Samarium Diiodide Acting on Acetone-Modeling Single Electron Transfer Energetics in Solution.

Samarium diiodide is a versatile single electron transfer (SET) agent with various applications in organic chemistry. Lewis structures regularly insinuate the existence of a ketyl radical when samarium diiodide binds a carbonyl group. The study presented here investigates this electron transfer by the means of computational chemistry. All electron CASPT2 calculations with the inclusion of scalar relativistic effects predict an endotherm electron transfer from samarium diiodide to acetone. Energies calculated with the PBE0-D3(BJ) functional and a small core pseudopotential are in good agreement with CASPT2. The calculations confirm the experimentally measured increase of the samarium diiodide reduction potential through the addition of hexamethylphosphoramide also known as HMPA.

HMPA-Catalyzed Transfer Hydrogenation of 3-Carbonyl Pyridines and Other N-Heteroarenes with Trichlorosilane.

A method for the HMPA (hexamethylphosphoric triamide)-catalyzed metal-free transfer hydrogenation of pyridines has been developed. The functional group tolerance of the existing reaction conditions provides easy access to various piperidines with ester or ketone groups at the C-3 site. The suitability of this method for the reduction of other N-heteroarenes has also been demonstrated. Thirty-three examples of different substrates have been reduced to designed products with 45⁻96% yields.

Total Synthesis of the Marine Alkaloid Discoipyrrole C via the MoOPH-Mediated Oxidation of a 2,3,5-Trisubstituted Pyrrole.

A total synthesis of the marine alkaloid discoipyrrole C (3) is described. In the pivotal step, the 2,3,5-trisubstituted pyrrole 19 was treated with MoOPH in the presence of MeOH, and the resulting methoxylated 1,2-dihydro-3H-pyrrol-3-one 20 subjected to reaction with potassium carbonate in MeOH then trifluoroacetic acid and H2O. This gave a mixture of target 3 and its dehydration product, and the structure of the former compound was confirmed by single-crystal X-ray analysis.

Elucidating Structural Characteristics of Biomass using Solution-State 2 D NMR with a Mixture of Deuterated Dimethylsulfoxide and Hexamethylphosphoramide.

Recent developments of NMR methods for characterization of lignocellulosic biomass allow improved understanding of plant cell-wall structures with minimal deconstruction and modification of biomass. This study introduces a new NMR solvent system composed of dimethylsulfoxide (DMSO-d6 ) and hexamethylphosphoramide (HMPA-d18 ). HMPA as a co-solvent enhanced swelling and mobility of the biomass samples; thereby it allowed enhancing signals of NMR spectra. The structural information of biomass was successfully analyzed by the proposed NMR solvent system (DMSO-d6 /HMPA-d18 ; 4:1, v/v) with different biomass. The proposed bi-solvent system does not require derivatization or isolation of biomass, facilitating a facile sample preparation and involving with no signals overlapping with biomass peaks. It also allows analyzing biomass with a room-temperature NMR probe instead of cryo-probes, which are traditionally used for enhancing signal intensities.

Indole synthesis from N-allenyl-2-iodoanilines under mild conditions mediated by samarium(II) diiodide.

A novel method for indole skeleton synthesis under mild conditions mediated by samarium(ii) diiodide has been developed. The reaction of N-allenyl-2-iodoaniline derivatives with SmI2 in the presence of HMPA and i-PrOH at 0 °C afforded indole derivatives in high yields.

Phycocyanobilin in solution--a solvent triggered molecular switch.

We present a computational investigation of the conformational response of phycocyanobilin (PCB) to the ability of solvents to form hydrogen bonds. PCB is the chromophore of several proteins in light harvesting complexes. We determine the conformational distributions in different solvents (methanol and hexamethylphosphoramide HMPT) by means of ab initio molecular dynamics simulations and characterize them via ab initio calculations of NMR chemical shift patterns. The computed trajectories and spectroscopic fingerprints illustrate that the energy landscape is very complex and exhibits various conformations of similar energy. We elucidate the strong influence of the solvent characteristics on the structural and spectroscopic parameters. Specifically, we predict a cis-trans isomerization of phycocyanobilin upon switching from the aprotic to the protic solvent, which explains an experimentally observed change in the NMR patterns. In the context of technological molecular recognition, solvent induced conformational switching can be considered a precursor mechanism to the recognition of single molecules.

