Isolation by crystallization of translational isomers of a bistable donor-acceptor [2]catenane.

The template-directed synthesis of a bistable donor-acceptor [2]catenane wherein both translational isomers--one in which a tetrathiafulvalene unit in a mechanically interlocked crown ether occupies the cavity of a cyclobis(paraquat-p-phenylene) ring and the other in which a 1,5-dioxynaphthalene unit in the crown ether resides inside the cavity of the tetracationic cyclophane--exist in equilibrium in solution, has led to the isolation and separation by hand picking of single crystals colored red and green, respectively. These two crystalline co-conformations have been characterized separately at both the molecular and supramolecular levels, and also by dynamic NMR spectroscopy in solution where there is compelling evidence that the mechanically interlocked molecules are present as a complex mixture of translational, configurational, and conformational isomers wherein the isomerization is best described as being a highly dynamic and adaptable phenomenon.

Two metals are better than one in the gold catalyzed oxidative heteroarylation of alkenes.

We present a detailed study of the mechanism for oxidative heteroarylation, based on DFT calculations and experimental observations. We propose binuclear Au(II)-Au(II) complexes to be key intermediates in the mechanism for gold catalyzed oxidative heteroarylation. The reaction is thought to proceed via a gold redox cycle involving initial oxidation of Au(I) to binuclear Au(II)-Au(II) complexes by Selectfluor, followed by heteroauration and reductive elimination. While it is tempting to invoke a transmetalation/reductive elimination mechanism similar to that proposed for other transition metal complexes, experimental and DFT studies suggest that the key C-C bond forming reaction occurs via a bimolecular reductive elimination process (devoid of transmetalation). In addition, the stereochemistry of the elimination step was determined experimentally to proceed with complete retention. Ligand and halide effects played an important role in the development and optimization of the catalyst; our data provides an explanation for the ligand effects observed experimentally, useful for future catalyst development. Cyclic voltammetry data is presented that supports redox synergy of the Au···Au aurophilic interaction. The monometallic reductive elimination from mononuclear Au(III) complexes is also studied from which we can predict a ~15 kcal/mol advantage for bimetallic reductive elimination.

Phosphoramidite gold(I)-catalyzed diastereo- and enantioselective synthesis of 3,4-substituted pyrrolidines.

In this article the utility of phosphoramidite ligands in enantioselective Au(I) catalysis was explored in the development of highly diastereo- and enantioselective Au(I)-catalyzed cycloadditions of allenenes. A Au(I)-catalyzed synthesis of 3,4-disubstituted pyrrolidines and γ-lactams is described. This reaction proceeds through the enantioselective Au(I)-catalyzed cyclization of allenenes to form a carbocationic intermediate that is trapped by an exogenous nucleophile, resulting in the highly diastereoselective construction of three contiguous stereogenic centers. A computational study (DFT) was also performed to gain some insight into the underlying mechanisms of these cycloadditions. The utility of this new methodology was demonstrated through the formal synthesis of (-)-isocynometrine.

An unusual hydrogen migration/C-H activation reaction with group 3 metals.

A novel hydrogen migration from the phenyl ring to the pyridine ring of an yttrium pyridyl complex supported by a 1,1'-ferrocene diamide ligand is reported. Density functional theory calculations were instrumental in probing the mechanism for this transformation.

Phosphine-catalyzed annulations of azomethine imines: allene-dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] pathways.

In this paper we describe the phosphine-catalyzed [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] annulations of azomethine imines and allenoates. These processes mark the first use of azomethine imines in nucleophilic phosphine catalysis, producing dinitrogen-fused heterocycles, including tetrahydropyrazolo-pyrazolones, -pyridazinones, -diazepinones, and -diazocinones. Counting the two different reaction modes in the [3 + 3] cyclizations, there are five distinct reaction pathways-the choice of which depends on the structure and chemical properties of the allenoate. All reactions are operationally simple and proceed smoothly under mild reaction conditions, affording a broad range of 1,2-dinitrogen-containing heterocycles in moderate to excellent yields. A zwitterionic intermediate formed from a phosphine and two molecules of ethyl 2,3-butadienoate acted as a 1,5-dipole in the annulations of azomethine imines, leading to the [3 + 2 + 3] tetrahydropyrazolo-diazocinone products. The incorporation of two molecules of an allenoate into an eight-membered-ring product represents a new application of this versatile class of molecules in nucleophilic phosphine catalysis. The salient features of this protocol--the facile access to a diverse range of nitrogen-containing heterocycles and the simple preparation of azomethine imine substrates--suggest that it might find extensive applications in heterocycle synthesis.

