Experimental and theoretical aspects of magnetic circular dichroism and magnetic circularly polarized luminescence in the UV, visible and IR ranges: A review.

A historical sketch of the MCD (magnetic circular dichroism) spectroscopy is reported in its experimental and theoretical aspects. MCPL (magnetic circularly polarized luminescence) is also considered. The main studies are presented encompassing porphyrinoid systems, aggregates and materials, as well as simple organic molecules useful for the advancement of the interpretation. The MCD of chiral systems is discussed with special attention to new studies of natural products with potential pharmaceutical valence, including Amaryllidaceae alkaloids and related isocarbostyrils. Finally, the vibrational form of MCD, called MVCD, which is recorded in the IR part of the spectrum is also discussed. A final brief note on perspectives is given.

CPL of Mellein and Related Natural Compounds: Analysis of the ESIPT Phenomenon.

(R)-(-)-Mellein, (3R,4R)-4-hydroxymellein and (3R,4S)-4-hydroxymellein obtained from fungi, i.e. from Diplodia globulosa, were investigated as a class of natural products presenting ESIPT (excited state intramolecular proton transfer) phenomenon, through fluorescence and CPL (circularly polarized luminescence). The study was preceded by the assessment of the absolute configuration through ECD and VCD (electronic and vibrational circular dichroism) spectroscopies in addition to NMR spectra. It is found that ESIPT takes place in these systems very rapidly, and no dual fluorescence has been observed. The experimental study is backed up by TD-DFT calculations of ECD and CPL spectra, plus MD dynamics to follow proton transfer in the excited state and careful analysis of the puckering dynamics of the lactone ring. Deprotonated forms of the three compounds were also investigated by the same chiroptical experimental and theoretical methods, showing how one can find in natural compounds not only biological activity but also biologically compatible sensing probes.

Chiral Teropyrenes: Synthesis, Structure, and Spectroscopic Studies.

We present the inaugural synthesis of a chiral teropyrene achieved through a four-fold alkyne benzannulation catalyzed by InCl3, resulting in good yields. The product underwent thorough characterization using FT-Raman and FT-IR spectroscopies, demonstrating a close agreement with calculated spectra. X-ray crystallographic analysis unveiled a notable twist in the molecule's backbone, with an end-to-end twist angle of 51°, consistent with computational predictions. Experimentally determined enantiomeric inversion barriers revealed a significant energy barrier of 23 kcal/mol, facilitating the isolation of enantiomers for analysis via circular dichroism (CD) and circularly polarized luminescence (CPL) spectroscopies. These findings mark significant strides in the synthesis and characterization of chiral teropyrenes, offering insights into their structural and spectroscopic properties.

Neurodegeneration: can metabolites from Eremurus persicus help?

The number of patients affected by neurodegenerative diseases is increasing worldwide, and no effective treatments have been developed yet. Although precision medicine could represent a powerful tool, it remains a challenge due to the high variability among patients. To identify molecules acting with innovative mechanisms of action, we performed a computational investigation using SAFAN technology, focusing specifically on HuD. This target belongs to the human embryonic lethal abnormal visual-like (ELAV) proteins and plays a key role in neuronal plasticity and differentiation. The results highlighted that the molecule able to bind the selected target was (R)-aloesaponol-III-8-methyl ether [(R)-ASME], a metabolite extracted from Eremurus persicus. Notably, this molecule is a TNF-α inhibitor, a cytokine involved in neuroinflammation. To obtain a suitable amount of (R)-ASME to confirm its activity on HuD, we optimized the extraction procedure. Together with ASME, another related metabolite, germichrysone, was isolated. Both ASME and germichrysone underwent biological investigation, but only ASME confirmed its ability to bind HuD. Given the multifactorial nature of neurodegenerative diseases, we decided to investigate ASME as a proteasome activator, being molecules endowed with this kind of activity potentially able to counteract aggregations of dysregulated proteins. ASME was able to activate the considered target both in enzymatic and cellular assays. Therefore, ASME may be considered a promising hit in the fight against neurodegenerative diseases.

