Nonlinear optical spectroscopy of chiral molecules

We review nonlinear optical processes that are specific to chiral molecules in solution and on surfaces. In contrast to conventional natural optical activity phenomena, which depend linearly on the electric field strength of the optical field, we discuss how optical processes that are nonlinear (quadratic, cubic, and quartic) functions of the electromagnetic field strength may probe optically active centers and chiral vibrations. We show that nonlinear techniques open entirely new ways of exploring chirality in chemical and biological systems: The cubic processes give rise to nonlinear circular dichroism and nonlinear optical rotation and make it possible to observe dynamic chiral processes at ultrafast time scales. The quadratic second-harmonic and sum-frequency-generation phenomena and the quartic processes may arise entirely in the electric-dipole approximation and do not require the use of circularly polarized light to detect chirality. They provide surface selectivity and their observables can be relatively much larger than in linear optical activity. These processes also give rise to the generation of light at a new color, and in liquids this frequency conversion only occurs if the solution is optically active. We survey recent chiral nonlinear optical experiments and give examples of their application to problems of biophysical interest.     

Crystallization and solid-state reaction as a route to asymmetric synthesis from achiral starting materials

Many molecules which are achiral can crystallize in chiral (enantiomorphic) crystals and, under suitable conditions, crystals of only one chirality may be obtained. The formation of right- or left-handed crystals in excess is equally probable. Lattice-controlled (topochemical) photochemical or thermal solid-state reactions may then afford stable, optically active products. In the presence of the chiral products, achiral reactants may preferentially produce crystals of one chirality, leading to a feedback mechanism for the generation and amplification of optical activity. Amplification of optical activity can also be achieved by solid-state reactions. The optical synthesis of biologically relevant compounds by such routes may be envisaged.     

Modeling revealed circular dichroism for quinacrine in the presence of heparin

A simple model is presented that accounts for revealed circular dichroism signals that are observed as a function of enantiopreferential drug binding to a chiral selector. According to this model, the intensity of such signals depends heavily on the differences in enantiomer-selector association constants as well as the differences in bound vs. unbound molar ellipticity values for the chromophore containing species. The proposed model is supported by circular dichroism and capillary electrophoresis results obtained using quinacrine, a tricyclic, antimalarial drug, and heparin, a highly-sulfated glycosaminoglycan. This strategy also explores the role that revealed circular dichroism may play in the optical activity observed for some drugs in the presence of heparin, as has previously been illustrated for chiral drugs in the presence of DNA.     

Copper-catalyzed divergent kinetic resolution of racemic allylic substrates

When a racemic mixture is fully consumed the products may still be enantiomerically enriched. In particular, the regiodivergent kinetic resolution is a process in which a single chiral catalyst or reagent reacts with a racemic substrate to form regioisomers possessing an opposite configuration on the newly-formed stereogenic centers. This review reports the major advances in the field of the copper-catalyzed regiodivergent and stereodivergent kinetic resolution of allylic substrates with organometallic reagents. The chiral recognition matching phenomena found with particular allylic substrates with the absolute configuration of the chiral catalyst allows in some cases an excellent control of the regio- and stereoselectivity, sheding some light on the so-called "black-box" mechanism of a copper-catalyzed asymmetric allylic alkylation.     

Life and chirality beyond the earth.

An attempt is made to show that the phenomenon of chirality- of which optical activity is but one consequence- is by no means restricted to life on Earth, but is common throughout the universe. Several independent sources have been investigated including: statistical fluctuations; stereoselective physical factors; and energetic differences between enantiomeric molecules. It is emphasised that a search for chirality as an indicator for life elsewhere in space provides an excellent tool for the fascinating question of exobiology. Still one must be aware of the limitations of the experimental methods and their interpretations.     

Life and chirality beyond the earth

An attempt is made to show that the phenomenon of chirality—of which optical activity is but one consequence—is by no means restricted to life on Earth, but is common throughout the universe. Several independent sources have been investigated including: statistical fluctuations; stereoselective physical factors; and energetic differences between enantiomeric molecules. It is emphasised that a search for chirality as an indicator for life elsewhere in space provides an excellent tool for the fascinating question of exobiology. Still one must be aware of the limitations of the experimental methods and their interpretations.     

