Chiroptical phenomena in reverse micelles: the case of (1R,2S)-dodecyl (2-hydroxy-1-methyl-2-phenylethyl)dimethylammonium bromide (DMEB).

(1R,2S)-Dodecyl(2-hydroxy-1-methyl-2-phenylethyl)dimethylammonium bromide (DMEB) aggregates dispersed in carbon tetrachloride have been investigated by Fourier transform infrared (FT-IR), vibrational circular dichroism (VCD) and (1)H nuclear magnetic resonance (NMR) spectroscopy at various surfactant concentration and water-to-surfactant molar ratio. Experimental data indicate that, even at the lowest investigated concentration and in absence of added water, DMEB molecules associate in supramolecular assemblies. At higher DMEB concentration the aggregates can confine water molecules, making it plausible to think that DMEB form reverse micelles and that water molecules are quite uniformly distributed among them and mainly located in the proximity of surfactant head groups. Moreover, the water state in DMEB reverse micelles has been found to be different from that in pure water, due to system-specific water/surfactant head group interactions. (1)H NMR diffusion measurements of both water and DMEB emphasize their joined translational motion characterized by a diffusion rate one order of magnitude lower than that of free molecules. Finally, VCD allowed us to show some characteristics of the association of optically active DMEB molecules as reverse micelles and water confinement inside; namely, we monitored the vibrational optical activity of deuterated hydroxyl bonds of the self-assembled DMEB molecules and their interaction with D(2)O molecules.

Chiroptical spectroscopic techniques based on fluorescence.

Among the various chiroptical spectroscopic methods circular dichroism (CD), optical rotatory dispersion (ORD), Raman optical activity (ROA), the methods based on fluorescence have so far played a marginal role. Fluorescence detected circular dichroism and circularly polarized luminescence (CPL) were both introduced many years ago with important, but not so frequent, applications. In particular, CPL, which requires specialist hardware, has been restricted by the limited number of users. Recent interest, which has increased in the field of material science particularly, where the emission properties are more attractive and important than the absorption ones, has motivated new application fields and may change the situation in the future.

Experimental and calculated CPL spectra and related spectroscopic data of camphor and other simple chiral bicyclic ketones.

UV, circular dichroism (CD), fluorescence and circularly polarized luminescence (CPL) spectra were recorded for a set of four related [2.2.1] bicyclic compounds ((1S,4S)-and (1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one, namely (1S)- and (1R)-camphor (), (1S,4R)-4,7,7-trimethylbicyclo[2.2.1]hept-5-en-2-one, (1S)-dehydro-epicamphor (), (1S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2,5-dione, (1S)-5-oxocamphor (), (1S,4R)- and (1R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione, (1S)- and (1R)-camphorquinone ()) and a set of three related [2.2.2] bicyclic compounds (1S,4S)-bicyclo[2.2.2]octan-2,5-dione (saturated diketone ()), (1R,4R)-bicyclo[2.2.2]oct-7-en-2,5-dione (unsaturated diketone ()), ((1S,4S)-bicyclo[2.2.2]oct-7-en-5(S)-ol-2-one (which we refer to as unsaturated hydroxy-ketone ()). For the latter three compounds also mid-IR vibrational circular dichroism (VCD) spectra were recorded and are presented. Time-Dependent Density Functional (TD-DFT) calculations provide a satisfactory interpretation of both absorption and emission chiroptical spectra and permit insight into ground and excited state electronic properties. We discuss the applicability of the octant rule or of other approximated models to rationalize the observed sign of the CPL.

Conformational studies of Phe-rich foldamers by VCD spectroscopy and ab initio calculations.

Employing VCD spectroscopy, we demonstrate that the structural behavior of the oligomers Boc-(L-Phe-L-Oxd)(n)-OBn is similar from n = 2 to n = 6; ab initio calculations for the n = 1 case provide physical insight into the conformational properties. Further information is gained by IR, (1)H NMR, and ECD spectroscopies. ECD spectra suggest the presence of different conformations between n = 1 on one side and longer chain foldamers on the other side. VCD and absorption IR spectra in methanol solutions can be interpreted as indicative of a PPII structure. In the case of Boc-L-Phe-L-Oxd-OBn, VCD spectra in CCl(4) and detailed DFT computational analysis allow one to demonstrate that the most populated conformers exhibit backbone dihedral angles similar to those of a PPII geometry. This is a remarkable outcome, as we had previously demonstrated that the Boc-(L-Ala-D-Oxd)(n)-OBn series folds in a ß-band ribbon spiral that is a subtype of the 3(10) helix.

