping conditions is studied.

Tetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies.

Heparin-like oligosaccharides mediate numerous important biological interactions, of which many are implicated in various diseases. Synthetic improvements are central to the development of such oligosaccharides as therapeutics and, in addition, there are no methods to elucidate the pharmacokinetics of structurally defined heparin-like oligosaccharides. Here we report an efficient two-cycle [4+4+4] tetrasaccharide-iteration-based approach for rapid chemical synthesis of a structurally defined heparin-related dodecasaccharide, combined with the incorporation of a latent aldehyde tag, unmasked in the final step of chemical synthesis, providing a generic end group for labelling/conjugation. We exploit this latent aldehyde tag for (3)H radiolabelling to provide the first example of this kind of agent for monitoring in vivo tissue distribution and in vivo stability of a biologically active, structurally defined heparin related dodecasaccharide. Such studies are critical for the development of related saccharide therapeutics, and the data here establish that a biologically active, synthetic, heparin-like dodecasaccharide provides good organ distribution, and serum lifetimes relevant to developing future oligosaccharide therapeutics.