Nanoscale Carbonate Ion-Selective Amperometric/Voltammetric Probes Based on Ion-Ionophore Recognition at the Organic/Water Interface: Hidden Pieces of the Puzzle in the Nanoscale Phase.

Here, we report on the successful demonstration and application of carbonate (CO32-) ion-selective amperometric/voltammetric nanoprobes based on facilitated ion transfer (IT) at the nanoscale interface between two immiscible electrolyte solutions. This electrochemical study reveals critical factors to govern CO32--selective nanoprobes using broadly available Simon-type ionophores forming a covalent bond with CO32-, i.e., slow dissolution of lipophilic ionophores in the organic phase, activation of hydrated ionophores, peculiar solubility of a hydrated ion-ionophore complex near the interface, and cleanness at the nanoscale interface. These factors are experimentally confirmed by nanopipet voltammetry, where a facilitated CO32- IT is studied with a nanopipet filled with an organic phase containing the trifluoroacetophenone derivative CO32-ionophore (CO32-ionophore VII) by voltammetrically and amperometrically sensing CO32- in water. Theoretical assessments of reproducible voltammetric data confirm that the dynamics of CO32- ionophore VII-facilitated ITs (FITs) follows the one-step electrochemical (E) mechanism controlled by both water-finger formation/dissociation and ion-ionophore complexation/dissociation during interfacial ITs. The yielded rate constant, k0 = 0.048 cm/s, is very similar to the reported values of other FIT reactions using ionophores forming non-covalent bonds with ions, implying that a weak binding between CO32- ion-ionophore enables us to observe FITs by fast nanopipet voltammetry regardless of the nature of bondings between the ion and ionophore. The analytical utility of CO32--selective amperometric nanoprobes is further demonstrated by measuring the CO32- concentration produced by metal-reducing bacteria Shewanella oneidensis MR-1 as a result of organic fuel oxidation in bacterial growth media in the presence of various interferents such as H2PO4-, Cl-, and SO42-.

The mechanistic duality of (thio)urea organocatalysts for ring-opening polymerization.

Among the various catalysts for ROP, H-bonding organocatalysts stand out in the precise level of reaction control they are able to render during ROP. The H-bonding class of organocatalysts are thought to effect ROP via dual activation of both monomer and chain end. (Thio)urea mediated ROP has experienced a renaissance as a new polymerization mechanism - mediated by imidate or thioimidate species - facilitates new modes of reactivity and new synthetic abilities. Indeed, the urea class of H-bond donors has been shown to be more active than their corresponding thioureas. The imidate mechanism remains highly active in polar solvents and exhibits remarkable control - and 'living' behavior - under solvent-free conditions, and a broad range of temperatures is accessible. The advancements in synthetic abilities have all evolved through a greater understanding of reaction mechanism. Through the continued synergistic advances of catalysis and material, the (thio)urea class of catalyst can find use in a host of potential applications, research and industrial environments.

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells.

The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.

Topical Developments in High-Field Dynamic Nuclear Polarization.

We report our recent efforts directed at improving high-field DNP experiments. We investigated a series of thiourea nitroxide radicals and the associated DNP enhancements ranging from ε = 25 to 82 that demonstrate the impact of molecular structure on performance. We directly polarized low-gamma nuclei including 13C, 2H, and 17O using trityl via the cross effect. We discuss a variety of sample preparation techniques for DNP with emphasis on the benefit of methods that do not use a glass-forming cryoprotecting matrix. Lastly, we describe a corrugated waveguide for use in a 700 MHz / 460 GHz DNP system that improves microwave delivery and increases enhancements up to 50%.

N-Heterocyclic carbene-based gold etchants.

N-Heterocyclic carbenes (NHCs) are an emerging alternative to thiols for the formation of stable self-assembled monolayers (SAMs) on gold. We examined several different species that have been used to produce NHC-based monolayers on gold, namely 1,3-diisopropyl-5-nitrobenzimidazolium iodide, 1,3-diisopropyl-5-nitrobenzimidazolium hydrogen carbonate, bis(1,3-diisopropyl-5-nitrobenzimidazolium)gold(I) iodide, and 1,3-diisopropyl-5-nitrobenzimidazole-2-ylidene. Contrary to expectation, solutions containing the first two species in tetrahydrofuran and dichloromethane caused visible loss of gold from thin-film-coated glass slides. The use of toluene solutions of all species resulted in no apparent dissolution of gold. We present scanning electron micrographs and elemental imaging analyses by energy dispersive X-ray spectroscopy to examine the effect of solutions of each species on the gold film. This work highlights the risk of unwanted etching during some routes to NHC-based surface functionalization but also the potential for deliberate etching, with the outcome determined by choice of chemically synthesized organic species and solvent.