Mid-IR and CH stretching vibrational circular dichroism spectroscopy to distinguish various sources of chirality: The case of quinophaneoxazoline based ruthenium(II) complexes.

Five diastereomers of ruthenium(II) complexes based on quinolinophaneoxazoline ligands were investigated by vibrational circular dichroism (VCD) in the mid-IR and CH stretching regions. Diastereomers differ in three sources of chirality: the planar chirality of the quinolinophane moiety, the central chirality of an asymmetric carbon atom of the oxazoline ring, and the chirality of the ruthenium atom. VCD, allied to DFT calculations, has been found to be effective in disentangling the various forms of chirality. In particular, a VCD band is identified in the CH stretching region directly connected to the chirality of the metal. The analysis of the calculated VCD spectra is carried out by partitioning the complexes into fragments. The anharmonic analysis is also performed with a recently proposed reduced-dimensionality approach: such treatment is particularly important when examining spectroscopic regions highly perturbed by resonances, like the CH stretching region.

Scaling-up VPT2: A feasible route to include anharmonic correction on large molecules.

Vibrational analysis plays a crucial role in the investigation of molecular systems. Though methodologies like second-order vibrational perturbation theory (VPT2) have paved the way to more accurate simulations, the computational cost remains a difficult barrier to overcome when the molecular size increases. Building upon recent advances in the identification of resonances, we propose an approach making anharmonic simulations possible for large-size systems, typically unreachable by standard means. This relies on the fact that, often, only portions of the whole spectra are of actual interest. Therefore, the anharmonic corrections can be included selectively on subsets of normal modes directly related to the regions of interest. Starting from the VPT2 equations, we evaluate rigorously and systematically the impact of the truncated anharmonic treatment onto simulations. The limit and feasibility of the reduced-dimensionality approach are detailed, starting on a smaller model system. The methodology is then challenged on the IR absorption and vibrational circular dichroism spectra of an organometallic complex in three different spectral ranges.

Can Magnetic Dipole Transition Moment Be Engineered?

The development of chiral compounds with enhanced chiroptical properties is an important challenge to improve device applications. To that end, an optimization of the electric and magnetic dipole transition moments of the molecule is necessary. Nevertheless, the relationship between chemical structure and such quantum mechanical properties is not always clear. That is the case of magnetic dipole transition moment (m) for which no general trends for its optimization have been suggested. In this work we propose a general rationalization for improving the magnitude of m in different families of chiral compounds. Performing a clustering analysis of hundreds of transitions, we have been able to identify a single group in which |m| value is maximized along the helix axis. More interestingly, we have found an accurate linear relationship (up to R2 =0.994) between the maximum value of this parameter and the area of the inner cavity of the helix, thus resembling classical behavior of solenoids. This research provides a tool for the rationalized synthesis of compounds with improved chiroptical responses.

Sigma receptor and aquaporin modulators: chiral resolution, configurational assignment, and preliminary biological profile of RC752 enantiomers.

The key role of chiral small molecules in drug discovery programs has been deeply investigated throughout last decades. In this context, our previous studies highlighted the influence of the absolute configuration of different stereocenters on the pharmacokinetic, pharmacodynamic and functional properties of promising Sigma receptor (SR) modulators. Thus, starting from the racemic SR ligand RC752, we report herein the isolation of the enantiomers via enantioselective separation with both HPLC and SFC. After optimization of the eco-sustainable chiral SFC method, both enantiomers were obtained in sufficient amount (tens of mg) and purity (ee up to 95%) to allow their characterization and initial biological investigation. Both enantiomers a) displayed a high affinity for the S1R subtype (Ki = 15.0 ± 1.7 and 6.0 ± 1.2 nM for the (S)- and (R)-enantiomer, respectively), but only negligible affinity toward the S2R (> 350 nM), and b) were rapidly metabolized when incubated with mouse and human hepatic microsomes. Furthermore, the activity on AQP-mediated water permeability indicated a different functional profile for the enantiomers in terms of modulatory effect on the peroxiporins gating.

