Spectroscopic Discrimination of Diastereomeric Complexes Involving an Axially Chiral Receptor.

The infrared multiphoton dissociation (IRMPD) spectra of electrospray ionization (ESI)-formed proton-bound complexes between the axially chiral multifunctional macrocycle MaR and d- and l-phenylalanine (PD and PL ) or d- and l-3,4-dihydroxyphenylalanine (DD and DL ) are recorded in the ν˜ =2800-3700 cm-1 region. Whereas the diastereomeric [MaR ⋅H⋅PD ]+ and [MaR ⋅H⋅PL ]+ complexes do not show any significant spectral differences, the spectrum of [MaR ⋅H⋅DD ]+ clearly diverges from that of its [MaR ⋅H⋅DL ]+ diastereomer. A comparison of the experimental spectra with the B3LYP/6-31G**-calculated harmonic vibrational frequencies of a number of stable structures indicates the formation, in the ESI source, of very similar spectroscopically active structures, with the protonated amino acid placed outside the flat cavity of the macrocycle and hydrogen-bonded at its O2 center. Different spectral signatures of the [MaR ⋅H⋅DD ]+ and [MaR ⋅H⋅DL ]+ complexes are attributed to the coexistence of several stable rotamers in the ESI source.

Chlorine Para-Substitution of 1-Phenylethanol: Resonant Photoionization Spectroscopy and Quantum Chemical Calculations of Hydrated and Diastereomeric Complexes.

The conformational landscape of (S)-1-(4-chlorophenyl)ethanol, its monohydrated complex, and its diastereomeric adducts with R- and S-butan-2-ol, have been investigated by resonant two-photon ionization (R2PI) spectroscopy coupled with time-of-flight mass spectrometry. Theoretical calculations at the D-B3LYP/6-31++G** level of theory have been performed to assist in the interpretation of the spectra and in the assignment of the structures. The R2PI spectra and the predicted structures have been compared with those obtained on the analogous non-halogenated and fluorinated systems, i.e., (R)-1-phenylethanol and (S)-1-(4-fluorophenyl)ethanol, respectively. It appears that the presence of chlorine atom in the para position of the aromatic ring does not influence the overall geometry of bare molecule and its complexes with respect to the non-halogenated analogous systems. Anyway, it affects the electron density in the π system, and in turn the strength of OH···π and CH···π interactions. A spectral chiral discrimination is evident from the R2PI spectra of the diastereomeric adducts of (S)-1-(4-chlorophenyl)ethanol with the two enantiomers of butan-2-ol.

Boyer's Reaction and Transetherification: Mechanism and New Perspectives.

The progress and stereochemistry of Boyer's reaction were analyzed using several simple, chiral, alcoholic substrates, a variable amount of BiBr3 and different solvents. Basic solvents inhibit the reaction, while cyclohexane works very well; thus, it was our choice for the present study. In contrast to previous works, BiBr3 behaves as a true catalyst, being not consumed during the reaction. Although poisoning of the catalyst occurs to some extent, it does not prejudice the reaction yields (>90%). Gas chromatography/mass spectrometry (GC-MS) monitoring of the reaction revealed that, for example, in the presence of alcohol , isomeric ethers transetherificate to . We propose a unifying mechanistic model for both Boyer's and transetherification reactions, in which the electronic properties of n-adducts intermediates, formed by combination of bismuth(III) of BiBr3 and oxygen atoms of alcohols and ethers, play the key role for both the reactivity and the stereochemical outcome of the reaction.

Electronic structure and conformational flexibility of D-cycloserine.

