calque

Workshops

Vibrational Optical Activity: Interplay of Theory and Experiment

September 23, 2012 to September 27, 2012
Location : Scuola Normale Superiore, Pisa, Italy

Organisers

  • Chiara Cappelli (Scuola Normale Superiore Pisa, Italy)
  • Kenneth Ruud (University of Tromso, Norway)
  • Magdalena Pecul-Kudelska (University of Warsaw, Poland)
  • Rina Dukor (BioTools Inc., USA, USA)

Supports

   CECAM

University of Pisa

   E4 Computer Engineering SpA

Centre for Theoretical and Computational Chemistry, Norway

   Cost

BioTools Inc.

Gaussian Inc.

   Scuola Normale Superiore

PCCP

Description

Please notice that the maximum number of allowed participants is limited to 100.

Chiral molecules are omnipresent in nature, ensuring a proper functioning of all living organisms. As a consequence, they are contained in many pharmacological drugs, constitute basic food ingredients, and are vital for modern chemical and nano-technology industries. For instance, the interaction between a chiral species, such as an enzyme or a receptor, can be of fundamental importance in the manifestation of a given property, such as the smell of a piece of fruit or the antibacterial behaviour of a drug. S-(+)-carvone smells for instance like caraway, whereas its mirror image, R-(-)-carvone, smells like spearmint. The fact that the two enantiomers are perceived as smelling differently proves that also the olfactory receptors must contain chiral groups, allowing them to respond more strongly to one enantiomer than to the other.
The knowledge of absolute configurations is also mandatory in many industrial applications. For pharmaceutical applications, it is required by law that the absolute configuration of chiral drugs is known and that the biological activity of the compounds is tested for both enantiomers. Production of new drugs also requires a verification of the enantiomeric purity of the compounds. This leads to the need for characterizing their chiral purity and conformation.
A traditional way of obtaining information about the absolute configuration of molecules is through X-ray crystallography. However, for many biologically relevant molecules and drugs, it is not possible to make the crystals that are needed for X-ray studies. Chemical interconversion of a compound of unknown absolute configuration into another of known configuration is an alternative approach for determining the absolute configuration of molecules, but it is inherently time consuming, destructive, and depends on derived substances of known configuration that may not exist.
The role of spectroscopy in this field is therefore crucial. There are several chiroptical phenomena which can be used for the purpose, some of them involving electronic responses (natural optical rotation, optical rotatory dispersion, or electronic circular dichroism) and some involving vibrational response (vibrational circular dichroism, vibrational Raman optical activity). We plan to focus on the latter, since electronic spectra (such as ORD and ECD) provide relatively little information in comparison with vibrational spectroscopy, as there are many more bands sensitive to the details of the molecular structure in the vibrational domain than for the different electronic states accessible to experimental investigation. Furthermore, quantum chemical calculations play an important role in vibrational chiroptical spectroscopy, because it is only by comparing calculations and experiments directly that the assignment of the absolute configuration of a molecule can be done unambiguously, since the calculated value surely refers to only one of the enantiomerically pure substances.
Vibrational circular dichroism (VCD) and vibrational Raman optical activity (ROA) have gained increasing interest both in the scientific community and in the pharmaceutical industry. In addition to the assignment of absolute configurations, these spectroscopies can also be used to gain information on other aspects of molecular structure, because the vibrational optical activity signals are sensitive to the local environment of the various oscillating modes of the molecular system. ROA and VCD are therefore being increasingly utilized also as probes of the conformational structure of biopolymers,
The use of (vibrational) optical activity for structure assignment is however almost impossible without combining experimental measurements with quantum chemical calculations. This requires the availability of quantum mechanical programs for predicting the spectroscopic signals in a computationally viable manner. The enormous increase in the availability of computational techniques (and computational codes) in the last few years has made it possible to perform such comparisons also by non-experts. The impact that quantum chemistry has had on the field of vibrational chiroptical spectroscopy is so significant that Polavarapu (one of the leading experimentalists in the field) speaks of a “Renaissance in chiroptical spectroscopic methods for molecular structure determination“ [1] following the development of new reliable and efficient QM computational techniques.