Stacked or Folded? Impact of Chelate Cooperativity on the Self-Assembly Pathway to Helical Nanotubes from Dinucleobase Monomers.

Self-assembled nanotubes exhibit impressive biological functions that have always inspired supramolecular scientists in their efforts to develop strategies to build such structures from small molecules through a bottom-up approach. One of these strategies employs molecules endowed with self-recognizing motifs at the edges, which can undergo either cyclization-stacking or folding-polymerization processes that lead to tubular architectures. Which of these self-assembly pathways is ultimately selected by these molecules is, however, often difficult to predict and even to evaluate experimentally. We show here a unique example of two structurally related molecules substituted with complementary nucleobases at the edges (i.e., G:C and A:U) for which the supramolecular pathway taken is determined by chelate cooperativity, that is, by their propensity to assemble in specific cyclic structures through Watson-Crick pairing. Because of chelate cooperativities that differ in several orders of magnitude, these molecules exhibit distinct supramolecular scenarios prior to their polymerization that generate self-assembled nanotubes with different internal monomer arrangements, either stacked or coiled, which lead at the same time to opposite helicities and chiroptical properties.

Circularly polarized luminescence of natural products lycorine and narciclasine: role of excited-state intramolecular proton-transfer and test of pH sensitivity.

Circularly polarized luminescence (CPL) is increasingly gaining interest not only for its applicative potentialities but also for providing an understanding of the excited state properties of chiral molecules. However, applications of CPL are mainly in the field of materials science: special organic molecules and polymers, metal (lanthanide) complexes, and organic dyes are actively and intensely studied. So far natural compounds have not been investigated much. We fill the gap here by measuring circular dichroism (CD) and CPL of lycorine and narciclasine, the most abundant known alkaloid and isocarbostyril from Amaryllidaceae, which exhibit a large spectrum of biological activities and are promising anticancer compounds. Dual fluorescence detection in narciclasine led us to unveil an occurring excited-state intramolecular proton transfer (ESIPT) process, this mechanism well accounts for the Stokes shift and CPL spectra observed in narciclasine. The same molecule is interesting also as a pH chiroptical switch. Both in absorption and emission, lycorine and narciclasine are also studied computationally via density functional theory (DFT) calculations further shedding light on their properties.

Fluorescence detected circular dichroism (FDCD) of a stereodynamic probe.

The use of chiroptical techniques in combination with stereodynamic probes is becoming one of the leading strategies for chiral sensing. While in most of the reported studies circular dichroism (CD) is the adopted spectroscopic technique, examples regarding the use of vibrational CD (VCD), circularly polarized luminescence (CPL), and Raman optical activity (ROA) are emerging as innovative tools. In this communication, an anthracene-decorated tris(2-pyridylmethyl)amine zinc complex (TPMA) is reported for its capability to act as a chiral sensor using either CD or fluorescence detected circular dichroism (FDCD). The latter technique offers the unique possibility to determine the enantiomeric excess of a series of carboxylic acids at sensor concentrations down to 0.1 µM. Limitations and possibilities opened by the use of this methodology, in particular regarding the specificity of the probe in the presence of another contaminant, are discussed.

Insights into the Structures of Bilirubin and Biliverdin from Vibrational and Electronic Circular Dichroism: History and Perspectives.

