Fernando Coelho

Venturi Easy Ambient Sonic-Spray Ionization

The development and illustrative applications of an ambient ionization technique termed Venturi easy ambient sonic-spray ionization (V-EASI) is described. Its dual mode of operation with Venturi self-pumping makes V-EASI applicable to the direct mass spectrometric analysis of both liquid (V(L)-EASI) and solid (V(S)-EASI) samples. V-EASI is simple and easy to assemble, operating solely via the assistance of a sonic stream of nitrogen or air. The sonic gas stream causes two beneficial and integrated effects: (a) the self-pumping of solutions via the Venturi effect and (b) sonic-spray ionization (SSI) of analytes either in solution or resting on solid surfaces. In its liquid mode, V(L)-EASI is applicable to analytes in solution, forming negatively and/or positively charged intact molecular species in a soft fashion with little or no fragmentation. In its solid mode, V(S)-EASI relies on Venturi self-pumping of a proper SSI solvent solution in combination with SSI to form a stream of bipolar charged droplets that bombard the sample surface, causing desorption and ionization of the analyte molecules. As for its precursor technique (EASI), V-EASI generates bipolar droplets with considerably lower average charging, which increases selectivity for ionization with high signal-to-noise ratios and clean spectra dominated by single molecular species with minimal solvent ions. V-EASI also operates in a voltage-, heat-, and radiation-free fashion and is therefore free of thermal, electrical, or discharge interferences.

The Bridge Connecting Gas‐Phase and Solution Chemistries

Mass spectrometry (MS) has long served as the gas-phase nursery for exotic ions of ephemeral existence and reactions of ephemeral occurrence in solution. These examples include CH5 , the first ever pentavalent form of carbon, which was later formed in a superacid solution by Olah and Schlosberg; and many elusive ionized molecules such as the prototype carbonyl ylide in its “excentric” distonic ion form, CH2 O CH2, with an apparently bizarre separation of charge and spin sites. MS has also served as the gas-phase medium in which to form key ions and hence probe reaction mechanisms and establish intrinsic reactivity orders. Gaseous NO2 , for instance, was used to settle the mechanism of electrophilic aromatic nitration, a chemical canon that was enthusiastically debated over for decades. Intrinsic physicochemical properties and catalysis, most particularly directed to the activation of inert C H bonds, have also been extensively investigated in gas-phase reactions of (organo)metallic ions. MS was born, however, with a “genetic defect”, that is, “blindness” to neutral species. But an elegant strategy was elaborated, and distant charge sites (negative or positive) were used as charged tags to allow MS to manipulate otherwise neutral species such as radicals. However, skepticism obscured the beauty of gas-phase ion chemistry because the high vacuum was considered by many as an eccentric environment with no bridge to the “real world” of solutions. But John Fenn came to the rescue with his Nobel Prize winning electrospray ionization (ESI) technique. To paraphrase Fenn: “ESI made the power and elegance of MS applicable to both gas-phase and solution ions”. ESI was revolutionary since it brought MS down to the “real world” of solutions by “fishing” solution ions directly into the gas phase. ESI-MS provides continuous snapshots of the dynamic ionic composition of reaction solutions, and ESI-MS “ion fishing” investigations of reaction mechanisms are therefore free from the gas-phase skepticism; the MS bridge is still being used since ions are transferred to the gas phase for MS analysis but they are fished from the reaction medium exactly at the moment of action, and stay mostly undisturbed in the gas phase during their flight to the MS detector. But ESI is also blind to neutral species. To again overcome this limitation, the elegant concept of charged tags developed in the gas phase was brought into solution to facilitate the “flight to the moon”, as Scheme 1 exemplifies. In his Nobel lecture, Fenn summarized ESI as “wings for molecular elephants”; similarly, the combination of ESI and charged tags can be viewed as “charged wings for the flying fish of reaction intermediates” (Figure 1). The gas phase continued to play a major role since the gaseous intermediates can still be investigated by MS to access intrinsic reactivities and functions in the specific reaction step they were fished from. ESI has also allowed

Ultrasound in Baylis -Hillman reactions with aliphatic and aromatic aldehydes: scope and limitations

The utilization of ultrasound radiation in the Baylis–Hillman reaction with several aldehydes (aromatics and aliphatics) and different α,β-unsaturated reactants is described. For all aldehydes tested, the utilization of ultrasound sources augmented the reaction rate and the chemical yields. The use of ultrasound with two different catalysts (tri-n-butylphosphine and 1,4-diazabicyclo[2.2.2]octane [DABCO]) was also investigated. It was clearly demonstrated that DABCO is much more effective for catalyzing a Baylis–Hillman reaction under the influence of ultrasound than is tri-n-butylphosphine. No effect on reaction rate was observed when the concentration of DABCO was increased.

Dualistic Nature of the Mechanism of the Morita-Baylis-Hillman Reaction Probed by Electrospray Ionization Mass Spectrometry

The Morita-Baylis-Hillman (MBH) reaction allows chemists to form new sigma C-C bonds in a single-step straightforward manner and thus to construct densely functionalized molecules for further chemical manipulation. Using electrospray ionization for transferring ions directly from solution to the gas phase, and mass (and tandem mass) spectrometry for mass and structural assignments, new key intermediates for the rate-determining step of the MBH reaction have been successfully intercepted and structurally characterized. These ESI-MS data provide experimental evidence supporting recent suggestions, based on kinetic experiments and theoretical calculations, for the dualist nature of the proton-transfer step of the MBH mechanism.

Diastereoselectivity in heterogeneous catalytic hydrogenation of Baylis–Hillman adducts. Total synthesis of (±)-sitophilate

Abstract We describe herein a highly diastereoselective total synthesis of racemic sitophilate, based on the results obtained in a diastereoselective heterogeneous catalytic hydrogenation reaction of a set of Baylis–Hillman adducts originating from aliphatic aldehydes.

Reação de Baylis-Hillman: uma estratégia para a preparação de intermediários multifuncionalizados para síntese orgânica

The Baylis-Hillman reaction has significantly advanced in the last ten years as demonstrated by a number of applications described in the literature. In this report we show some aspects of this reaction, including scope, limitations and perspectives.

An easy and stereoselective synthesis of N-boc-dolaproine via the Baylis-Hillman reaction

Abstract In this communication we report a stereoselective total synthesis of N -Boc-dolaproine (Dap), an amino acid residue of the antineoplastic pentapeptide Dolastatin 10. Our strategy is based on a Baylis–Hillman reaction between N -Boc-prolinal and methyl acrylate, followed by a diastereoselective double bond hydrogenation and hydrolysis of the ester function.

An approach to substituted dihydroisoquinolin-1(2H)-ones from Baylis–Hillman adducts

In this communication we describe an easy and straightforward alternative method for the preparation of 3,4-substituted isoquinolin-1(2H)-ones, using Baylis–Hillman adducts as starting material.

AN ALTERNATIVE ROUTE TO THE SYNTHESIS OF LIGNANS INTERMEDIATES

The preparation of β-hydroxylignans intermediates via Baylis-Hillman reaction isdes cribed.

Diastereoselective formation of a quaternary center in a pyroglutamate derivative. Formal synthesis of Monatin

Abstract In this communication we describe a highly diastereoselective formation of a quaternary center present in the structure of Monatin, a potent sweetening agent isolated from natural sources. The synthesis of a derivative useful for biological studies on the interactions of this type of sweetening substance on taste receptors is described. The strategy relies on the oxidation of an enolate originating from a pyroglutamate derivative followed by a highly diastereoselective alkylation with an electrophile obtained from indole.