Mechanically stabilized tetrathiafulvalene radical dimers.

Two donor-acceptor [3]catenanes-composed of a tetracationic molecular square, cyclobis(paraquat-4,4'-biphenylene), as the π-electron deficient ring and either two tetrathiafulvalene (TTF) and 1,5-dioxynaphthalene (DNP) containing macrocycles or two TTF-butadiyne-containing macrocycles as the π-electron rich components-have been investigated in order to study their ability to form TTF radical dimers. It has been proven that the mechanically interlocked nature of the [3]catenanes facilitates the formation of the TTF radical dimers under redox control, allowing an investigation to be performed on these intermolecular interactions in a so-called "molecular flask" under ambient conditions in considerable detail. In addition, it has also been shown that the stability of the TTF radical-cation dimers can be tuned by varying the secondary binding motifs in the [3]catenanes. By replacing the DNP station with a butadiyne group, the distribution of the TTF radical-cation dimer can be changed from 60% to 100%. These findings have been established by several techniques including cyclic voltammetry, spectroelectrochemistry and UV-vis-NIR and EPR spectroscopies, as well as with X-ray diffraction analysis which has provided a range of solid-state crystal structures. The experimental data are also supported by high-level DFT calculations. The results contribute significantly to our fundamental understanding of the interactions within the TTF radical dimers.

Donor-acceptor oligorotaxanes made to order.

Five donor-acceptor oligorotaxanes made up of dumbbells composed of tetraethylene glycol chains, interspersed with three and five 1,5-dioxynaphthalene units, and terminated by 2,6-diisopropylphenoxy stoppers, have been prepared by the threading of discrete numbers of cyclobis(paraquat-p-phenylene) rings, followed by a kinetically controlled stoppering protocol that relies on click chemistry. The well-known copper(I)-catalyzed alkyne-azide cycloaddition between azide functions placed at the ends of the polyether chains and alkyne-bearing stopper precursors was employed during the final kinetically controlled template-directed synthesis of the five oligorotaxanes, which were characterized subsequently by (1)H NMR spectroscopy at low temperature (233 K) in deuterated acetonitrile. The secondary structures, as well as the conformations, of the five oligorotaxanes were unraveled by spectroscopic comparison with the dumbbell and ring components. By focusing attention on the changes in chemical shifts of some key probe protons, obtained from a wide range of low-temperature spectra, a picture emerges of a high degree of folding within the thread protons of the dumbbells of four of the five oligorotaxanes-the fifth oligorotaxane represents a control compound in effect-brought about by a combination of C-H···O and π-π stacking interactions between the π-electron-deficient bipyridinium units in the rings and the π-electron-rich 1,5-dioxynaphthalene units and polyether chains in the dumbbells. The secondary structures of a foldamer-like nature have received further support from a solid-state superstructure of a related [3]pseudorotaxane and density functional calculations performed thereon.

Mechanically bonded macromolecules.

Mechanically bonded macromolecules constitute a class of challenging synthetic targets in polymer science. The controllable intramolecular motions of mechanical bonds, in combination with the processability and useful physical and mechanical properties of macromolecules, ultimately ensure their potential for applications in materials science, nanotechnology and medicine. This tutorial review describes the syntheses and properties of a library of diverse mechanically bonded macromolecules, which covers (i) main-chain, side-chain, bridged, and pendant oligo/polycatenanes, (ii) main-chain oligo/polyrotaxanes, (iii) poly[c2]daisy chains, and finally (iv) mechanically interlocked dendrimers. A variety of highly efficient synthetic protocols--including template-directed assembly, step-growth polymerisation, quantitative conjugation, etc.--were employed in the construction of these mechanically interlocked architectures. Some of these structures, i.e., side-chain polycatenanes and poly[c2]daisy chains, undergo controllable molecular switching in a manner similar to their small molecular counterparts. The challenges posed by the syntheses of polycatenanes and polyrotaxanes with high molecular weights are contemplated.