The first comprehensive investigation of the effect of conformational flexibility of gaseous D-cycloserine on the valence and core electronic structures is reported here. The seven most stable conformers among the twelve structures calculated at the MP2/6-311++G** level of theory were assumed to properly describe the properties of the investigated compound. Taking into account the contribution of these isomers, the valence photoelectron spectrum (UPS) was simulated by the Outer Valence Green' s Function (OVGF) method. A different sensitivity towards the conformational flexibility of the outermost photoelectron bands was exhibited in the simulated spectrum. The comparison of the theoretical UPS with the experimental one allowed a detailed assignment of the outermost valence spectral region. The composition and bonding properties of the relevant MOs of the most stable conformers were analyzed in terms of leading Natural Bond Orbital (NBO) contributions to the HF/6-311++G** canonical MOs. The C1s, N1s, and O1s photoelectron spectra (XPS) were theoretically simulated by calculating the vertical Ionization Energies (IEs) of the relevant conformers using the ΔSCF approach. The different IE chemical shift spread of the XPS components associated with various conformers, which is expected to affect the experimental spectra, could be evaluated by simulated XPS, thus providing a new insight into the core electronic structure. The comparison of the theoretical results with the experimental ones unraveled that the atomic XPS components are not mixed by conformational flexibility of D-cycloserine, and that the specific vibronic structure of different spectral components should play a crucial role in determining different relative intensities and band shapes observed in the experiment.

Conformational sensitivity in photoelectron circular dichroism of 3-methylcyclopentanone.

A study of (R)-3-methylcyclopentanone [(R)-3-MCP] by photoelectron spectroscopy and photoelectron circular dichroism (PECD) is presented. The synchrotron radiation gas-phase photoelectron spectra of (R)-3-MCP were measured and are discussed on the basis of different theoretical methodologies. The experimental dichroism of (R)-3-MCP for selected deconvoluted valence states and for the carbonyl carbon 1s core state are reported and reproduced well by calculated dispersions generated by considering the contributions of two different conformers. The theoretical dichroic parameters are calculated by employing a multicentre basis set of B-spline functions and a Kohn-Sham Hamiltonian. Temperature-dependent PECD studies of the HOMO state and the carbonyl carbon 1s core level allowed the separation of the contributions of each conformer by photoelectron dichroism. This new approach clearly shows how the PECD methodology is sensitive to conformational and structural changes of unoriented (R)-3-MCP in the gas phase, opening up new perspectives in the characterisation of chiral molecular systems.

The effect of fluorine substitution on chiral recognition: interplay of CH···π, OH···π and CH···F interactions in gas-phase complexes of 1-aryl-1-ethanol with butan-2-ol.

The molecular diastereomeric complexes between R-1-phenyl-1-ethanol, S-1-(4-fluorophenyl)ethanol and S-1-(2-fluorophenyl)ethanol and R and S-butan-2-ol, isolated under molecular beam conditions in the gas phase, have been investigated by mass-selective resonant two-photon ionization (R2PI) and infrared depleted R2PI (IR-R2PI). The comparison of the three systems allowed us to highlight the significance of specific intermolecular interactions in the chiral discrimination process. The interpretation of the results is based on theoretical predictions mainly at the D-B3LYP/6-31++G** level of theory. The homo and heterochiral complexes are endowed with fine differences in intermolecular interactions, namely strong OH···O, and weaker CH···π, OH···π, CH···F as well as repulsive interactions. The presence of a fluorine atom in the para position of the aromatic ring does not influence the overall geometry of the complex whilst it affects the electron density in the π system and the strength of CH···π and OH···π interactions. The role and the importance of CH···F intermolecular interactions are evident in the complexes with fluorine substitution in the ortho position. While the ortho hetero complex is structurally analogous to the hetero para and non-fluorinated structures, butan-2-ol in the ortho homo adduct adopts a different conformation in order to establish a CH···F intermolecular interaction.

Chirality effects on the IRMPD spectra of basket resorcinarene/nucleoside complexes.