Detection and identification of optical activity using polarimetry – applications to biophotonics,biomedicine and biochemistry

Polarized light that is reflected or transmitted through chiral specimens can be used to detect and identify biological and chemical materials including human tissue. The determination of the silent footprints of the chiral properties of the biological materials on scattered polarized light is the basis for these investigations. It is of primary importance to identify which combinations of the elements of the Mueller matrix for reflected or for transmitted light can be used to determine the optical activity of the biochemical materials. The optical activity of chiral materials is characterized by optical rotation and circular dichroism. The explicit analytical dependence of these specific elements of the Mueller matrix, upon the angles of incidence and scatter, upon the wavelength and upon the type of chirality has the potential to provide experimentalists with guidance in determining the optimum use of optical polarimetric scatterometers. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Spectroscopic properties of the nonplanar amide group: a computational study

Experimental studies suggest that amide bond may significantly deviate from planar arrangement even in linear peptides and proteins. In order to find out the extent to which such deviation may influence principal amide spectroscopic properties, we conducted a computational study of nonplanar N-methylacetamide (NMA) conformers. Vibrational absorption, Raman, and electronic spectra including optical activity were simulated with ab initio and density functional theory (DFT) methods. According to the results, small nonplanarity deviations may be detectable by nonpolarized spectroscopic techniques, albeit as subtle spectral changes. The optical activity methods, such as the vibrational circular dichroism (VCD), Raman optical activity (ROA), and electronic circular dichroism (CD, ECD), provide enhanced information about the amide nonplanarity, because planar amide is not optically active (chiral). For VCD, however, the inherently chiral contribution in most peptides and proteins most probably provides very weak signal in comparison with other contributions, such as the dipolar coupling. For the electronic CD, the nonplanarity contribution is relatively big and causes a strong CD couplet in the n-pi* absorption region accompanied by a red frequency shift. The pi-pi* CD region is relatively unaffected. The ROA spectroscopy appears most promising for the nonplanarity detection and the inherent chiral signal may dominate entire spectral parts. The amide I and III vibrational ROA bands are most challenging experimentally because of their relatively weak coupling to other peptide vibrations.     

Why is it important to simultaneously use more than one chiroptical spectroscopic method for determining the structures of chiral molecules?

In recent years, four different chiroptical spectroscopic methods, namely vibrational circular dichroism, vibrational Raman optical activity, electronic circular dichroism, and optical rotatory dispersion, have become popular for establishing the absolute configuration and predominant conformations of chiral molecules in solution state. Many individual laboratories normally utilize only one of these methods to derive the molecular structural information. Although that approach may be satisfactory for most of the molecules studied, it is to be noted that in some instances a single method can give ambiguous conclusions or may not give complete structural information. This article summarizes the situations where simultaneous use of more than one chiroptical spectroscopic method is required to obtain molecular structural information and recommends the routine application of more than one chiroptical spectroscopic method for any given molecule.     

手性化合物制备的方法

手性是自然界最重要的属性之一,分子手性识别在生命活动中起着极为重要的作用。同一化合物的两个对映体之间不仅具有不同的光学性质和物理化学性质,而且它们具有不同的生物活性,比如在药理上,药物作用包括酶的抑制、膜的传递、受体结合等均和药物的立体化学有关;手性药物的对映体的生物学活性、毒性、代谢和药物素质完全不同。手性化合物的制备已成为当前国内外较热门的研究课题之一。本文从非生物法和生物法两个方面较全面地综述了手性化合物的制备方法,希望为相关研究者提供参考 。     

Can biological homochirality result from a phase transition?

The problem of chiral purity in living organisms is still one of the prominent difficulties in the study of the origins of life. In particular the parity non-conservation known to occur in weak interactions could not be related to this lack of symmetry: these physical forces, though universal, are very weak and up to now no amplification process had been proposed.In 1991, A. Salam remarked that, due to the attractive character of the parity violating force in electro-weak interactions, a phase transition at low temperature should exist, leading eventually to enantiomeric purity.We undertook then a series of experimental tests, looking for a sizeable change in the optical activity of cystine molecules. We found no evidence for the phase transition down to 0.01 K. The interpretation of these negative results will be discussed, and future experiments proposed.     