Dynamic nuclear polarization with a water-soluble rigid biradical.

A new biradical polarizing agent, bTbtk-py, for dynamic nuclear polarization (DNP) experiments in aqueous media is reported. The synthesis is discussed in light of the requirements of the optimum, theoretical, biradical system. To date, the DNP NMR signal enhancement resulting from bTbtk-py is the largest of any biradical in the ideal glycerol/water solvent matrix, ε = 230. EPR and X-ray crystallography are used to characterize the molecule and suggest approaches for further optimizing the biradical distance and relative orientation.

Organocatalytic synthesis of quinine-functionalized poly(carbonate)s.

The ring-opening polymerization of substituted cyclic carbonates with 1-(3,5-bis-trifluoromethyl-phenyl)-3-cyclohexyl-thiourea (TU)/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) organocatalysts afford highly functionalized oligocarbonates. The fluorescent alkaloid quinine can be readily incorporated into the oligocarbonates either by initiation from quinine or by ring-opening polymerization of a quinine-functionalized cyclic carbonate (MTC-Q). Copolymerization of MTC-Q with a boc-protected guanidinium cyclic carbonate affords, after deprotection, highly water-soluble cationic copolymers functionalized with both quinine and pendant guanidinium groups. When multiple quinine groups are attached to the oligomers, they exhibit minimal fluorescence due to self-quenching. Upon hydrolysis, the fluorescence intensity increases, providing a potential strategy for monitoring the hydrolysis rates in real time.

Using Surrogate Insects in Acid Bioassays for Development of New Controls for Varroa destructor (Arachnida: Varroidae).

Resistance to traditional synthetic compounds by Varroa destructor Anderson and Trueman and shortcomings of the organic acid class of acaracides commonly used in varroa management requires continual development of new controls. V. destructor, however, are difficult to obtain for use in control bioassays because they are obligate parasites that cannot be easily reared outside of a honey bee colony. We conducted bioassays using other, more easily obtainable species to find organisms that could be used as surrogates for V. destructor when testing new potential controls. We compared the toxicities of acetic acid, lactic acid, formic acid, and oxalic acid at 0.005%, 0.05%, 0.5%, 5%, and 50% (20% oxalic acid only) concentrations based on natural volatility (nonheated) for the control of two beetle species, Oryzaephilus surinamensis L. and Alphitobius diaperinus Panzer, greater wax moth larvae, Galleria mellonella L., and V. destructor. The assay results were consistent across all species with formic acid and acetic acid showing 100% mortality of all four test species at 50% concentration. The assays also provided insight into the method of application (vaporization or contact) needed to cause mortality. Our results show that other organisms can be used in place of V. destructor for initial testing of acids and possibly other chemicals for control of the ectoparasite.

Polycondensation of butenediol: synthesis of telechelic 2-butene-1,4-diol oligomers.

The catalytic condensation of cis-2-butene-1,4-diol with CpRu(MQA)(C(3)H(5)) (Cp = cyclopentadienyl, MQA = 4-methoxyquinoline-2-carboxylate) generates poly(2-butenediol), an unsaturated telechelic polyether diol with molecular weights between 400 and 4600 g/mol. This Ru(IV) allyl catalyst enchains 2-butene-1,4-diol primarily as the linear trans-2-butenyl ether (92%) along with vinyl branches (8%). These telechelic oligomers are useful chain extenders and macromonomers, as demonstrated by their use in the synthesis of poly(lactide)-b-poly(butenediol)-b-poly(lactide) triblock copolymers. Model studies support a proposed mechanism involving the formation of Ru(IV) allyl intermediates from allylic alcohols and chain growth by selective nucleophilic displacement at the terminus of the Ru(IV) allyl to generate trans-2-butenyl ether linkages.

Oligocarbonate molecular transporters: oligomerization-based syntheses and cell-penetrating studies.