The IRMPD spectra of the ESI-formed proton-bound complexes of the R,R,R,R- and S,S,S,S-enantiomers of a bis(diamido)-bridged basket resorcin[4]arene (R and S) with cytosine (1), cytidine (2), and cytarabine (3) were measured in the region 2800-3600 cm(-1). Comparison of the IRMPD spectra with the corresponding ONIOM (B3LYP/6-31(d):UFF)-calculated absorption frequencies allowed the assessment of the vibrational modes that are responsible for the observed spectroscopic features. All of the complexes investigated, apart from [R⋅H⋅3](+), showed similar IRMPD spectra, which points to similar structural and conformational landscapes. Their IRMPD spectra agree with the formation of several isomeric structures in the ESI source, wherein the N(3)-protonated guest establishes noncovalent interactions with the host amidocarbonyl groups that are either oriented inside the host cavity or outside it between one of the bridged side-chains and the upper aromatic nucleus. The IRMPD spectrum of the [R⋅H⋅3](+) complex was clearly different from the others. This difference is attributed to the effect of intramolecular hydrogen-bonding interactions between the C(2')-OH group and the aglycone oxygen atom of the nucleosidic guest upon repulsive interactions between the same oxygen atom and the aromatic rings of the host.

Enantioselective supramolecular devices in the gas phase. Resorcin[4]arene as a model system.

This review describes the state-of-art in the field of the gas-phase reactivity of diastereomeric complexes formed between a chiral artificial receptor and a biologically active molecule. The presented experimental approach is a ligand-displacement reaction carried out in a nano ESI-FT-ICR instrument, supported by a thermodynamic MS-study and molecular-mechanics and molecular-dynamics (MM/MD) computational techniques. The noncovalent ion-molecule complexes are ideal for the study of chiral recognition in the absence of complicating solvent and counterion effects.

The "bridge" game: role of the fourth player in chiral recognition.

A new team player: The "three-point interaction" model, which is usually employed to rationalize chiral recognition, does not account for the amazing enantioselectivity measured for the receptors of many proteic acceptors. Gas-phase experiments have indicated that at least a fourth "player" must be considered: the rigidity that a receptor opposes to distortions of its cavity resulting from noncovalent interactions with a chiral molecule (see picture).

Unprecedented gas-phase chiroselective logic gates.

The gas-phase encounters between 2-aminobutane and proton-bound chiral resorcin[4]arene/nucleoside complexes behave in the gas phase as supramolecular "chiroselective logic gates" by releasing the nucleoside depending on the resorcin[4]arene and the 2-aminobutane configurations.

Chiral recognition between 1-(4-fluorophenyl)ethanol and 2-butanol: higher binding energy of homochiral complexes in the gas phase.

Diastereomeric adducts between (S)-1-(4-fluorophenyl)-ethanol and R and S 2-butanol, formed by supersonic expansion, have been investigated by means of a combination of mass selected resonant two-photon ionization-spectroscopy and infrared depletion spectroscopy. Chiral recognition is evidenced by the specific spectroscopic signatures of the S(1)← S(0) electronic transition as well as different frequencies and intensities of the OH stretch vibrational mode in the ground state. D-DFT calculations have been performed to assist in the analysis of the spectra and the determination of the structures. The homochiral and heterochiral complexes show slight structural differences, in particular in the interaction of the alkyl groups of 2-butanol with the aromatic ring. The experimental results show that the homochiral [FE(S)·B(S)] complex is more stable than the heterochiral [FE(S)·B(R)] diastereomer in both the ground and excited states. The binding energy difference has been evaluated to be greater than 0.60 kcal mol(-1).

Does a chiral alcohol really racemize when its OH group is protected with Boyer's reaction?

Chiral reactants have been employed for assessing the real stereochemistry of the BiBr3-catalyzed synthesis of benzylic ethers, a very useful reaction for protecting alcoholic groups. The results of this investigation are in clear contrast with the conclusions of previous studies (Boyer et al., Tetrahedron 2001;57:1917-1921). Indeed, chiral GC-MS analysis of the ethereal products gives unequivocal evidence of the complete racemization of the benzylic moiety and the complete retention of configuration of the protected alcoholic substrate. Such findings make BiBr3 a powerful and stereochemically preservative catalyst for benzylation of chiral alcohols, and a potential candidate for orthogonal protecting group strategies applicable to polyhydroxy compounds.

Conformational landscape of supersonically expanded 1-(fluorophenyl)ethanols and their monohydrated clusters.