Mechanistic study of gold(I)-catalyzed intermolecular hydroamination of allenes.

The intermolecular hydroamination of allenes occurs readily with hydrazide nucleophiles, in the presence of 3-12% Ph(3)PAuNTf(2). Mechanistic studies have been conducted to establish the resting state of the gold catalyst, the kinetic order of the reaction, the effect of ligand electronics on the overall rate, and the reversibility of the last steps in the catalytic cycle. We have found the overall reaction to be first order in gold and allene and zero order in nucleophile. Our studies suggest that the rate-limiting transition state for the reaction does not involve the nucleophile and that the active catalyst is monomeric in gold(I). Computational studies support an "outersphere" mechanism and predict that a two-step, no intermediate mechanism may be operative. In accord with this mechanistic proposal, the reaction can be accelerated with the use of more electron-deficient phosphine ligands on the gold(I) catalyst.

Bimetallic reductive elimination from dinuclear Pd(III) complexes.

In 2009, we reported C-halogen reductive elimination reactions from dinuclear Pd(III) complexes and implicated dinuclear intermediates in Pd(OAc)(2)-catalyzed C-H oxidation chemistry. Herein, we report results of a thorough experimental and theoretical investigation of the mechanism of reductive elimination from such dinuclear Pd(III) complexes, which establish the role of each metal during reductive elimination. Our results implicate reductive elimination from a complex in which the dinuclear core is intact and suggest that redox synergy between the two metals is responsible for the facile reductive elimination reactions observed.

Mechanism of C-F reductive elimination from palladium(IV) fluorides.

The first systematic mechanism study of C-F reductive elimination from a transition metal complex is described. C-F bond formation from three different Pd(IV) fluoride complexes was mechanistically evaluated. The experimental data suggest that reductive elimination occurs from cationic Pd(IV) fluoride complexes via a dissociative mechanism. The ancillary pyridyl-sulfonamide ligand plays a crucial role for C-F reductive elimination, likely due to a kappa(3) coordination mode, in which an oxygen atom of the sulfonyl group coordinates to Pd. The pyridyl-sulfonamide can support Pd(IV) and has the appropriate geometry and electronic structure to induce reductive elimination.

Dearomatization reactions of N-heterocycles mediated by group 3 complexes.

Group 3 (Sc, Y, Lu, La) benzyl complexes supported by a ferrocene diamide ligand are reactive toward aromatic N-heterocycles by mediating their coupling and, in a few cases, the cleavage of their C-N bonds. When these complexes reacted with 2,2'-bipyridine or isoquinoline, they facilitated the alkyl migration of the benzyl ligand onto the pyridine ring, a process accompanied by the dearomatization of the N-heterocycle. The products of the alkyl-transfer reactions act as hydrogen donors in the presence of aromatic N-heterocycles, ketones, and azobenzene. Experimental and computational studies suggest that the hydrogen transfer takes place through a concerted mechanism. An interesting disproportionation reaction of the dearomatized, alkyl-substituted isoquinoline complexes is also reported.

Conformations of N-heterocyclic carbene ligands in ruthenium complexes relevant to olefin metathesis.

The structure of ruthenium-based olefin metathesis catalyst 3 and model pi-complex 5 in solution and in the solid state are reported. The N-tolyl ligands, due to their lower symmetry than the traditional N-mesityl substituents, complicate this analysis, but ultimately provide explanation for the enhanced reactivity of 3 relative to standard catalyst 2. The tilt of the N-tolyl ring provides additional space near the ruthenium center, which is consistent with the enhanced reactivity of 3 toward sterically demanding substrates. Due to this tilt, the more sterically accessible face bears the two methyl substituents of the N-aryl rings. These experimental studies are supported by computational studies of these complexes by DFT. The experimental data provides a means to validate the accuracy of the B3LYP and M06 functionals. B3LYP provides geometries that match X-ray crystal structural data more closely, though it leads to slightly less (approximately 0.5 kcal mol-1) accuracy than M06 most likely because it underestimates attractive noncovalent interactions.

Reactions of group III biheterocyclic complexes.