In this work we review research activities on a few of the most relevant structural aspects of bilirubin (BR) and biliverdin (BV). Special attention is paid to the exocyclic C=C bonds being in mostly Z rather than E configurations, and to the overall conformation being essentially different for BR and BV due to the presence or absence of the double C=C bond at C-10. In both cases, racemic mixtures of each compound of either M or P configuration are present in achiral solutions; however, imbalance between the two configurations may be easily achieved. In particular, results based on chiroptical spectroscopies, both electronic and vibrational circular dichroism (ECD and VCD) methods, are presented for chirally derivatized BR and BV molecules. Finally, we review deracemization experiments monitored with ECD data from our lab for BR in the presence of serum albumin and anesthetic compounds.

Chiral Single-Molecule Potentiometers Based on Stapled ortho- Oligo(phenylene)ethynylenes.

We report on the chemical design of chiral molecular junctions with stress-dependent conductance, whose helicity is maintained during the stretching of a single molecule junction due to the stapling of both ends of the inner helix. In the reported compounds, different conductive pathways are observed, with clearly different conductance values and plateau-length distributions, attributed to different conformations of the helical structures. The large chiro-optical responses and the potential use of these molecules as unimolecular spin filters have been theoretically proved using state-of-the-art Density Functional Theory (DFT) calculations, including a fully ab-initio estimation of the CISS-originating spin polarization which is done, for the first time, for a realistic molecular system.

(BO)2 -Doped Tetrathia[7]helicene: A Configurationally Stable Blue Emitter.

Helicenes combine two central themes in chemistry: extended π-conjugation and chirality. Hetero-atom doping preserves both characteristics and allows modulation of the electronic structure of a helicene. Herein, we report the (BO)2 -doped tetrathia[7]helicene 1, which was prepared from 2-methoxy-3,3'-bithiophene in four steps. 1 is formally derived by substituting two (Mes)B-O moieties in place of (H)C=C(H) fragments in two benzene rings of the parent tetrathia[7]helicene. X-ray crystallography revealed a dihedral angle of 50.26(9)° between the two terminal thiophene rings. The (P)-/(M)-1 enantiomers were separated by chiral HPLC and are configurationally stable at room temperature. The experimentally determined enantiomerization barrier of 27.4±0.1 kcal mol-1 is lower than that of tetrathia[7]helicene (39.4±0.1 kcal mol-1 ). The circular dichroism spectra of (P)- and (M)-1 show a perfect mirror-image relationship. 1 is a blue emitter (λem =411 nm) with a photoluminescence quantum efficiency of ΦPL =6 % (cf. tetrathia[7]helicene: λem ≈405 nm, ΦPL =5 %).

Inherently chiral helicene-substituted thioalkyl porphyrazine complexes: synthesis and electronic and chiroptical properties.

The chiral Ni(II) and Pd(II) complexes of [6]helicene thioethyl porphyrazine have been synthesized and their spectroscopic, electrochemical, and chiroptical properties have been investigated by experimental and computational analyses. In these compounds, the tetrapyrrole macrocycle is ß-substituted with an inherently chiral extended aromatic moiety potentially suitable to establish attractive π-π interactions with nanocarbons and endowed with helical chirality, both features providing interesting properties for optoelectronic applications. Experimental and density functional theory computational analyses highlight the presence of HOMO-LUMO charge-transfer transitions between the helicene moiety and the porphyrazine macrocycle. These compounds behave as mono-substituted push-pull systems without any typical electron-withdrawing or electron-donating groups and thus appear promising for optoelectronics. The enantiomers of the Ni(II) complex have been separated by chiral HPLC and their absolute configuration has been established by density functional theory computational analysis of electronic circular dichroism spectra. The magnetic circular dichroism spectrum of this complex has also been recorded providing better insight into its electronic structure.

Anharmonic Aspects in Vibrational Circular Dichroism Spectra from 900 to 9000 cm-1 for Methyloxirane and Methylthiirane.

