Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules.

The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, 99mTc, and the therapeutic radionuclide, 188Re, can potentially enable receptor-targeted "theranostic" treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type Ph2PCH2CH2P(CH2CH2-Glc)2 (L, where Glc = a glucose moiety) using the readily accessible Ph2PCH2CH2PH2 and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media. Furthermore, the resulting glucose-chelator conjugates can be radiolabeled with either 99mTc(V) or 188Re(V) in high radiochemical yields (>95%), to furnish separable mixtures of cis- and trans-[M(O)2L2]+ (M = Tc, Re). Single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution in healthy mice show that each isomer possesses favorable pharmacokinetic properties, with rapid clearance from blood circulation via a renal pathway. Both cis-[99mTc(O)2L2]+ and trans-[99mTc(O)2L2]+ exhibit high stability in serum. This new class of functionalized diphosphine chelators has the potential to provide access to receptor-targeted dual diagnostic/therapeutic pairs of radiopharmaceutical agents, for molecular 99mTc SPECT imaging and 188Re systemic radiotherapy.

XFEL Crystal Structures of Peroxidase Compound II.

Oxygen activation in all heme enzymes requires the formation of high oxidation states of iron, usually referred to as ferryl heme. There are two known intermediates: Compound I and Compound II. The nature of the ferryl heme-and whether it is an FeIV =O or FeIV -OH species-is important for controlling reactivity across groups of heme enzymes. The most recent evidence for Compound I indicates that the ferryl heme is an unprotonated FeIV =O species. For Compound II, the nature of the ferryl heme is not unambiguously established. Here, we report 1.06 Šand 1.50 Šcrystal structures for Compound II intermediates in cytochrome c peroxidase (CcP) and ascorbate peroxidase (APX), collected using the X-ray free electron laser at SACLA. The structures reveal differences between the two peroxidases. The iron-oxygen bond length in CcP (1.76 Å) is notably shorter than in APX (1.87 Å). The results indicate that the ferryl species is finely tuned across Compound I and Compound II species in closely related peroxidase enzymes. We propose that this fine-tuning is linked to the functional need for proton delivery to the heme.

Oxidative Addition of Alkenyl and Alkynyl Iodides to a AuI Complex.

The first isolated examples of intermolecular oxidative addition of alkenyl and alkynyl iodides to AuI are reported. Using a 5,5'-difluoro-2,2'-bipyridyl ligated complex, oxidative addition of geometrically defined alkenyl iodides occurs readily, reversibly and stereospecifically to give alkenyl-AuIII complexes. Conversely, reversible alkynyl iodide oxidative addition generates bimetallic complexes containing both AuIII and AuI centers. Stoichiometric studies show that both new initiation modes can form the basis for the development of C-C bond forming cross-couplings.

Zirconium-Nitrogen Intermolecular Frustrated Lewis Pairs.

A series of intermolecular transition metal frustrated Lewis pairs (FLPs) based on zirconocene alkoxide complexes ([Cp2Zr(OMes)]+ 1 or ([Cp*2Zr(OMes)]+ 2) with nitrogen Lewis bases (NEt3, NEtiPr2, pyridine, 2-methylpyridine, 2,6-lutidine) are reported. The interaction between Zr and N depends on the specific derivatives used, in general more sterically encumbered pairs leading to a more frustrated interaction; however, DOSY NMR spectroscopy reveals these interactions to be dynamic in nature. The pairs undergo typical FLP-type reactivity with D2, CO2, THF, and PhCCD. The catalytic dehydrocoupling of Me2NH·BH3 is also reported. Comparisons can be made with previous work employing phosphines as Lewis bases suggesting that hard-hard or hard-soft acid-base considerations are of little importance compared to the more prominent roles of steric bulk and basicity.

Anion Recognition by a Bioactive Diureidodecalin Anionophore: Solid-State, Solution, and Computational Studies.

Recent work has identified a bis-(p-nitrophenyl)ureidodecalin anion carrier as a promising candidate for biomedical applications, showing good activity for chloride transport in cells yet almost no cytotoxicity. To underpin further development of this and related compounds, a detailed structural and binding investigation is reported. Crystal structures of the transporter as five solvates confirm the diaxial positioning of urea groups while revealing a degree of conformational flexibility. Structures of complexes with Cl- , Br- , NO3- , SO42- and AcO- , supported by computational studies, show how the binding site can adapt to accommodate these anions. 1 H NMR binding studies revealed exceptionally high affinities for anions in DMSO, decreasing in the order SO42- >H2 PO4- ≈HCO3- ≈AcO- ≫HSO4- >Cl- >Br- >NO3- >I- . Analysis of the binding results suggests that selectivity is determined mainly by the H-bond acceptor strength of different anions, but is also modulated by receptor geometry.