Vibrational and electronic circular dichroism of dimethyl mesobilirubins-XIIIα.

The vibrational circular dichroism (VCD) spectra of (αR,α'R)-, (αS,α'S)-, (ßR,ß'R)-, and (ßS,ß'S)-dimethylmesobilirubin-XIIIα have been recorded in the range of 1800-900 cm(-1) in CDCl3 solution and in mixed DMSO-d6/CDCl3 solutions. Ab initio density functional theory (DFT) calculations predict IR vibrational absorption (VA) and VCD spectra in excellent to good correspondence with observed data. The same calculations confirmed the ridge-tile conformation that has been known for a long time. Assignment of vibrational normal modes (NMs) sheds light on the relative importance of local moieties and groups in determining conformational properties of the molecules, as well as their interaction with solvent molecules. Time-dependent DFT (TDDFT) calculations were also performed to provide an understanding of electronic circular dichroism (ECD) spectra and confirm the well-known interpretation based on the exciton model.

Ultraviolet, circular dichroism, fluorescence, and circularly polarized luminescence spectra of regioregular poly-[3-((S)-2-methylbutyl)-thiophene] in solution.

Ultraviolet (UV), Circular Dichroism (CD), Fluorescence, and Circularly Polarized Luminescence (CPL) spectra were recorded for mixed chloroform/methanol and chloroform/butanol solutions of regioregular poly[3-((S)-2-methylbutyl)-thiophene]. An evaluation of the chiral and nonchiral components in solution is proposed on the basis of the UV and CD spectra. The fluorescence and CPL spectra are observed in a wavelength range where some UV and CD activity still appears. For this reason, the observed CPL features are strongly influenced by CD. A general procedure for evaluating true CPL spectra is proposed, when absorption and emission coexist.

Triggering dissymmetry in achiral dye molecules by chiral solvents: Circular dichroism experiments and DFT calculations.

The electronic circular dichroism spectra of achiral product "Lumogen F Red" (ROT-300) in four different chiral solvents are recorded at different temperatures. DFT calculations allow to identify two enantiomeric conformers for ROT-300. In vacuo they are equally populated; in chiral solvents one enantiomer prevails. Thermodynamic quantities involved in the chiral preference are derived.

Experimental and calculated vibrational and electronic circular dichroism spectra of 2-Br-hexahelicene.

The vibrational circular dichroism (VCD) and IR absorption spectra of the (-)-enantiomer of 2-Br-hexahelicene have been measured and interpreted by use of density functional theory (DFT) calculations. From time dependent DFT calculations we also interpret the electronic circular dichroism (ECD) spectra of 2-Br-hexahelicene. We compare the calculated IR, VCD and ECD spectra to the corresponding calculated data of hexahelicene and 2-aza-hexahelicene; for the last compound we also recorded the ECD spectra. Comparison with current literature allows an insight to be gained on the meaning and usefulness of some VCD features.

Comparative analysis of IR and vibrational circular dichroism spectra for a series of camphor-related molecules.

The absorption spectra and vibrational circular dichroism (VCD) spectra in the mid-IR range 1600-950 cm(-1) of 10 camphor-related compounds have been recorded and compared to DFT calculated spectra at the B3PW91/TZ2P level and have been examined together with the corresponding data of the parent molecules. The rigidity of the bridged structure common to all compounds investigated permits (a) identification of three spectroscopic regions in the mid-IR range that can be "used" separately by the interested stereochemist for structural diagnosis and assignment of some major characteristics of the VCD spectra in these regions to what we call "skeletal chiral sense" and (b) recognition of possible conformers for flexible substituent groups, when present. VCD spectra of the 10 molecules have been recorded and analyzed also in the CH-stretching region, 3100-2800 cm(-1). Here, we have been able to identify and characterize features of vibrational excitons by comparison of data within the 10-molecule class. To find a theoretical justification of result (a), we have examined the potential energy distribution of the normal modes in the mid-IR range, the partitioning of the calculated rotational strengths in terms of contributions from all couples of internal coordinates, the angle formed by the two vectors, the electric dipole transition moment and the magnetic dipole transition moment, and finally the overlap of normal modes of different molecules. A discussion is provided as to the usability of the introduced algorithms.

Spectroscopic and structural investigation of the confinement of D and L dimethyl tartrate in lecithin reverse micelles.

