Didier Siri

Properties of dinitroxides for use in dynamic nuclear polarization (DNP)

We have investigated the properties of a series of dinitroxides as polarizing agents for SS NMR/DNP applications. Our results clearly establish that an orthogonal relative orientation of electron g tensors is a crucial requirement to obtain high enhancement DNP factors. Moreover, the ratio of the proton Larmor frequency over the e(-)-e(-) dipolar coupling (omega(H)/omega(D)) influences the efficiency of the cross effect (CE) mechanism, thus the Ree distance between the unpaired electrons must be adapted to omega(H).

Tandem radical addition–aldol condensations: evidence for the formation of zinc enolates in diethylzinc mediated radical additions to N-enoyloxazolidinones

Diethylzinc mediated addition of alkyl radicals to chiral N-enoyloxazolidinones is immediately followed by homolytic substitution at zinc leading to a zinc enolate; the trapping of the latter in a subsequent aldol condensation serves as a useful mechanistic probe; overall this reaction sequence constitutes a novel example of a one pot, three-component, radical-polar crossover reaction.

Memory of chirality in cascade rearrangements of enediynes.

The cascade rearrangement of chiral enediynes 1c-e, involving successively 1,3-proton shift, Saito-Myers cyclization, 1,5-hydrogen atom transfer, and intramolecular coupling of the resulting biradical, proceeded at 80 °C to form tri- and tetracyclic heterocycles possessing a quaternary stereogenic center with a very high level of memory of chirality.

Prediction of nitroxide hyperfine coupling constants in solution from combined nanosecond scale simulations and quantum computations

We present a combined theoretical approach based on analyzing molecular dynamics trajectories (at the nanosecond scale) generated by use of classical polarizable force fields and on quantum calculations to compute averaged hyperfine coupling constants. That method is used to estimate the constant of a prototypical nitroxide: the dimethylnitroxide. The molecule is embedded during the simulations in a cubic box containing about 500 water molecules and the molecular dynamics is generated using periodic conditions. Once the trajectories are achieved, the nitroxide and its first hydration shell molecules are extracted, and the coupling constants are computed by considering the latter aggregates by means of quantum computations. However, all the water molecules of the bulk are also accounted for during those computations by means of the electrostatic potential fitted method. Our results exhibit that in order to predict accurate and reliable coupling constants, one needs to describe carefully the out-of-plane motion of the nitroxide nitrogen and to sample trajectories with a time interval of 400 fs at least to generate an uncorrelated large set of nitroxide structures. Compared to Car-Parrinello molecular dynamics techniques, our approach can be used readily to compute hyperfine coupling constants of large systems, such as nitroxides of great size interacting with macromolecules such as proteins or polymers.

Chemically Triggered C–ON Bond Homolysis of Alkoxyamines. Quaternization of the Alkyl Fragment

The C-ON bond homolysis in alkoxyamine 2a can be chemically triggered by the protonation of the 4-pyridylalkyl fragment. The resulting 15-fold increase in k(d) (Chem. Commun. 2011, 47, 4291-4293) was investigated experimentally and theoretically by quaternization of the pyridyl moiety using methylating (MeOTs), acylating (AcCl), and benzylating (PhCH(2)Br) agents as well as by oxidation of the pyridyl moiety into N-oxide and by the formation of a dative bond with BH(3) as a Lewis acid.

Spin-Trapping Evidence for the Formation of Alkyl, Alkoxyl, and Alkylperoxyl Radicals in the Reactions of Dialkylzincs with Oxygen

The reactions of dialkylzincs (Me(2)Zn, Et(2)Zn, and nBu(2)Zn) with oxygen have been investigated by EPR spectroscopy using spin-trapping techniques. The use of 5-diethoxyphosphoryl-5-methyl-1-pyrrroline N-oxide (DEPMPO) as a spin-trap has allowed the involvement of alkyl, alkylperoxyl, and alkoxyl radicals in this process to be probed for the first time. The relative ratio of the corresponding spin-adducts depends strongly on the nature of the R group, which controls the C-Zn bond dissociation enthalpy, and on the experimental conditions (excess of spin-trap compared with R(2)Zn and vice versa). The results have demonstrated that Et(2)Zn and, to a lesser extent, nBu(2)Zn are much better traps for oxygen-centered species than Me(2)Zn. When the dialkylzincs were used in excess with respect to the spin-trap, the concentration of the oxygen-centered radical adducts of DEPMPO was much lower for Et(2)Zn and nBu(2)Zn than for Me(2)Zn. A detailed reaction mechanism is discussed and C-Zn, O-Zn, and O-O bond dissociation enthalpies for the proposed reaction intermediates were calculated at the UB3LYP/6-311++G(3df,3pd)//UB3LYP/6-31G(d,p) level of theory to support the rationale.

The molecular electrostatic potential and drug design

Abstract The molecular electrostatic potential (MEP) is now a classical tool in chemical activity analysis, especially in drug design. In this paper we discuss, from different MEP applications in drug studies, significant results obtained over the last few years. This analysis led us to define how the MEP can be used in drug design, and the limits of its application, whatever the accuracy of the method used to calculate it.

Switching from (R)- to (S)-selective chemoenzymatic DKR of amines involving sulfanyl radical-mediated racemization

Chemoenzymatic dynamic kinetic resolution (DKR) of amines involving sulfanyl radical-induced racemization happened to be the very first switchable DKR process allowing the synthesis of either (R)- or (S)-amides, in good yield and high enantiomeric excess, depending on the nature of the enzyme; the different steps of the development of (S)-selective DKR are discussed.

Chemically Triggered C–ON Bond Homolysis in Alkoxyamines. Part 2: DFT Investigation and Application of the pH Effect on NMP

In recent work, a 15-fold increase in the C-ON bond homolysis rate constant kd of 4-pyridylethyl-SG1-based alkoxyamine was observed upon protonation of the pyridyl moiety in organic solvent. In this report, the pH dependence of kd (pKa = 4.7) is investigated in D2O/CD3OD (v/v 1:1). A 64-fold increase in kd is observed at acidic pH. Calculations show that the increase in kd upon protonation is due to both an increase in the stabilization of the protonated 4-pyridylethyl radical and an increase of the destabilization of the starting materials through an increase in the polarity of the alkyl fragment. This new alkoxyamine is applied to NMP of styrene and sodium styrene sulfonate.

Theoretical study of the photochemical generation of triplet acetophenone

Acetophenone has a rich photochemistry, which strongly depends on the absorbing state. For example, the excitation to the lowest singlet excited state (S1) leads to a triplet population with a phosphorescence quantum yield of one, while the excitation to S2 leads to photocleavage reactions. Here, we rationalize the photochemistry of acetophenone after being absorbed into the S1, S2 and S3 states by performing a systematic study of all the singlet and triplet minimum energy structures and state crossings between the relevant electronic states. We calculate these structures at the complete-active space self-consistent field (CASSCF) level of theory and at the correlated extended second-order quasi-degenerate multi-reference perturbation theory (XMCQDPT2), emphasizing the importance of correlation effects in the determination of structures.