Iron Precatalysts with Bulky Tri(tert-butyl)cyclopentadienyl Ligands for the Dehydrocoupling of Dimethylamine-Borane.

In an attempt to prepare new Fe catalysts for the dehydrocoupling of amine-boranes and to provide mechanistic insight, the paramagnetic FeII dimeric complex [Cp'FeI]2 (1) (Cp'=η5 -((1,2,4-tBu)3 C5 H2 )) was used as a precursor to a series of cyclopentadienyl FeII and FeIII mononuclear species. The complexes prepared were [Cp'Fe(η6 -Tol)][Cp'FeI2 ] (2) (Tol=C6 H5 Me), [Cp'Fe(η6 -Tol)][BArF4 ] (3) (BArF4 =[B(C6 H3 (m-CF3 )2 )4 ]- ), [N(nBu)4 ][Cp'FeI2 ] (4), Cp'FeI2 (5), and [Cp'Fe(MeCN)3 ][BArF4 ] (6). The electronic structure of the [Cp'FeI2 ]- anion in 2 and 4 was investigated by SQUID magnetometry, EPR spectroscopy and ab initio Complete Active Space Self Consistent Field-Spin Orbit (CASSCF-SO) calculations, and the studies revealed a strongly anisotropic S=2 ground state. Complexes 1-6 were investigated as catalysts for the dehydrocoupling of Me2 NH⋅BH3 (I) in THF at 20 °C to yield the cyclodiborazane product [Me2 N-BH2 ]2 (IV). Complexes 1-4 and 6 were active dehydrocoupling catalysts towards I (5 mol % loading), however 5 was inactive, and ultra-violet (UV) irradiation was required for the reaction mediated by 3. Complex 6 was found to be the most active precatalyst, reaching 80 % conversion to IV after 19 h at 22 °C. Dehydrocoupling of I by 1-4 proceeded via formation of the aminoborane Me2 N=BH2 (II) as the major intermediate, whereas for 6 the linear diborazane Me2 NH-BH2 -NMe2 -BH3 (III) could be detected, together with trace amounts of II. Reactions of 1 and 6 with Me3 N⋅BH3 were investigated in an attempt to identify Fe-based intermediates in the catalytic reactions. The σ-complex [Cp'Fe(MeCN)(κ2 -H2 BH⋅NMe2 H][BArF4 ] was proposed to initially form in dehydrocoupling reactions involving 6 based on ESI-MS (ESI=Electrospray Ionisation Mass Spectroscopy) and NMR spectroscopic evidence. The latter also suggests that these complexes function as precursors to iron hydrides which may be the true catalytic species.

A new strategy for the synthesis of diverse benzo[a]carbazoles via a divergent catalytic Michael reaction.

A new type of divergent tandem Michael addition of α,α-dicyanomethylidenecarbazoles with ß-nitrostyrenes afforded multifunctional benzo[a]carbazoles [BCs] and benzodihydro[a]carbazoles [BDHCs] in good yields. In addition, the direct multicomponent transformation of α,α-dicyanomethylidenecarbazoles, acenaphthenequinone and malononitrile results in the formation of unreported imino and amino functionalized spiro[acenaphthylene-8',4-benzo[a]carbazole] hybrids via amine-controlled divergent reactions. The spiro products were also obtained in good yields. The structures of the synthesized cycloadducts were confirmed by elemental analysis, spectral data (FT-IR, 1H, 13C NMR and HRMS) and by single-crystal X-ray diffraction studies.The application of this divergent tandem Michael addition protocol is beneficial from the viewpoint of the diversity-oriented one-pot synthesis of benzo[a]carbazole derivatives from simple starting materials.

(-)-Cytisine: Access to a stereochemically defined and functionally flexible piperidine scaffold.

N-Benzyl cytisine undergoes an efficient C(6)-N(7) cleavage via directed C(6) lithiation, borylation and oxidation to provide a "privileged" heterocyclic core unit comprising a highly functionalised, cis-3,5-disubstituted piperidine in enantiomerically pure form. The potential offered by this unit as a means to explore chemical space has been evaluated and methods have been defined (and illustrated) that allow for selective manipulation of N(1), C(3'), and the pyridone N. The pyridone core can also be diversified via bromination (at C(3'') and C(5'')) which is complementary to direct C-H activation based on Ir-catalyzed borylation to provide access to C(4''). The use of a boronate-based 1,2-migration as an alternative trigger to mediate C(6)-N(7) cleavage of cytisine was evaluated but failed. However, the stability of the intermediate boronate opens a new pathway for the elaboration of cytisine itself using both Matteson homologation and Zweifel olefination.