Morphological and chiral symmetry breaking in reaction-diffusion systems

Morphological and chiral symmetry breaking in reaction-diffusion systems is considered on the basis of the theory of imperfect codimension-two bifurcations. A new type of pattern selection with two triggers is elucidated: (1) morphologically asymmetric structures displaying optical activity can probably be originated from initially racemic and homogeneous conditions when chiral interaction, having the characteristic strength delta (such as electroweak interaction and circularly polarized light) as well as external field, having the characteristic strength eta (such as gravitational field and electrostatic field) are considered; (2) the selective sensitivity of molecular chirality and morphological asymmetry is omicron(delta 1/3) and omicron(eta 1/3), respectively; the sensitivity of mode-mode interaction between chiral polarization and concentration vector is omicron(delta 2/3) or omicron(eta 2/3), respectively. The relation of these conclusions to the life problem is discussed briefly.     

Polarimetric detection in high-performance liquid chromatography

Chiroptical detection for HPLC is particularly useful as a selective detection method for chiral molecules, and in enantiomeric purity determination with partial chiral separation or without chiral separation. The recent development of laser-based polarimeters with microdegree sensitivity has increased the applicability of optical rotation detection in HPLC. The detection limit of these instruments is submicrogram on-column for many chiral compounds in analytical HPLC. A variety of applications of the selective detection of optically active molecules are reviewed. The use of polarimetric detection with partial chiral separation is considered, both as an aid to method development and for enantiomeric purity determination. Finally applications to enantiomeric purity determination without chiral separation are reviewed, with the dual use of nonchirally selective and chiroptical detectors to determine the total amount and optical purity of the analyte. Determinations of chiral purity for samples of high enantiomeric excess are described, which with laser-based instrumentation may give accuracies of better than +/- 1% with sample loadings of 50 micrograms on an achiral column. Applications to the study of enantioselective reactions are also considered, with determination of enantiomeric excess in near-racemates to better than +/- 0.1%.     

Optically active porous hybrid particles constructed by alkynylated cellulose nanocrystals,helical substituted polyacetylene,and inorganic silica for enantio-differentiating towards naproxen

This article reports on a novel type of ternary chiral porous hybrid particles (TCPHPs) constructed by alkynylated cellulose nanocrystals (A-CNCs), helical substituted polyacetylene, and inorganic silica. The resulting TCPHPs combine the respective advantages of the three components. A-CNCs serve as stabilizer, co-monomer, and chiral source simultaneously and transfer their chirality to the resulting helical substituted polyacetylenes in the course of copolymerization with achiral acetylenic monomer following “sergeants and soldiers rule”. Helical substituted polyacetylenes form chiral helical structures and thus endow TCPHPs with the anticipated optical activity. Inorganic silica constitutes the rigid framework and is covalently bonded with the organic components through hydrolysis of Si-O-Et groups. Phase separation between the organic and inorganic components renders TCPHPs with abundant pores. Scanning electron microscope (SEM) images confirm the formation of spherical particles with porous structures. Circular dichroism spectra demonstrate the optical activity of the chiral hybrid particles. The as-prepared TCPHPs exhibit capacity for enantio-differentiating performance towards chiral naproxen.     

Solution structure and dynamics of biomolecules from Raman optical activity

Raman optical activity (ROA) measures vibrational optical activity by means of a small difference in the intensity of Raman scattering from chiral molecules in right and left circularly polarized incident laser light. The ROA spectra of a wide range of biomolecules in aqueous solution can now be measured routinely. Because of its sensitivity to the chiral elements of biomolecular structure, ROA provides new information about solution structure and dynamics complementary to that supplied by conventional spectroscopic techniques. This article provides a brief introduction to the theory and practice of ROA spectroscopy followed by a review of recent ROA results on polypeptides, proteins, carbohydrates, nucleic acids and viruses which illustrate how new insight into current problems of structure, folding and function may be obtained from ROA studies.     

Analysis of the stereochemistry of lipoxygenase-derived hydroxypolyenoic fatty acids by means of chiral phase high-pressure liquid chromatography

A chiral phase HPLC method was developed for the simultaneous determination of the positional and optical isomers of the lipoxygenase-derived hydroxypolyenoic fatty acids. With a Bakerbond chiral phase HPLC column (dinitrobenzoyl phenylglycine as chiral phase) the positional and optical isomers of the reduced dioxygenation products (by triphenylphosphine or borohydride) of linoleic acid and arachidonic acid were separated after methylation of the carboxylic groups. No cumbersome chemical derivatization such as conversion to a diastereomer was necessary. As compared with the methods used up till now chiral phase HPLC proved to be simpler and more sensitive. About 10 pmol of hydroxy fatty acids suffice for an analysis. The chiral phase HPLC can be used for the preparative separation of the optical antipodes of the lipoxygenase products. An optical purity of more than 90% can be reached in one preparative run. The method was applied to the determination of the stereochemistry of the dioxygenation products of polyenoic fatty acids formed by the lipoxygenases from soybeans, reticulocytes, pea seeds (isoenzyme I and II), tomato fruits, by the quasilipoxygenase activity of hemoglobin, and by the methylene blue-mediated photooxidation of arachidonic acid.     