When coupled with ab initio computations, chiroptical spectroscopies also provide other information, such as conformational ratios important in determining reactivities of biomolecules. In particular, ROA is well suited for studies of large biomolecules in their aqueous environment [2]. The strength and reliability of vibrational chiroptical spectroscopy is in this respect certified by the fact that the US Food and Drug Administration (FDA) has approved Vibrational Optical Activity as a technique for determining the enantiomeric purity of chiral compounds.
From the point of view of theoretical chemists, vibrational chiroptical spectroscopies offers a unique chance of working in a field where the advancement of theory lays the ground for the studies of new and more complex systems, and where the interplay between theory and experiment is a necessity. Furthermore, the QM theory behind chiroptical properties is challenging, both from the purely theoretical and the computational point of view. Chiroptical properties arise formally from a mixture of electric, magnetic and vibrational responses and require the evaluation not only of energetic parameters, but also of the response of the molecular system to the electric and magnetic components of the radiation. In the particular case of vibrational optical activity, both the electronic and nuclear components of the system have to be treated accurately, as they both contribute to the phenomenon to the same extent. There is therefore an ongoing interest in developing new computational methods that would allow, on the one hand, to describe electron correlation in large molecular systems (the use of DFT has surely increased the range of the currently affordable systems, but it‘s predictive powers remains an area of lively scientific debate), and, on the other hand, to treat nuclear motion in an appropriately accurate manner (which requires going beyond the harmonic approximation). A consistent handling of the dependence of ROA spectra on the frequency of the incident light, allowing for a uniform description of off-resonance, pre-resonance and resonance ROA, is a related challenge.
Another aspect of chiroptical spectroscopy that calls for cooperation between theoretical and experimental chemists is the investigation of the effects of the molecular environment. Chiroptical measurements are only rarely carried out for systems that can be regarded as isolated [3]. More commonly, the experiments are performed on solvated system. Solvent effects can be very important, and there have been reports that not only the order of magnitude, but also the sign of the properties can change with the polarity of the solvent. Accounting for solvent effects in the calculations is therefore crucial, especially in the determination of absolute configurations, and much effort has been put into this topic in recent years.
A related topic is the application of chiroptical techniques to systems interacting with surfaces or nanostructures (small metal clusters). Such interactions can increase the Raman scattering cross sections (so called surface-enhanced Raman scattering, or SERS) enormously and some enhancement is also observed in IR spectra (surface-enhanced IR, or SEIRA). This takes place also in the case of chiroptical vibrational spectroscopies. Thus, in parallel to the development of the above-mentioned SERS and SEIRA techniques, their chiral counterparts have started to be developed, so that we can at present speak of SEROA and SEVCD. However, if the computational modeling of “conventional” vibrational optical activity techniques is already well advanced, the modeling of surface-enhanced chiroptical techniques is still on its infancy, with a unified theoretical framework still not being available in the case of SEROA, although proposals have been put forth [4]. The main difficulty in this case is the intrinsic difficulty of coupling an accurate description of the chiroptical property with a sufficiently accurate description of the surface (or the metal cluster) in order to yield a reasonable physical description of the system, while at the same time keeping the whole system computationally tractable. We also consider the progress in this field to be impeded by scarce interactions between theoretical chemists and specialists in surface spectroscopy. Therefore, one of the main goals of the proposed workshop is to stimulate the exchange of expertise between theoreticians and experimentalists in order to highlight the needs of the experimental sciences and how the current state-of-the-art computational techniques can help to fulfill them. Also, the presentation of the most novel challenges in the experimental methodology would hopefully stimulate theoreticians to push the development of novel strategies/models for meeting tthemfrom experiment.