The effects of the presence of the ring fluorine atom on the conformational landscape of supersonically expanded isomeric 1-(fluorophenyl)ethanols and their monohydrated clusters are investigated by resonant two-photon ionization (R2PI) spectroscopy, coupled with time-of-flight (TOF) mass spectrometry. In contrast to the very simple spectrum of 1-phenylethanol, the lack of structural symmetry of the aromatic rings of isomeric 1-(fluorophenyl)ethanols generates more complicated spectra, characterized by several low-frequency progressions of bands. Their interpretation is based on the strict correspondence with theoretical predictions at the D-B3LYP/6-31G** level of theory. Monohydration of the 1-(fluorophenyl)ethanol isomers favours exclusive formation of the corresponding conformers, characterized by the O-H...O(w)-H...pi intracomplex interaction and whose excitation spectrum exhibits features attributed to the C(1)-C(alpha) torsion plus intermolecular water torsion.

Gas-phase facial diastereoselectivity of equatorial and axial 4-chloro-adamant-2-yl cations.

The acid-catalyzed addition of CH3(18)OH to 2-methylene-adamantanes bearing a chlorine atom in the 4-equatorial (1e) or 4-axial (1a) position has been investigated in the gas phase, at 760 Torr, in the 40-120 degrees C temperature range. Two different experimental approaches were employed: (1) by adding neutral CH3(18)OH to the 2-methyl-4-Cl-adamant-2-yl cation, generated by protonation of the corresponding 2-methylene-4-Cl-adamantane (the extracomplex reaction) and (2) by reaction of 2-methylene-4-Cl-adamantane with CH3(18)OH2+, generated by methylation of H2(18)O (the intracomplex reaction). The crucial role of the nature of the noncovalent intermediates involved along the reaction coordinates emerges from the difference between the results obtained in the extracomplex and intracomplex reactions for both substrates investigated. The kinetic and stereochemical results indicate that the 4-Cl substituent plays a different role depending on its equatorial or axial orientation. Examination of the experimental results in the light of MP2/6-31G* theoretical calculations provides important information about the intrinsic factors governing the facial diastereoselectivity of trigonal carbocations. The effects due to differential face solvation phenomena emerge from the comparison of the present gas-phase results with those obtained from strictly related studies in solution.

Interactions of vinca alkaloid subunits with chiral amido[4]resorcinarenes: a dynamic, kinetic, and spectroscopic study.

The stereoselectivity of the reaction between (R)-(-)-2-butylamine and the diastereomeric proton-bound complexes of (+)-catharanthine (C) or (-)-vindoline (V) with some chiral amido[4]resorcinarenes has been investigated in the gas phase by ESI-FT-ICR-MS. The reaction stereoselectivity (0.56 < k(homo)/k(hetero) < 16.9) is found to depend critically on the functional groups present in the chiral pendants of the hosts. Rationalisation of the kinetic results is based on careful computational and spectroscopic studies of the most stable conformations of (+)-catharanthine and its protonated form in the isolated state and in water, as well as in a representative host structure. The emerging picture points to the relevant diastereomeric proton-bound complexes as quasi-degenerate, thus suggesting that their stereoselectivity in the guest exchange reaction is mostly due to kinetic factors. The results of this study may represent a starting point for a deeper comprehension of the intrinsic factors that endow these molecules, and their dimeric forms, with their biochemical properties.

Gas-phase enantioselectivity of chiral N-linked peptidoresorc[4]arene isomers toward dipeptides.

The gas-phase enantioselectivity of cone N-linked peptidoresorc[4]arenes (generally symbolized as M) toward the homologue dipeptides (generally symbolized as A) has been evaluated by measuring the kinetics of the A release from the diastereomeric [M x H x A](+) complexes induced by (R)-(-)-2-butylamine (B). In most cases investigated, the heterochiral [M x H x A](+) complexes, namely those wherein the configuration of the A guest is opposite to that of the host M pendants, react faster (up to 5 times) than the homochiral analogues, wherein guest A guest has the same configuration of the host M pendants. The kinetic results, discussed in the light of previous MS and NMR evidence, indicate that both the efficiency and the enantioselectivity of the guest exchange reaction depend essentially on the structure and the relative stability of the diastereomeric [M x H x A](+) complexes. These, in turn, depend on the functional groups and the configuration of both the guest and the host pendants. The absence of any significant effects of the B configuration indicates that, in all systems investigated, the dipeptide guest A is predominantly located outside the host chiral cavity.