Imaging polarimetry for high throughput chiral screening

Imaging polarimetry was demonstrated as a highly parallel method of determining optical rotation of biochemical samples. The imaging polarimeter utilized a bright, uniform light source wavelength-filtered to near the sodium D line, a sample array flanked by inlet and analyzing polarizers, and a CCD camera fitted with an equal-perspective telecentric lens. The prototype apparatus was demonstrated to have an optical resolution better than 0.08 degrees. The potential for high throughput screening was demonstrated by imaging chiral solutions in 1536-well microtiter plates and by real-time monitoring of 30 simultaneous chiral enzymatic reactions. Improvements in polarizer and CCD technology may broadly expand the technique's applicability to fields such as directed evolution and combinatorial chemistry, where screening throughput is currently limiting for chiral applications.     

Emergence of molecular chirality due to chiral interactions in a biological environment

We explore the interplay between tunneling process and chiral interactions in the discrimination of chiral states for an ensemble of molecules in a biological environment. Each molecule is described by an asymmetric double-well potential and the environment is modeled as a bath of harmonic oscillators. We carefully analyze different time-scales appearing in the resulting master equation at both weak- and strong-coupling limits. The corresponding results are accompanied by a set of coupled differential equations characterizing optical activity of the molecules. We show that, at the weak-coupling limit, chiral interactions prohibit the coherent racemization induced by decoherence effects and thus preserve the initial chiral state. At the strong-coupling limit, considering the memory effects of the environment, Markovian behavior is observed at long times.     

Electrostatic chiral distinction: Tetrahedral model dimers

Although chiral distinction plays a pervasive role in chemistry, a complete understanding of how this takes place is still lacking. In this work, we expand the earlier described minimal requirement of so called four‐point interactions (vide infra). We focus on chiral point charge model systems as a means to aid in the dissection of the underlying, operative principles. We also construct models with defined symmetry characteristics. By considering extensive constellations of diastereomeric complexes, we are able to identify emerging principles for chiral distinction. As previously postulated, all the diastereomeric complexes, regardless of their nominal contact‐points, possess a chiral distinction energy. In the comparison of complexes, we find that, contrary to chemical intuition, the magnitude of chiral distinction does not correlate with the stability of the complexes, i.e., consideration of low energy complexes may not be an effective way to evaluate chiral distinction. Similarly, we do not find a correlation between the number of contact‐points and chiral distinction. Moreover, favorable interactions and facile chiral distinction appear to be unrelated. We also see some tendency for greater chiral distinction in less symmetric systems, although this may not be general. These studies can now form the basis to fold in higher levels of complexity into the models so as to gain further insights into the nature of chiral distinction. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Recent advances in methods of direct optical resolution

Very great advances have been made in the field of direct optical resolution of organic compounds by chromatographic techniques. Chiral capillary gas chromatography now permits a determination of the enantiomeric composition of a few nanograms of a compound present in a mixture of many others. Coupled with high resolution mass spectrometry the technique will additionally permit structural elucidation; of great interest in pheromone research and related areas. Analytical separations of enantiomers are now also carried out by high-performance liquid chromatography (HPLC) methods based on a variety of principles. Basically, two main types are used, differing as to whether the mobile phase has to be a chiral medium or not. Two-dimensional HPLC, whereby compounds separated on a non-chiral column are progressively and automatically transferred to a chiral column for optical resolution, has been used successsfully for chiral amino acid separations. Many different chiral sorbents for preparative LC and HPLC resolutions have been prepared; some of these are now used in columns capable of producing pure enantiomers from a given racemate at a rate of the order of one gram/hour in continuous, automatic HPLC procedures. Apart from all important applications of these results of optical resolution technology, an increased knowledge of the underlying chiral recognition phenomena responsible for enantioselection has also been achieved.