Unprecedented biomimetic homodimerization of oroidin and clathrodin marine metabolites in the presence of HMPA or phosphonate salt tweezers.

The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin·(1)/2HCl salt or clathrodin·(1)/2HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure 19. The common process was rationalized from tautomeric precursors I and III.

1,4-Chirality transfer via the ester enolate Claisen rearrangements in the preparation of (25R)- and (25S)-cholestenoic acids.

Two variants of the Claisen rearrangement were evaluated for a stereoselective construction of a C-25 stereogenic center in cholestenoic acids based on 1,4-chirality transfer. Johnson orthoester Claisen rearrangement of (22R)- and (22S)-propargyl enol ethers proceeded in a highly stereoselective manner to give (25R)- and (25S)-isomeric allenes. The stereochemical outcome of the Ireland-Claisen rearrangement of 22-allylic alcohols was dependent on the configuration of the C-22 hydroxyl group and the geometry of the enol ether. The latter could be controlled by the solvent (THF or a mixture of THF/HMPA) chosen for the generation of silyl enolate.

Preparation and use of samarium diiodide (SmI(2)) in organic synthesis: the mechanistic role of HMPA and Ni(II) salts in the samarium Barbier reaction.

Although initially considered an esoteric reagent, SmI(2) has become a common tool for synthetic organic chemists. SmI(2) is generated through the addition of molecular iodine to samarium metal in THF.(1,2-3) It is a mild and selective single electron reductant and its versatility is a result of its ability to initiate a wide range of reductions including C-C bond-forming and cascade or sequential reactions. SmI(2) can reduce a variety of functional groups including sulfoxides and sulfones, phosphine oxides, epoxides, alkyl and aryl halides, carbonyls, and conjugated double bonds.(2-12) One of the fascinating features of SmI-(2)-mediated reactions is the ability to manipulate the outcome of reactions through the selective use of cosolvents or additives. In most instances, additives are essential in controlling the rate of reduction and the chemo- or stereoselectivity of reactions.(13-14) Additives commonly utilized to fine tune the reactivity of SmI(2) can be classified into three major groups: (1) Lewis bases (HMPA, other electron-donor ligands, chelating ethers, etc.), (2) proton sources (alcohols, water etc.), and (3) inorganic additives (Ni(acac)(2), FeCl(3), etc).(3) Understanding the mechanism of SmI(2) reactions and the role of the additives enables utilization of the full potential of the reagent in organic synthesis. The Sm-Barbier reaction is chosen to illustrate the synthetic importance and mechanistic role of two common additives: HMPA and Ni(II) in this reaction. The Sm-Barbier reaction is similar to the traditional Grignard reaction with the only difference being that the alkyl halide, carbonyl, and Sm reductant are mixed simultaneously in one pot.(1,15) Examples of Sm-mediated Barbier reactions with a range of coupling partners have been reported,(1,3,7,10,12) and have been utilized in key steps of the synthesis of large natural products.(16,17) Previous studies on the effect of additives on SmI(2) reactions have shown that HMPA enhances the reduction potential of SmI(2) by coordinating to the samarium metal center, producing a more powerful,(13-14,18) sterically encumbered reductant(19-21) and in some cases playing an integral role in post electron-transfer steps facilitating subsequent bond-forming events.(22) In the Sm-Barbier reaction, HMPA has been shown to additionally activate the alkyl halide by forming a complex in a pre-equilibrium step.(23) Ni(II) salts are a catalytic additive used frequently in Sm-mediated transformations.(24-27) Though critical for success, the mechanistic role of Ni(II) was not known in these reactions. Recently it has been shown that SmI(2) reduces Ni(II) to Ni(0), and the reaction is then carried out through organometallic Ni(0) chemistry.(28) These mechanistic studies highlight that although the same Barbier product is obtained, the use of different additives in the SmI(2) reaction drastically alters the mechanistic pathway of the reaction. The protocol for running these SmI(2)-initiated reactions is described.