A new family of guanidinium-rich molecular transporters featuring a novel oligocarbonate backbone with 1,7-side chain spacing is described. Conjugates can be rapidly assembled irrespective of length in a one-step oligomerization strategy that can proceed with concomitant introduction of probes (or by analogy drugs). The new transporters exhibit excellent cellular entry as determined by flow cytometry and fluorescence microscopy, and the functionality of their drug delivery capabilities was confirmed by the delivery of the bioluminescent small molecule probe luciferin and turnover by its intracellular target enzyme.

Cyclic guanidine organic catalysts: what is magic about triazabicyclodecene?

The bicyclic guanidine 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD) is an effective organocatalyst for the formation of amides from esters and primary amines. Mechanistic and kinetic investigations support a nucleophilic mechanism where TBD reacts reversibly with esters to generate an acyl-TBD intermediate that acylates amines to generate the amides. Comparative investigations of the analogous bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO) reveal it to be a much less active acylation catalyst than TBD. Theoretical and mechanistic studies imply that the higher reactivity of TBD is a consequence of both its higher basicity and nucleophilicity than TBO as well as the high reactivity of the acyl-TBD intermediate, which is sterically prevented from adopting a planar amide structure.

Triclocarban: Commercial Antibacterial and Highly Effective H-Bond Donating Catalyst for Ring-Opening Polymerization.

The antibacterial compound, triclocarban (TCC), is shown to be a highly effective H-bond donating catalyst for ring-opening polymerization (ROP) when applied with an H-bond accepting base cocatalyst. These ROPs exhibit the characteristics of "living" polymerizations. TCC is shown to possess the high activity characteristic of urea (vs thiourea) H-bond donors. The urea class of H-bond donors is shown to remain highly active in H-bonding solvents, a trait that is not displayed by the corresponding thiourea H-bond donors. Two H-bond donating ureas that are electronically similar to TCC are evaluated for their efficacy in ROP, and a mechanism of action is proposed. This "off-the-shelf" H-bond donor is among the most active and most controlled organocatalysts for the ROP of lactones.

Intramolecular electron transfer in cofacially pi-stacked fluorenes: evidence of tunneling.

The one-electron reduction of neutral pi-stacked di- and trifluorenes (F-2 and F-3) in HMPA, where ion association is absent, results in the formation of anion radicals in which the odd electron resides predominantly on just one of the external fluorene moieties, as established by EPR spectroscopy. However, in the case of tetrafluorene, introduction of a single electron leads to a kinetically controlled anion radical F-4(int)*- in which the odd electron undergoes rapid exchange between two central fluorene rings, where the anionic charge is partially shielded from solvation due to the presence of external fluorene rings. On a time scale of minutes, anion radical F-4(int)*- converts to a thermodynamically stabilized anion radical F-4(ext)*-, with the electron exhibiting coupling from the protons on an external fluorene moiety. The charge and spin residing on an external moiety allow efficient solvation of the anionic charge. A similar fast exchange of a single electron (probably with the involvement of quantum mechanical tunneling) among three and four internal fluorene moieties is initially observed via EPR spectroscopy in the penta- and hexafluorene derivatives, F-5 and F-6, respectively.

Controlled Organocatalytic Ring-Opening Polymerization of ε-Thionocaprolactone.

For the first time, the controlled ring-opening polymerization (ROP) of ε-thionocaprolactone (tnCL) is conducted. The organocatalytic ROP of tnCL occurs without carbonyl scrambling, leading to homopoly(ε-thionocaprolactone) (PtnCL). The ROP by base catalysts alone is proposed to proceed via a nucleophilic mechanism, while the addition of an H-bond donating thiourea (TU) is shown to provide excellent reaction control. The increased reaction control provided by the TU occurs in the virtual absence of binding between tnCL and TU, and a mechanistic account for this observation is discussed. The monomer ring strain is measured and found to be similar to δ-valerolactone (VL). Copolymers with VL are synthesized, and the resulting analysis of the copolymer materials properties provides the only known physical characterizations of poly(thio(no)ester-co-ester)s.

Bis- and Tris-Urea H-Bond Donors for Ring-Opening Polymerization: Unprecedented Activity and Control from an Organocatalyst.

A new class of H-bond donating ureas was developed for the ring-opening polymerization (ROP) of lactone monomers, and they exhibit dramatic rate acceleration versus previous H-bond mediated polymerization catalysts. The most active of these new catalysts, a tris-urea H-bond donor, is among the most active organocatalysts known for ROP, yet it retains the high selectivity of H-bond mediated organocatalysts. The urea cocatalyst, along with an H-bond accepting base, exhibits the characteristics of a "living" ROP, is highly active, in one case, accelerating a reaction from days to minutes, and remains active at low catalyst loadings. The rate acceleration exhibited by this H-bond donor occurs for all base cocatalysts examined. A mechanism of action is proposed, and the new catalysts are shown to accelerate small molecule transesterifications versus currently known monothiourea catalysts. It is no longer necessary to choose between a highly active or highly selective organocatalyst for ROP.