The confinement of D and L dimethyl tartrate in lecithin reverse micelles dispersed in cyclohexane has been investigated by FT-IR, polarimetry, electronic and vibrational circular dichroism (ECD and VCD), 1H NMR, and small-angle X-ray scattering (SAXS). Measurements have been performed at room temperature as a function of the solubilizate-to-surfactant molar ratio (R) at fixed lecithin concentration. The analysis of experimental data indicates that the dimethyl tartrate molecules are solubilized within reverse micelles in proximity to the surfactant head groups in the same way for the D and L forms. The encapsulation of dimethyl tatrate within lecithin reverse micelles involves changes in its H-bonds, from what is observed in the pure solid or in CCl4 solutions; this is a consequence of the establishment of specific solute-surfactant headgroup interactions and of confinement effects. In the 0 < or = R < or = 1.7 range, SAXS profiles of dimethyl tartrate/lecithin/ cyclohexane micellar solutions are well-described by a model of interacting polydisperse spherical micellar cores whose mean radius does not change appreciably with R (i.e., it changes from about 18 to 20 angstroms). 1H NMR diffusion measurements of both dimethyl tartrates and lecithin were rationalized in terms of collective translational motions of the entire micellar aggregate and of their molecular diffusion among clusters of reverse micelles. The association of optically active lecithin with D and L dimethyl tartrate leads to the formation of self-organized supramolecular aggregates whose interesting chiroptical features are evidenced by polarimetry and CD.

Electronic and vibrational circular dichroism spectra of chiral 4-X-[2.2]paracyclophanes with X containing fluorine atoms.

The absorption IR and vibrational circular dichroism (VCD) spectra of both enantiomers of 4-X-[2.2]paracyclophanes (X = F, CH(2)F, COCF(3)) have been recorded in the mid-IR and CH stretching regions. The electronic CD (ECD) spectra have been collected as well. VCD spectra in the two IR regions, 900-1700 cm(-1) and 2700-3200 cm(-1), have been compared with the corresponding DFT calculated spectra. The absolute configuration assignment was confirmed as previously determined. We have shown that, to various extents, the VCD and ECD spectra bear some information on the relative mobility of the two phenyl rings and on the existence of different conformers for the X group. It has been observed that X = F and X = CH(2)F groups do not change the conformational and electronic properties of the parent X = H and X = CH(3) molecules. The X = COCF(3) group brings in a large perturbation to the [2.2]paracyclophanes, and the role of fluorine is less important than that of oxygen.

Determination of the absolute configuration of aromatase and dual aromatase-sulfatase inhibitors by vibrational and electronic circular dichroism spectra analysis.

The absolute configuration of a newly designed, letrozole-based chiral aromatase inhibitor that could not be defined by crystallographic techniques has been determined by means of vibrational and electronic circular dichroism and by optical rotation measurements combined with density functional theory calculations on possible conformers. The same absolute configurational assignment can be applied to the individual enantiomeric sulfamate esters, which are derived from the corresponding enantiomers of the chirally separated parent phenols, based on the similarity of the ECD spectrum of the sulfamate derivative to that of its phenolic precursor. The two enantiomeric sulfamate esters studied here are the first examples of nonsteroidal dual aromatase-sulfatase inhibitor whose activities have been evaluated on optically resolved enantiomers.

Assessment of configurational and conformational properties of naringenin by vibrational circular dichroism.

The electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra of both enantiomers of naringenin (4',5,7-trihydroxyflavanone) in acetonitrile solution have been measured. The enantiomers were obtained by chiral HPLC separation of the racemic sample. DFT calculations have been performed for relevant conformers and subsequent evaluations of VCD spectra are compared with VCD experiments: safe assignment of the absolute configuration is provided, based in particular on the VCD data. The relevance of the rotational conformers of the hydroxyl groups and of the mobility of phenol moiety is studied: based on this, we provide a first interpretation of the observed intense and broad couplet at 1325/1350 cm(-1). Four conformers contribute to this pattern with different sign and amplitude as shown by DFT calculations. Time dependent DFT calculations have been performed and compared with ECD experimental data, under the same assumption of conformational properties and mobilities investigated by VCD.

Molecular dynamics simulation of aqueous solutions of 26-unit segments of p(NIPAAm) and of p(NIPAAm) "doped" with amino acid based comonomers.