Inorganic Triphenylphosphine.

A completely inorganic version of one of the most famous organophosphorus compounds, triphenylphosphine, has been prepared. A comparison of the crystal structures of inorganic triphenylphosphine, PBaz3 (where Baz=B3 H2 N3 H3 ) and PPh3 shows that they have superficial similarities and furthermore, the Lewis basicities of the two compounds are remarkably similar. However, their oxygenation and hydrolysis reactions are starkly different. PBaz3 reacts quantitatively with water to give PH3 and with the oxidizing agent ONMe3 to give the triply-O-inserted product P(OBaz)3 , an inorganic version of triphenyl phosphite; a corresponding transformation with PPh3 is inconceivable. Thermodynamically, what drives these striking differences in the chemistry of PBaz3 and PPh3 is the great strength of the B-O bond.

Influence of Ring Strain and Bond Polarization on the Ring Expansion of Phosphorus Homocycles.

Heterolytic cleavage of homoatomic bonds is a challenge, as it requires separation of opposite charges. Even highly strained homoatomic rings (e.g., cyclopropane and cyclobutane) are kinetically stable and do not react with nucleophiles or electrophiles. In contrast, cycloalkanes bearing electron-donating/withdrawing substituents on adjacent carbons have polarized C-C bonds and undergo numerous heterolytic ring-opening and expansion reactions. Here we show that upon electrophile activation phosphorus homocycles exhibit analogous reactivity, which is modulated by the amount of ring strain and extent of bond polarization. Neutral rings (tBuP)3, 1, or (tBuP)4, 2, show no reactivity toward nitriles, but the cyclo-phosphinophosphonium derivative [(tBuP)3Me]+, [3Me]+, undergoes addition to nitriles giving five-membered P3CN heterocycles. Because of its lower ring strain, the analogous four-membered ring, [(tBuP)4Me]+, [4Me]+, is thermodynamically stable with respect to cycloaddition with nitriles, despite similar P-P bond polarization. We also report the first example of isonitrile insertion into cyclophosphines, which is facile for polarized derivatives [3Me]+ and [4Me]+, but does not proceed for neutral 1 or 2, despite the calculated exothermicity of the process. Finally, we assessed the reactions of [4R]+ R = H, Cl, F toward 4-dimethylaminopyridine (dmap), which suggest that the site of nucleophilic attack varies with the extent of P-P bond polarization. These results deconvolute the influence of ring strain and bond polarization on the chemistry of inorganic homocycles and unlock new synthetic possibilities.

Addition of a Cyclophosphine to Nitriles: An Inorganic Click Reaction Featuring Protio, Organo, and Main-Group Catalysis.

The addition of a cyclotriphosphine to a broad range of nitriles gives access to the first examples of free 1-aza-2,3,4-triphospholenes in a rapid, ambient temperature, one-pot, high-yield protocol. The reaction produces electron-rich heterocycles (four lone pairs) and features homoatomic σ-bond heterolysis, thereby combining the key features of the 1,3-dipolar cycloaddition chemistry of azides and cyclopropanes. Also reported is the first catalytic addition of P-P bonds to the C≡N bond. The coordination chemistry of the new heterocycles is explored.

Spin Changes Accompany Ultrafast Structural Interconversion in the Ground State of a Cobalt Nitrosyl Complex.

Ultrafast, reversible intersystem crossing (ISC) is reported under ambient conditions for the electronic ground state of the pentacoordinate cobalt nitrosyl complexes, [CoX2 (NO)(PMePh2 )2 ] (X=Cl, Br), in solution. ISCs on such short timescales are more typically observed in electronically excited states reached by absorption of ultraviolet or visible light. Singlet and triplet electron spin states of the complex, corresponding to two different isomers, are populated at room temperature, and the two isomers exchange on a timescale of a few picoseconds. Ultrafast two-dimensional infrared spectroscopy observes the change in wavenumber of the NO ligand band accompanying the isomerization and associated ISC on the (spin) adiabatic ground potential energy surface. Comparison of the dynamics of the chloro- and bromo-complexes shows that inertial effects of the ligand motion have a greater effect than spin-orbit coupling on determining the forward and reverse isomerization and ISC rates.