Vibrational circular dichroism (VCD) spectra and the corresponding IR spectra of the chiral isomers of methyloxirane and of methylthiirane have been reinvestigated, both experimentally and theoretically, with particular attention to accounting for anharmonic corrections, as calculated by the GVPT2 approach. De novo recorded VCD spectra in the near IR (NIR) range regarding CH-stretching overtone transitions, together with the corresponding NIR absorption spectra, were also considered and accounted for, both with the GVPT2 and with the local mode approaches. Comparison of the two methods has permitted us to better describe the nature of active "anharmonic" modes in the two molecules and the role of mechanical and electrical anharmonicity in determining the intensities of VCD and IR/NIR data. Finally, two nonstandard IR/NIR regions have been investigated: the first one about ≈2000 cm-1, involving mostly two-quanta bending mode transitions, the second one between 7000 and 7500 cm-1 involving three-quanta transitions containing CH-stretching overtones and HCC/HCH bending modes.

Synthesis and Stereochemical Characterization of a Novel Chiral α-Tetrazole Binaphthylazepine Organocatalyst.

A novel α-tetrazole-substituted 1,1'-binaphthylazepine chiral catalyst has been synthesized and its absolute configuration has been determined by DFT computational analysis of the vibrational circular dichroism (VCD) spectrum of its precursor. The VCD analysis, carried out through the model averaging method, allowed to assign the absolute configuration of a benzylic stereocenter in the presence of a chiral binaphthyl moiety. The 1,1'-binaphthylazepine tetrazole and the nitrile its immediate synthetic precursor, have been preliminarily tested as chiral organocatalysts in the asymmetric intramolecular oxa-Michael cyclization of 2-hydroxy chalcones for the synthesis of chiral flavanones obtaining low enantioselectivity.

Resolution of a Configurationally Stable Hetero[4]helicene.

We have developed an efficient chemical resolution of racemic hydroxy substituted dithia-aza[4]helicenes (DTA[4]H) 1(OH) using enantiopure acids as resolving agents. The better diastereomeric separation was achieved on esters prepared with (1S)-(-)-camphanic acid. Subsequent simple manipulations produced highly optically pure (≥ 99% enantiomeric excess) (P) and (M)-1(OH) in good yields. The role of the position where the chiral auxiliary is inserted (cape- vs. bay-zone) and the structure of the enantiopure acid used on successful resolution are discussed.

Spectroscopic investigation on 1,2-substituted ferrocenes with only planar chirality: How chiroptical data are related to absolute configuration and to substituents.

Single enantiomers of three 1,2-substituted ferrocene derivatives, i.e. 1-methoxymethyl-2-hydroxymethylferrocene (1), 1-formyl-2-hydroxymethylferrocene (2) and 1-iodo-2-hydroxymethylferrocene (3), sharing the common hydroxymethyl substituent and the presence of planar chirality only, were investigated for their spectroscopic (IR and UV) and chiroptical (VCD and ECD) properties. Both enantiomers of 1 were obtained for the first time in optically pure form by lipase-catalyzed kinetic resolution of the corresponding racemate (±)-1 and separately converted into formyl derivatives (+)-2 and (-)-2. The experimental spectroscopic and chiroptical data were compared with DFT calculated spectra and excellent correspondence was found for all compounds, allowing one to confirm the previously assigned absolute configurations. The common features in the VCD spectra of a doublet between 940 and 965 cm-1 and the short-wavelength (about 200 nm) doublet and the longest wavelength band in the ECD spectra were analyzed to test whether they may be taken as markers of the absolute configuration (AC). The predominance of conformers with intramolecular hydrogen bond for the first two investigated compounds is predicted by conformational analysis and also confirmed by NMR.

Helicity control of a perfluorinated carbon chain within a chiral supramolecular cage monitored by VCD.

Confinement within supramolecular systems is the leading technology to finely tune guest functional properties. In this communication we report the synthesis of a chiral supramolecular cage able to bias the helicity of a perfluorinated carbon chain hosted within the cage. We monitor the phenomenon of chiral induction by Vibrational Circular Dichroism (VCD) experiments complemented by DFT calculations over the possible conformers.