Synergism and inhibition in the combination of visible light and HMPA in SmI2 reductions.

The reaction of six substrates (diphenylacetylene, benzonitrile, methyl benzoate, phenylacetylene, naphthalene, and 1-chloro-4-ethylbenzene) with SmI(2) in the presence of MeOH or TFE was studied. The reactions were monitored under three different conditions: (a) irradiation, (b) irradiation in the presence of HMPA, and (c) reactions in the presence of HMPA in the dark. The combination of visible light and HMPA was found in some cases to be synergistic, in others to be additive, and in four cases to be inhibitive. The Marcus theory provides a good understanding of the synergistic and the additivity phenomena. The inhibitive effect is traced to the post electron transfer step in which Sm(3+) plays an important role. Once coordinated to HMPA, Sm(3+) is less capable of assisting in the protonation of the radical anion or the expulsion of the leaving group. Ranking according to the substrate's electron affinity shows that inhibition is manifested for the three least electrophilic substrates: phenylacetylene, naphthalene, and 1-chloro-4-ethylbenzene. Typical of these substrates is the short lifetime of their radical anions. Thus, if a step consecutive to electron transfer is slow and cannot compete successfully with the rapid back electron transfer, the benefit of having the electron transfer step enhanced is much reduced.

Assignment of phycocyanobilin in HMPT using triple resonance experiments.

A complete assignment of all resonances of a small organic molecule is a prerequisite for a structure determination using NMR spectroscopy. This is conventionally obtained using a well-established strategy based on COSY, HMQC and HMBC spectra. In case of phycocyanobilin (PCB) in HMPT this strategy was unsuccessful due to the symmetry of the molecule and extreme signal overlap. Since (13)C and (15)N labeled material was available, an alternative strategy for resonance assignment was used. Triple resonance experiments derived from experiments conventionally performed for proteins are sensitive and easy to analyze. Their application led to a complete and unambiguous assignment using three types of experiments.

Prediction of contaminant persistence in aqueous phase: a quantum chemical approach.

At contaminated field sites where active remediation measures are not feasible, monitored natural attenuation is sometimes the only alternative for surface water or groundwater decontamination. However, due to slow degradation rates of some contaminants under natural conditions, attenuation processes and their performance assessment can take several years to decades to complete. Here, we apply quantum chemical calculations to predict contaminant persistence in the aqueous phase. For the test compound hexamethylphosphoramide (HMPA), P-N bond hydrolysis is the only thermodynamically favorable reaction that may lead to its degradation under reducing conditions. Through calculation of aqueous Gibbs free energies of activation for all potential reaction mechanisms, it is predicted that HMPA hydrolyzes via an acid-catalyzed mechanism at pH < 8.2, and an uncatalyzed mechanism at pH 8.2-8.5. The estimated half-lives of thousands to hundreds of thousands of years over the groundwater-typical pH range of 6.0 to 8.5 indicate that HMPA will be persistent in the absence of suitable oxidants. At pH 0, where the hydrolysis reaction is rapid enough to enable measurement, the experimentally determined rate constant and half-life are in excellent agreement with the predicted values. Since the quantum chemical methodology described herein can be applied to virtually any contaminant or reaction of interest, it is especially valuable for the prediction of persistence when slow reaction rates impede experimental investigations and appropriate QSARs are unavailable.

Structure and dynamics of α-aryl amide and ketone enolates: THF, PMDTA, TMTAN, HMPA, and crypt-solvated lithium enolates, and comparison with phosphazenium analogues.