Still in the same context, another very challenging topic in this field is the extension of the new bidimensional (2D) techniques to chiral systems, leading to the development of bidimensional chiroptical spectroscopies. Multidimensional vibrational spectroscopy provides detailed insight into the anharmonic nature of molecular vibrations, including the coupling of the different normal modes in a molecule. Multidimensional spectroscopies, both in the electronic and vibrational domain, can be made to be surface and interface specific, and thus represent powerful techniques for understanding molecular structure and reactivity at these symmetry-breaking regions, and would allow for in vivo characterization of for instance molecular interactions with cell membranes, allowing for a much needed insight into how to design drugs that penetrate cell membranes in an efficient manner. Multidimensional spectroscopy also holds great promise as a non-invasive microscopy technique since it a high degree of focality in combination with low-energy radiation, ensuring deep penetration depth. We believe the additional information that would be possible to extract when considering multidimensional chiroptical spectroscopies to be large and of a novel character, but the successful development of such new experimental techniques will require a theoretical understanding of what is being observed experimentally and correlating experimental observations to molecular structures and interactions through modeling.
The increasing interest in the field of 2D vibrational techniques is demonstrated by the emphasis this topic has recieved recently in the literature. In fact, after the appearance of a review by M. Cho in Chemical Reviews in 2008 [5], an entire issue of The Accounts of Chemical Research has been published in 2009 [6] on these topics, followed by numerous publications in the following years.
Research on 2D vibrational techniques has been so far mostly limited to 2D-IR spectroscopy. However, 2D optical spectroscopic methods using circularly polarized (CP) light beams have been theoretically proposed and reported for the measurement of the nonlinear optical activity of chiral molecules in isotropic media [5-11]. It has also been suggested that 2D CP-IR photon-echo spectroscopy can be a better tool for protein structure determination than 2D IR spectroscopy [6]. However, such techniques are far from being standard, and the extraction of structural information from the spectroscopic signals requires once again a close collaboration with computational chemists. The development of QM strategies for computing 2D signals have received so far very limited attention, being limited to date to very few attempts to simulate some parameters of 2D-IR spectra [see e.g. 12-15]. Very few attempts has been made to date to simulate a complete 2D vibrational chiroptical spectrum from fully ab initio data [16], in part due to a lack of awareness and in part due to the computational complexity of the problem. Therefore, another aim of the present workshop is to promote the understanding of such new experimental techniques by theoreticians, and on the other hand to give theoreticians the opportunity to promote the potentials of their (static and/or time-independent) methods, and in this was create a common ground for jointly developing this field of research.
[1] Polavarapu PL. Renaissance in chiroptical spectroscopic methods for molecular structure determination. Chem Rec 2007; 7: 125–136.
[2] Blanch E. et. al., Biochemistry 2003; 42: 4665.
[3] J.Sebestik and P.Bour, J.Phys.Chem.Lett. 2011; 2: 498
[4] B.G.Janesko and G.E.Scuseria, J.Chem.Phys. 2006; 125: 124704
[5] Cho M Coherent Two-Dimensional Optical Spectroscopy Chem. Rev. 2008; 108: 1331-1418.
[6] “Coherent Multidimensional Optical Spectroscopy” Acc. Chem. Res. 2009, volume 42, issue 9, Pages 1207-1469.
[7] Rhee H; Choi J-H, Cho M Infrared Optical Acivity: Electric Field Approaches in Time Domain Acc. Chem. Res. 2010; 43: 1527-1536.
[8] Choi J-H, Cho M Two-Dimensional Circularly Polarized IR Photon Echo Spectroscopy of Polypeptides: Four-Wave-Mixing Optical Activity Measurement.
[9] Choi, J.-H.; Cheon, S.; Lee, H.; Cho, M. Phys. Chem. Chem. Phys. 2008, 10, 3839–3856.
[10] Abramavicius, D.; Mukamel, S. J. Chem. Phys. 2006, 124, 034113.
[11] Jeon J; Yang S; Choi J-H; Cho M Acc. Chem. Res. 2009; 42: 1280-1289.
[12] Moran, A.; Mukamel, S. Proc. Nat. Acad. Sci. U.S.A. 2004, 101,506
[13] Ham, S.; Cha, S.; Choi, J.-H.; Cho, M. J. Chem. Phys. 2003, 119, 1451.
[14] Gorbunov, R. D.; Kosov, D. S.; Stock, G. J. Chem. Phys. 2005, 122, 224904.
[15] Biancardi, A; Cappelli, C.;  Mennucci, B.; Cammi, R. J. Phys. Chem. B 2010, 114, 4924–4930.
[16] Donaldson, P.M. et al., J.Chem.Phys. 2007, 127, 114513.