Gas-phase enantioselective reactions in noncovalent ion-molecule complexes.

Noncovalent diastereomeric ion-molecule complexes are produced in the gas phase and are ideal for the study of chiral recognition in the absence of complicating solvent and counterion effects. This review article describes the state-of-art in this field with special emphasis on the most recent mass spectrometric studies of the structure, dynamics, and reactivity of diastereomeric ion/molecule aggregates.

Molecular and supramolecular chirality: R2PI spectroscopy as a tool for the gas-phase recognition of chiral systems of biological interest.

In life sciences, diastereomeric chiral molecule/chiral receptor complexes are held together by a different combination of intermolecular forces and are therefore endowed with different stability and reactivity. Determination of these forces, which are normally affected in the condensed phase by solvent and supramolecular interactions, can be accomplished through the generation of diastereomeric complexes in the isolated state and their spectroscopic investigation. This review presents a detailed discussion of the mass resolved Resonant Two Photon Ionization (R2PI-TOF) technique in supersonic beams and introduces an overview of various other technologies currently available for the spectroscopic study of gas phase chiral molecules and supramolecular systems. It reports case studies primarily from our recent work using R2PI-TOF methodology for chiral recognition in clusters containing molecules of biological interest. The measurement of absorption spectra, ionization and fragmentation thresholds of diastereomeric clusters by this technique allow the determination of the nature of the intrinsic interactions, which control their formation and which affect their stability and reactivity.

Induced-fit in the gas phase: conformational effects on the enantioselectivity of chiral tetra-amide macrocycles.

The structure, stability, and reactivity of proton-bound diastereomeric [M x H x A]+ complexes between some amino acid derivatives (A) and several chiral tetra-amide macrocycles (M) have been investigated in the gas phase by ESI-FT-ICR and ESI-ITMS-CID mass spectrometry. The displacement of the A guest from the diastereomeric [M x H x A]+ complexes by reaction with the 2-aminobutane enantiomers (B) exhibits a distinct enantioselectivity with regards to the leaving amino acid A and, to a minor extent, to the amine reactant B. The emerging selectivity picture, discussed in the light of molecular mechanics calculations, provides compelling evidence that the most stable conformers of the selected chiral tetra-amide macrocycles M may acquire in the gas phase a different conformation by induced fit on complexation with some representative amino acid derivatives A. This leads to the coexistence in the gas phase of stable diastereomeric [M x H x A]+ eq-eq and ax-ax structures, in proportions depending on the configuration of A and M and characterized by different stability and reactivity toward the 2-aminobutane enantiomers. The enantioselectivity of the gas-phase A-to-B displacement in the diastereomeric [M x H x A]+ complexes essentially reflects the free energy gap between the homo- and heterochiral [M x H x A]+ complexes, except when the tetra-amidic host presents an additional macrocycle generated by a decamethylene chain. In this case, the measured enantioselectivity mostly reflects the stability difference between the relevant diastereomeric transition structures.

A kinetic study of guest displacement reactions on a host-guest complex with a photoswitchable calixarene.

The displacement processes of several guests, incorporated in a calixarene host system, were investigated in the gas phase by electrospray ionization-Fourier transform-ion cyclotron resonance (ESI-FT-ICR) mass spectrometry. The complexes resulting from a resorcin[4]arene host with ammonia and sec-butylamine guests were isolated in an ICR-cell, separately using both states of the photoswitch as well as two reference systems for the open and closed forms of the photoswitchable host. The isolated complexes were forced to exchange the guest by using methylamine, ethylamine and sec-butylamine, resulting in different reaction rates for all the measured systems. Especially, the reaction rates of both states of the photoswitch are dependent on the provided guest. Potential side effects like proton exchanges were examined by an H/D-exchange experiment. The results were investigated and supported by quantum chemical calculations (DFT).