A variety of multinuclear NMR techniques, in combination with X-ray diffraction methods, were used to probe the solution structure of α-aryl lithium enolates of bis(4-fluorobenzyl) ketone (1-H), phenyl 4-fluorobenzyl ketone (2-H), and N,N-dimethyl 4-fluorophenylacetamide (3-H) in ethereal solvents and in the presence of cosolvent additives PMDTA, TMTAN, HMPA, and cryptand [2.1.1]. All three enolates were dimers in THF solution, and were converted to monomers by the triamine additives, PMDTA and TMTAN. The exchange of the triamine-solvated monomers with their ethereal-solvated dimer counterparts was probed by using dynamic NMR (DNMR). The cosolvent HMPA formed monomers along with minor amounts of lithiate species, (RO)(2)Li(-) and (RO)(3)Li(2-), which were also observed when cryptand [2.1.1] was used as a cosolvent, or when mixed lithium-phosphazenium enolate solutions were prepared. Dynamic exchange of lithiate species was investigated by DNMR spectroscopy. The barrier to rotation of the conjugated 4-fluorophenyl ring of these diverse enolate structures was measured and found to be consistent with a resonance picture where lower aggregation states lead to increased delocalization of negative charge. The lithium enolate aggregates identified were compared to the "naked" α-4-fluorophenyl enolates generated with the phosphazene base P4. The barrier to aryl ring rotation was 2.7 kcal/mol higher for the phosphazenium enolate 3-Li·P4H compared to the dimer (3-Li)(2). Structural characterization of a phosphazenium enolate through X-ray crystallography was obtained for the first time. Additional aspects of the Schwesinger base P4 were investigated which included characterization of the solution exchange behavior of the protonated and unprotonated forms as well as determination of the solid state structure by X-ray diffraction.

Quantum chemical prediction of redox reactivity and degradation pathways for aqueous phase contaminants: an example with HMPA.

Models used to predict the fate of aqueous phase contaminants are often limited by their inability to address the widely varying redox conditions in natural and engineered systems. Here, we present a novel approach based on quantum chemical calculations that identifies the thermodynamic conditions necessary for redox-promoted degradation and predicts potential degradation pathways. Hexamethylphosphoramide (HMPA), a widely used solvent and potential groundwater contaminant, is used as a test case. Its oxidation is estimated to require at least iron-reducing conditions at low to neutral pH and nitrate-reducing conditions at high pH. Furthermore, the transformation of HMPA by permanganate is predicted to proceed through sequential N-demethylation. Experimental validation based on LC/TOF-MS analysis confirms the predicted pathways of HMPA oxidation by permanganate to phosphoramide via the formation of less methylated as well as singly and multiply oxygenated reaction intermediates. Pathways predicted to be thermodynamically or kinetically unfavorable are similarly absent in the experimental studies. Our newly developed methodology will enable scientists and engineers to estimate the favorability of contaminant degradation at a specific field site, suitable approaches to enhance degradation, and the persistence of a contaminant and its reaction intermediates.

On the mechanism of Lewis base catalyzed aldol addition reactions: kinetic and spectroscopic investigations using rapid-injection NMR.

The mechanistic foundations of the Lewis base catalyzed aldol addition reactions have been investigated. From a combination of low-temperature spectroscopic studies ((29)Si and (31)P NMR) and kinetic analyses using a rapid-injection NMR apparatus (RINMR), a correlation of the ground states and transition structures for the aldolization reactions has been formulated. The aldol addition of the tert-butylsilyl ketene acetal of tert-butyl propanoate with 1-naphthaldehyde is efficiently catalyzed by a combination of silicon tetrachloride and chiral phosphoramide Lewis bases. The rates and selectivities of the aldol additions are highly dependent on the structure of the Lewis bases: bisphosphoramides give the highest rate and selectivity, whereas a related monophosphoramide reacts slowly and with low selectivity. The monophosphoramide shows no nonlinear behavior. All of the additions show a first-order kinetic dependence on silyl ketene acetal and 1-naphthaldehyde and a zeroth-order dependence on silicon tetrachloride. The kinetic order in catalyst is structure dependent and is either half-, two-thirds-, or first-order. All of the phosphoramides are saturated with silicon tetrachloride in some form, and the resting-state species are mixtures of monomeric and dimeric, pentacoordinate cationic, or hexacoordinate neutral complexes. These data allow the formulation of a unified mechanistic scheme based on the postulate of a common reactive intermediate for all catalysts.

Noninvasive monitoring of HPMA copolymer-RGDfK conjugates by magnetic resonance imaging.