Group III alkyl complexes supported by a ferrocene diamide ligand (1,1'-fc(NSi(t)BuMe(2))(2)) have been found to be reactive toward aromatic N-heterocycles such as 1-methylimidazole and pyridines. These reactions were investigated experimentally and computationally. An initial C-H activation event is followed by a coupling reaction to form biheterocyclic complexes, in which one of the rings is dearomatized. In the case of 1-methylimidazole, the biheterocyclic compound could not be isolated and further led to an imidazole ring-opened product; in the case of pyridines, it transformed into an isomer with extended conjugation of double bonds. Mechanisms for both reactions are proposed on the basis of experimental and computational results. DFT calculations were also used to show that an energetically accessible pathway for the ring-opening of pyridines exists.

A push-button molecular switch.

The preparation, characterization, and switching mechanism of a unique single-station mechanically switchable hetero[2]catenane are reported. The facile synthesis utilizing a "threading-followed-by-clipping" protocol features Cu(2+)-catalyzed Eglinton coupling as a mild and efficient route to the tetrathiafulvalene-based catenane in high yield. The resulting mechanically interlocked molecule operates as a perfect molecular switch, most readily described as a "push-button" switch, whereby two discrete and fully occupied translational states are toggled electrochemically at incredibly high rates. This mechanical switching was probed using a wide variety of experimental techniques as well as quantum-mechanical investigations. The fundamental distinctions between this single-station [2]catenane and other more traditional bi- and multistation molecular switches are significant.

Functionally rigid and degenerate molecular shuttles.

The preparation and dynamic behavior of two functionally rigid and degenerate [2]rotaxanes (14 PF(6) and 24 PF(6)) in which a pi-electron deficient tetracationic cyclophane, cyclobis(paraquat-p-phenylene) (CBPQT(4+)) ring, shuttles back and forth between two pi-electron-rich naphthalene (NP) stations by making the passage along an ethynyl-phenylene-(PH)-ethynyl or butadiyne rod, are described. The [2]rotaxanes were synthesized by using the clipping approach to template-directed synthesis, and were characterized by NMR spectroscopic and mass spectrometric analyses. (1)H NMR spectra of both [2]rotaxanes show evidence for the formation of mechanically interlocked structures, resulting in the upfield shifts of the resonances for key protons on the dumbbell-shaped components. In particular, the signals for the peri protons on the NP units in the dumbbell-shaped components experienced significant upfield shifts at low temperatures, just as has been observed in the flexible [2]rotaxanes. Interestingly, the resonances for the same protons did not exhibit a significant upfield shift at 298 K, but rather only a modest shift. This phenomenon arises from the much reduced binding of the ethynyl-NP unit compared to the 1,5-dioxy-NP unit. This effect, in turn, increases the shuttling rate when compared to the 1,5-dioxy-NP-based rotaxane systems investigated previously. The kinetic and thermodynamic data of the shuttling behavior of the CBPQT(4+) ring between the NP units were obtained by variable-temperature NMR spectroscopy and using the coalescence method to calculate the free energies of activation (DeltaG(c) ( not equal)) of 9.6 and 10.3 kcal mol(-1) for 14 PF(6) and 24 PF(6), respectively, probed by using the rotaxane's alpha-bipyridinium protons. The solid-state structure of the free dumbbell-shaped compound (3) shows the fully rigid ethynyl-PH-ethynyl linker with a length (8.1 A) twice as long as that (3.8 A) of the butadiyne linker. Full-atomistic simulations were carried out with the DREIDING force field (FF) to probe the degenerate molecular shuttling processes, and afforded shuttling energy barriers (DeltaG( not equal)=10.4 kcal mol(-1) for 14 PF(6) and 24 PF(6)) that are in good agreement with the experimental values (DeltaG(c) ( not equal)=9.6 and 10.3 kcal mol(-1) for 14 PF(6) and 24 PF(6), respectively, probed by using their alpha-bipyridinium protons).

Experimentally-based recommendations of density functionals for predicting properties in mechanically interlocked molecules.