Small Molecule Activation by Intermolecular Zr(IV)-Phosphine Frustrated Lewis Pairs.

We report intermolecular transition metal frustrated Lewis pairs (FLPs) based on zirconocene aryloxide and phosphine moieties that exhibit a broad range of small molecule activation chemistry that has previously been the preserve of only intramolecular pairs. Reactions with D2, CO2, THF, and PhCCH are reported. By contrast with previous intramolecular examples, these systems allow facile access to a variety of steric and electronic characteristics at the Lewis acidic and Lewis basic components, with the three-step syntheses of 10 new intermolecular transition metal FLPs being reported. Systematic variation to the phosphine Lewis base is used to unravel steric considerations, with the surprising conclusion that phosphines with relatively small Tolman steric parameters not only give highly reactive FLPs but are often seen to have the highest selectivity for the desired product. DOSY NMR spectroscopic studies on these systems reveal for the first time the nature of the Lewis acid/Lewis base interactions in transition metal FLPs of this type.

Hydrogen-Bonded Homoleptic Fluoride-Diarylurea Complexes: Structure, Reactivity, and Coordinating Power.

Hydrogen bonding with fluoride is a key interaction encountered when analyzing the mode of action of 5'-fluoro-5'-deoxyadenosine synthase, the only known enzyme capable of catalyzing the formation of a C-F bond from F-. Further understanding of the effect of hydrogen bonding on the structure and reactivity of complexed fluoride is therefore important for catalysis and numerous other applications, such as anion supramolecular chemistry. Herein we disclose a detailed study examining the structure of 18 novel urea-fluoride complexes in the solid state, by X-ray and neutron diffraction, and in solution phase and explore the reactivity of these complexes as a fluoride source in SN2 chemistry. Experimental data show that the structure, coordination strength, and reactivity of the urea-fluoride complexes are tunable by modifying substituents on the urea receptor. Hammett analysis of aryl groups on the urea indicates that fluoride binding is dependent on σp and σm parameters with stronger binding being observed for electron-deficient urea ligands. For the first time, defined urea-fluoride complexes are used as fluoride-binding reagents for the nucleophilic substitution of a model alkyl bromide. The reaction is slower in comparison with known alcohol-fluoride complexes, but SN2 is largely favored over E2, at a ratio surpassing all hydrogen-bonded complexes documented in the literature for the model alkyl bromide employed. Increased second-order rate constants at higher dilution support the hypothesis that the reactive species is a 1:1 urea-fluoride complex of type [UF]- (U = urea) resulting from partial dissociation of the parent compound [U2F]-. The dissociation processes can be quantified through a combination of UV and NMR assays, including DOSY and HOESY analyses that illuminate the complexation state and H-bonding in solution.

Single oxygen-atom insertion into P-B bonds: on- and off-metal transformation of a borylphosphine into a borylphosphinite.

An oxygen atom is selectively inserted into the P-B bond of a borylphosphine (L1) by reaction with Me3 NO to afford the corresponding borylphosphinite (L2). This transformation can also be effected when L1 is coordinated to rhodium. The ν(CO) values for trans-[RhCl(CO)(L)2] reveal very different electronic properties for coordinated L1 and L2 which translate into the strikingly different performances of the complexes [RhCl(L)(cod)] (L= L1 or L2, cod=1,5-cyclooctadiene) in hydrosilylation and hydroboration catalysis.

B-Methylated Amine-Boranes: Substituent Redistribution, Catalytic Dehydrogenation, and Facile Metal-Free Hydrogen Transfer Reactions.