PURPOSE: To evaluate the tumor targeting potential of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gadolinium(Gd)-RGDfK conjugates by magnetic resonance (MR) T1-mapping. METHODS: HPMA copolymers with and without RGDfK were synthesized to incorporate side chains for Gd chelation. The conjugates were characterized by their side-chain contents and r(1) relaxivity. In vitro integrin-binding affinities of polymeric conjugates were assessed via competitive cell binding assays on HUVEC endothelial cells and MDA-MB-231 breast cancer cells. In vivo MR imaging was performed on MDA-MB-231 tumor-bearing SCID mice at different time points using non-targetable and targetable polymers. The specificity of alphavbeta3 targeting was assessed by using non-paramagnetic targetable polymer to block alphavbeta3 integrins followed by injection of paramagnetic targetable polymers after 2 h. RESULTS: The polymer conjugates showed relaxivities higher than Gd-DOTA. Endothelial cell binding studies showed that IC(50) values for the copolymer with RGDfK binding to alphavbeta3 integrin-positive HUVEC and MDA-MB-231 cells were similar to that of free peptide. Significantly lower T1 values were observed at the tumor site after 2 h using targetable conjugate (p < 0.012). In vivo blocking study showed significantly higher T1 values (p < 0.045) compared to targetable conjugate. CONCLUSION: These results demonstrate the potential of this conjugate as an effective targetable MR contrast agent for tumor imaging and therapy monitoring.

Lewis base-catalyzed conjugate reduction and reductive aldol reaction of alpha,beta-unsaturated ketones using trichlorosilane.

Lewis bases such as Ph3P=O and HMPA catalyze the 1,4-reduction of alpha,beta-unsaturated ketones with trichlorosilane, and because the 1,2-reduction of aldehydes scarcely proceeded under the conditions, one-pot reductive aldol reactions with aldehydes were successfully achieved; preliminary studies using a chiral Lewis base revealed a high potential for enantioselective catalysis.

Reactivity of the triple ion and separated ion pair of tris(trimethylsilyl)methyllithium with aldehydes: a RINMR study.

Low-temperature rapid-injection NMR (RINMR) experiments were performed on tris(trimethylsilyl)methyllithium. In THF/Me2O solutions, the separated ion (1S) reacted faster than can be measured at -130 degrees C with MeI and substituted benzaldehydes (k >/= 2 s -1), whereas the contact ion (1C) dissociated to 1S before reacting. Unexpectedly, the triple ion reacted faster with electron-rich benzaldehydes relative to electron-deficient ones. The addition of HMPA had no effect on the rate of reaction of the triple ion with p-diethylaminobenzaldehyde, and the immediate product of the reaction was the HMPA-solvated separated ion 1S, with the Peterson product forming only slowly. Thus, the aldehyde is catalyzing the dissociation of the triple ion. HMPA greatly decelerated the reaction of 1S (<10 -10), providing an estimate of the Lewis acid activating effect of a THF-solvated lithium cation in an organolithium addition to an aldehyde.

Lithium diisopropylamide solvated by hexamethylphosphoramide: substrate-dependent mechanisms for dehydrobrominations.

Lithium diisopropylamide-mediated dehydrobrominations of exo-2-bromonorbornane, 1-bromocyclooctene, and cis-4-bromo-tert-butylcyclohexane were studied in THF solutions and THF solutions with added hexamethylphosphoramide (HMPA). Rate studies reveal a diverse array of mechanisms based on mono-, di-, and trisolvated monomers as well as triple ions. The results are contrasted with analogous eliminations in THF in the absence of HMPA.

[Synthesis of substituted 3H-indole quaternary ammonium salt and study on its interaction with bovine serum albumin by fluorescence].

A substituted 3H-indole quaternary ammonium molecule was designed and synthesized using hexamethylphosphoramide (HMPA) as a solvent. The products were purified and characterized by IR, 1H-NMR, MS and elemental analysis. The binding reaction of this compound with bovine serum albumin (BSA) in aqueous solution was studied using fluorescence. Their binding constant is Ka = 1.995 x 10(5) dm3 x mol(-1) and the binding site number is n = 1.12. It is confirmed that the combination is a single static quenching process.