Mechanically interlocked molecules (rotaxanes and catenanes) have already revolutionized molecular electronics and have the promise of a similar impact in other areas of nanotechnology, ranging from nanoactuators to in vivo drug nanocarriers. However, it would be most useful to have quantitative criteria for predicting structures, binding, and excitation energies for use in designing molecules with mechanical bonds. We assess here the use of density functional theory (DFT) to a noncovalently bound complex and find that no density functional is fully satisfactory. However, we find that the new M06-suite of density functionals, which include attractive medium-range interactions, leads to dramatic improvements in the structures (error of 0.04 A in the interplanar distances for M06-L compared to 0.42 A for B3LYP) and excitation energies (within 0.08 eV for TD-M06-HF without empirical correction compared to 2.2 eV error for TD-B3LYP). However, M06 predicts the complex to be too strongly bound by 22.6 kcal mol(-1) (B3LYP leads to too weak a bond by 29 kcal mol(-1)), while current empirical FF DREIDING is too weakly bound by only 15 kcal mol(-1).

Relevance of cis- and trans-dichloride Ru intermediates in Grubbs-II olefin metathesis catalysis (H2IMesCl2Ru=CHR).

Using density functional theory with the B3LYP and M06 functionals, we show conclusively that the (H(2)IMes)(Cl)(2)Ru olefin metathesis mechanism is bottom-bound with the chlorides remaining trans throughout the reaction, thus attempts to effect diastereo- and enantioselectivity should focus on manipulations that maintain the trans-dichloro Ru geometry.

Environmental stress cracking performance of polyether and PDMS-based polyurethanes in an in vitro oxidation model.

Environmental stress cracking (ESC) was replicated in vitro on Optim™ (OPT) insulation, a polydimethylsiloxane-based polyurethane utilized clinically in cardiac leads, using a Zhao-type oxidation model. OPT performance was compared to that of two industry standard polyether urethanes: Pellethane® 80A (P80A), and Pellethane® 55D (P55D). Clinically relevant specimen configurations and strain states were utilized: low-voltage cardiac lead segments were held in a U-shape by placing them inside of vials. To study whether aging conditions impacted ESC formation, half of the samples were subjected to a pretreatment in human plasma for 7 days at 37°C; all samples were then aged in oxidative solutions containing 0.9% NaCl, 20% H2 O2 , and either 0 or 0.1M CoCl2 , with or without glass wool for 72 days at 37°C. Visual and SEM inspection revealed significant surface cracking consistent with ESC on all P80A and P55D samples. Sixteen of twenty P80A and 10/20 P55D samples also exhibited breaches. Seven of 20 OPT samples exhibited shallow surface cracking consistent with ESC. ATR-FTIR confirmed surface changes consistent with oxidation for all materials. The number average molecular weight decreased an average of 31% for OPT, 86% for P80A, and 56% for P55D samples. OPT outperformed P80A and P55D in this Zhao-type in vitro ESC model. An aging solution of 0.9% NaCl, 20% H2 O2 , and 0.1M CoCl2 , with glass wool provided the best combination of ESC replication and ease of use. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1544-1558, 2017.

The biostability of cardiac lead insulation materials as assessed from long-term human implants.

Accelerated in vitro biostability studies are useful for making relativistic comparisons between materials. However, no in vitro study can completely replicate the complex biochemical and biomechanical environment that a material experiences in the human body. To overcome this limitation, three insulation materials [Optim™ insulation (OPT), Pellethane® 55D (P55D), and silicone elastomer] from cardiac leads that were clinically implanted for up to five years were characterized using visual inspection, SEM, ATR-FTIR, GPC, and tensile testing. Surface cracking was not observed in OPT or silicone samples. Shallow cracking was observed in 17/41 (41%) explanted P55D samples. ATR-FTIR indicated minor surface oxidation in some OPT and P55D samples. OPT molecular weight decreased modestly (∼20%) at 2-3 years before stabilizing at 4-5 years. OPT tensile strength decreased modestly (∼25%) at 2-3 years before stabilizing at 4-5 years. OPT elongation at 4-5 years was unchanged from controls. P55D had no significant changes in molecular weight or tensile properties. Overall, results for OPT and P55D were consistent with and limited to cosmetic surface oxidation. Silicone demonstrated excellent biostability with no identifiable degradation. This study of explanted cardiac leads revealed that OPT, P55D, and silicone elastomer demonstrate similar and excellent biostability through five years of implantation in human patients.