The capture of sym-[8]annuldiyne: the cyclooctadienyne-eta2-ynyl potassium zwitterionic radical.

[reaction: see text] Reaction of 1,4-dibromo-[8]annulene (C(8)H(6)Br(2)) with potassium tert-butoxide in THF followed by exposure to potassium metal leads to the formation of the anion radical of sym-[8]annuldiyne. The rapid interchange of Jahn-Teller-induced alternating bond angle conformers of sym-[8]annuldiyne is halted by ion association with a metal-crown ether complex forming the cyclooctadienyne-eta(2)-ynyl potassium zwitterionic radical, rendering all four protons nonequivalent. Neutral sym-[8]annuldiyne can form the [2 + 2] polymer, which is not soluble in the THF solution.

Poly(thioester) by Organocatalytic Ring-Opening Polymerization.

Organocatalysts typically used for the ring-opening polymerization (ROP) of cyclic ester monomers are applied to a thiolactone, ε-thiocaprolactone (tCL). In the absence of an H-bond donor, a nucleophilic polymerization mechanism is proposed. Despite the decreased ability of thioesters and thiols (versus esters and alcohols) to H-bond, H-bonding organocatalysts-a thiourea in combination with an H-bond accepting base-are also effective for the ROP of tCL. The increased nucleophilicity of thiols (versus alcohols) is implicated in the increased Mw/Mn of the poly(thiocaprolactone) versus poly(caprolactone), but deleterious transesterification is suppressed in the presence of a thiourea. The thioester monomer, tCL, is shown to be thermodynamically similar to ε-caprolactam but kinetically similar to ε-caprolactone.

Rate Accelerated Organocatalytic Ring-Opening Polymerization of L-Lactide via the Application of a Bis(thiourea) H-bond Donating Cocatalyst.

A cocatalyst system consisting of an alkylamine base and a bis(thiourea) featuring a linear alkane tether is shown to dramatically increase the rate of ring-opening polymerization (ROP) of L-lactide versus previously disclosed monothiourea H-bond donors. Rate acceleration occurs regardless of the identity of the alkylamine cocatalyst, and the ROP remains controlled yielding poly(lactide) with narrow molecular weight distributions, predictable molecular weights and high selectivity for monomer. This H-bond mediated ROP of L-lactide constitutes a rare, clear example of rate acceleration with bis(thiourea) H-bond donors versus monothioureas, and the bis(thiourea) is shown to remain highly active for ROP at fractional percent catalyst loadings. Activation at a single monomer ester by both thiourea moieties is implicated as the source of rate acceleration.

Cooperative Hydrogen-Bond Pairing in Organocatalytic Ring-Opening Polymerization.

Thiourea (TU)/amine base cocatalysts are commonly employed for well-controlled, highly active "living" organocatalytic ring-opening polymerizations (ROPs) of cyclic esters and carbonates. In this work, several of the most active cocatalyst pairs are shown by 1H NMR binding studies to be highly associated in solution, dominating all other known noncovalent catalyst/reagent interactions during ROP. One strongly binding catalyst pair behaves kinetically as a unimolecular catalyst species. The high selectivity and activity exhibited by these ROP organocatalysts are attributed to the strong binding between the two cocatalysts, and the predictive utility of these binding parameters is applied for the discovery of a new, highly active cocatalyst pair.

High field dynamic nuclear polarization NMR with surfactant sheltered biradicals.

We illustrate the ability to place a water-insoluble biradical, bTbk, into a glycerol/water matrix with the assistance of a surfactant, sodium octyl sulfate (SOS). This surfactant approach enables a previously water insoluble biradical, bTbk, with favorable electron-electron dipolar coupling to be used for dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) experiments in frozen, glassy, aqueous media. Nuclear Overhauser enhancement (NOE) and paramagnetic relaxation enhancement (PRE) experiments are conducted to determine the distribution of urea and several biradicals within the SOS macromolecular assembly. We also demonstrate that SOS assemblies are an effective approach by which mixed biradicals are created through an assembly process.