We have performed 75-ns molecular dynamics (MD) simulations of aqueous solutions of a 26-unit NIPAAm oligomer at two temperatures, 302 and 315 K, below and above the experimentally determined lower critical solution temperature (LCST) of p(NIPAAm). We have been able to show that at 315 K the oligomer assumes a compact form, while it keeps a more extended form at 302 K. A similar behavior has been demonstrated for a similar NIPAAm oligomer, where two units had been substituted by methacryloyl-l-valine (MAVA) comonomers, one of them being charged and one neutral. For another analogous oligomer, where the same units had been substituted by methacryloyl-l-leucine (MALEU) comonomers, no transition from the extended to the more compact conformation has been found within the same simulation time. Statistical analysis of the trajectories indicates that this transition is related to the dynamics of the oligomer backbone, and to the formation of intramolecular hydrogen bonds and water-bridges between distant units of the solute. In the MAVA case, we have also evidenced an important role of the neutral MAVA comonomer in stabilizing the compact coiled structure. In the MALEU case, the corresponding comonomer is not equally efficacious and, possibly, is even hindering the readjustment of the oligomer backbone. Finally the self-diffusion coefficient of water molecules surrounding the oligomers at the two temperatures for selected relevant times is observed to characteristically depend on the distance from the solute molecules.

Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: synthesis, absolute configuration, and in vitro activity.

To explore aromatase inhibition and to broaden the structural diversity of dual aromatase-sulfatase inhibitors (DASIs), we introduced the steroid sulfatase (STS) inhibitory pharmacophore to letrozole. Letrozole derivatives were prepared bearing bis-sulfamates or mono-sulfamates with or without adjacent substituents. The most potent of the achiral and racemic aromatase inhibitor was 40 (IC 50 = 3.0 nM). Its phenolic precursor 39 was separated by chiral HPLC, and the absolute configuration of each enantiomer was determined using vibrational and electronic circular dichroism in tandem with calculations of the predicted spectra. Of the two enantiomers, ( R)-phenol ( 39a) was the most potent aromatase inhibitor (IC 50 = 0.6 nM, comparable to letrozole), whereas the ( S)-sulfamate, ( 40b) inhibited STS most potently (IC 50 = 553 nM). These results suggest that a new structural class of DASI for potential treatment of hormone-dependent breast cancer has been identified, and this is the first report of STS inhibition by an enantiopure nonsteroidal compound.

An operative approach to correct CD spectra distortions due to absorption flattening.

We discuss the influence of absorption flattening (AF) on CD spectra, aiming at finding a simple way to compensate the induced distortions. A simple algebraic formalism is proposed based on an unconventional measuring approach, which makes use of a commercial unit. Validation of the proposed compensation method for AF is conducted not only on the already studied CD Vis spectral region of a Co chiral complex with the use of an AF emulator, but also on the far UV CD spectra of poly-L-glutamic acid suspensions with different turbidity levels. Comparison with some correction factors proposed in the literature is presented.

Study of conformational properties of a biologically active peptide of fibronectin by circular dichroism, NMR and molecular dynamics simulation.

Circular dichroism (CD), and NMR spectra have been recorded and molecular dynamics (MD) simulations have been performed in water and water-trifluoroethanol (TFE) mixed solvent for a synthetic biologically active 13-amino-acid fragment of human fibronectin and two related peptides. The CD results are interpreted on the basis of statistical analyses of MD trajectories and of ensuing calculations of CD spectra based on Schellman's matrix method. It is observed that the peptide conformation is quite variable in water and loses its mobility with the addition of TFE. (1)H-NOE data were found to be consistent with the most abundant calculated conformation.

Detection by circular dichroism of conformational transitions in pH and thermosensitive copolymers based on N-isopropylacrylamide and N-methacryloyl-L-leucine.

Circular dichroism (CD) spectra in the region of 210-250 nm allow visualization of intrachain phase transition of pH- and thermosensitive polyelectrolytes. Indeed, in 0.001 M citrate and acetate buffers, at pH 4.0-5.5, aqueous solutions of a poly(N-isopropylacrylamide-co-N-methacryloyl-L-leucine) (NIPAAm-MALEU) copolymer containing 90.9 mol% of NIPAAm residues exhibit a well-defined sigmoidal increase in the CD signal at 220 nm with increasing temperature. This phenomenon is suggestive of a highly cooperative transition which occurs at lower temperatures compared to that observed by cloud point measurements. The change in the CD signal is less sharp at higher pH, indicating varying cooperativity with pH. For pH 6.0 and higher, no such phenomena are observed.

Vibrational circular dichroism in the near infrared: instrumental developments and applications.

Near infrared vibrational circular dichroism spectra in the region of 1300 to 800 nm were recorded for 12 enantiomeric pairs of molecules with a home-made dispersive apparatus. With respect to earlier measurements, a better signal-to-noise ratio was obtained, thus allowing a more precise determination of molecular parameters. A detailed examination of the spectra between 1300 and 1100 nm allowed us to correlate the data of the different molecules, based on local properties of given molecular moieties. The relevance of this correlation in configurational and/or conformational studies is discussed.