Although the dehydrogenation chemistry of amine-boranes substituted at nitrogen has attracted considerable attention, much less is known about the reactivity of their B-substituted analogues. When the B-methylated amine-borane adducts, RR'NH·BH2Me (1a: R = R' = H; 1b: R = Me, R' = H; 1c: R = R' = Me; 1d: R = R' = iPr), were heated to 70 °C in solution (THF or toluene), redistribution reactions were observed involving the apparent scrambling of the methyl and hydrogen substituents on boron to afford a mixture of the species RR'NH·BH3-xMex (x = 0-3). These reactions were postulated to arise via amine-borane dissociation followed by the reversible formation of diborane intermediates and adduct reformation. Dehydrocoupling of 1a-1d with Rh(I), Ir(III), and Ni(0) precatalysts in THF at 20 °C resulted in an array of products, including aminoborane RR'N═BHMe, cyclic diborazane [RR'N-BHMe]2, and borazine [RN-BMe]3 based on analysis by in situ (11)B NMR spectroscopy, with peak assignments further supported by density functional theory (DFT) calculations. Significantly, very rapid, metal-free hydrogen transfer between 1a and the monomeric aminoborane, iPr2N═BH2, to yield iPr2NH·BH3 (together with dehydrogenation products derived from 1a) was complete within only 10 min at 20 °C in THF, substantially faster than for the N-substituted analogue MeNH2·BH3. DFT calculations revealed that the hydrogen transfer proceeded via a concerted mechanism through a cyclic six-membered transition state analogous to that previously reported for the reaction of the N-dimethyl species Me2NH·BH3 and iPr2N═BH2. However, as a result of the presence of an electron donating methyl substituent on boron rather than on nitrogen, the process was more thermodynamically favorable and the activation energy barrier was reduced.

Cooperative Lewis pairs based on late transition metals: activation of small molecules by platinum(0) and B(C6 F5 )3.

A Lewis basic platinum(0)-CO complex supported by a diphosphine ligand and B(C6 F5 )3 act cooperatively, in a manner reminiscent of a frustrated Lewis pair, to activate small molecules such as hydrogen, CO2 , and ethene. This cooperative Lewis pair facilitates the coupling of CO and ethene in a new way.

Facile hydrolysis and alcoholysis of palladium acetate.

Palladium(II) acetate is readily converted into [Pd3 (µ(2) -OH)(OAc)5 ] (1) in the presence of water in a range of organic solvents and is also slowly converted in the solid state. Complex 1 can also be formed in nominally anhydrous solvents. Similarly, the analogous alkoxide complexes [Pd3 (µ(2) -OR)(OAc)5 ] (3) are easily formed in solutions of palladium(II) acetate containing a range of alcohols. An examination of a representative Wacker-type oxidation shows that the Pd-OH complex 1 and a related Pd-oxo complex 4 can be excluded as potential catalytic intermediates in the absence of exogenous water.

Backbone-functionalised ruthenium diphosphine complexes for catalytic upgrading of ethanol and methanol to iso-butanol.

Efficient catalysts for Guerbet-type ethanol/methanol upgrading to iso-butanol have been developed via Michael addition of a variety of amines to ruthenium-coordinated dppen (1,1-bis(diphenylphosphino)ethylene). All catalysts produce over 50% iso-butanol yield with >90% selectivity in 2 h with catalyst 1 showing the best activity (74% yield after this time). The selectivity and turnover number approach 100% and 1000 respectively using catalyst 6. The presence of uncoordinated functionalised donor groups in these complexes results in a more stable catalyst compared to unfunctionalised analogues.

A metal complex based fluorescent chemodosimeter for selective detection of 2,4-dinitrophenol and picric acid in aqueous media.

This work describes the syntheses, characterization, crystal structures, absorption and emission spectra and DFT calculations of three dizinc(II) compounds of the composition [ZnII2L(µ1,1-N3)(N3)2] (1) [Zn2L'(2,4-dinitrophenolate)2] (2) and [Zn2L'(picrate)2] (3), respectively, (where HL is the 1 : 2 condensation product of 4-ethyl-2,6-diformylphenol and N-methylethylenediamine and H2L' (a diamino-diimino-diphenol system) is a new type of macrocyclic ligand). Compound 1 is water soluble and its aqueous solution exhibits intense fluorescence properties. 2,4-Dinitrophenol (DNP) and picric acid (PA) selectively quench the fluorescence intensity of 1 to a significant extent, revealing that 1 is a fluorescence sensor of DNP and PA. Compounds 2 and 3 were prepared by mixing 1 with DNP and PA. As a huge change in the system (acyclic to macrocyclic) occurs while exhibiting sensing behaviour, it is evident that 1 senses DNP and PA through a chemodosimetric approach in aqueous media. For sensing nitroaromatic compounds, compound 1 acts as (i) a rare chemodosimeter, (ii) a rare metal containing chemodosimeter and (iii) a rare fluorescent chemosensor in aqueous media. Based on the ESI-MS and single crystal X-ray structures, it has been possible to establish a mechanism for the conversion of the acyclic system in 1 to a new type of macrocyclic system in 2 and 3. It has been established from DFT calculations that ground state complexation via charge transfer and IFE can be considered as the major reason for the DNP/PA stimulated strong fluorescence quenching.