Chiral molecules are omnipresent in nature, ensuring a proper functioning of all living organisms. As a consequence, they are contained in many pharmacological drugs, constitute basic food ingredients, and are vital for modern chemical and nano-technology industries. For instance, the interaction between a chiral species, such as an enzyme or a receptor, can be of fundamental importance in the manifestation of a given property, such as the smell of a piece of fruit or the antibacterial behaviour of a drug. S-(+)-carvone smells for instance like caraway, whereas its mirror image, R-(-)-carvone, smells like spearmint. The fact that the two enantiomers are perceived as smelling differently proves that also the olfactory receptors must contain chiral groups, allowing them to respond more strongly to one enantiomer than to the other.
The knowledge of absolute configurations is also mandatory in many industrial applications. For pharmaceutical applications, it is required by law that the absolute configuration of chiral drugs is known and that the biological activity of the compounds is tested for both enantiomers. Production of new drugs also requires a verification of the enantiomeric purity of the compounds. This leads to the need for characterizing their chiral purity and conformation.A traditional way of obtaining information about the absolute configuration of molecules is through X-ray crystallography. However, for many biologically relevant molecules and drugs, it is not possible to make the crystals that are needed for X-ray studies. Chemical interconversion of a compound of unknown absolute configuration into another of known configuration is an alternative approach for determining the absolute configuration of molecules, but it is inherently time consuming, destructive, and depends on derived substances of known configuration that may not exist.
The role of spectroscopy in this field is therefore crucial. There are several chiroptical phenomena which can be used for the purpose, some of them involving electronic responses (natural optical rotation, optical rotatory dispersion, or electronic circular dichroism) and some involving vibrational response (vibrational circular dichroism, vibrational Raman optical activity). We plan to focus on the latter, since electronic spectra (such as ORD and ECD) provide relatively little information in comparison with vibrational spectroscopy, as there are many more bands sensitive to the details of the molecular structure in the vibrational domain than for the different electronic states accessible to experimental investigation. Furthermore, quantum chemical calculations play an important role in vibrational chiroptical spectroscopy, because it is only by comparing calculations and experiments directly that the assignment of the absolute configuration of a molecule can be done unambiguously, since the calculated value surely refers to only one of the enantiomerically pure substances.
Vibrational circular dichroism (VCD) and vibrational Raman optical activity (ROA) have gained increasing interest both in the scientific community and in the pharmaceutical industry. In addition to the assignment of absolute configurations, these spectroscopies can also be used to gain information on other aspects of molecular structure, because the vibrational optical activity signals are sensitive to the local environment of the various oscillating modes of the molecular system. ROA and VCD are therefore being increasingly utilized also as probes of the conformational structure of biopolymers,The use of (vibrational) optical activity for structure assignment is however almost impossible without combining experimental measurements with quantum chemical calculations. This requires the availability of quantum mechanical programs for predicting the spectroscopic signals in a computationally viable manner. The enormous increase in the availability of computational techniques (and computational codes) in the last few years has made it possible to perform such comparisons also by non-experts. The impact that quantum chemistry has had on the field of vibrational chiroptical spectroscopy is so significant that Polavarapu (one of the leading experimentalists in the field) speaks of a “Renaissance in chiroptical spectroscopic methods for molecular structure determination“ [1] following the development of new reliable and efficient QM computational techniques.When coupled with ab initio computations, chiroptical spectroscopies also provide other information, such as conformational ratios important in determining reactivities of biomolecules. In particular, ROA is well suited for studies of large biomolecules in their aqueous environment [2]. The strength and reliability of vibrational chiroptical spectroscopy is in this respect certified by the fact that the US Food and Drug Administration (FDA) has approved Vibrational Optical Activity as a technique for determining the enantiomeric purity of chiral compounds.
From the point of view of theoretical chemists, vibrational chiroptical spectroscopies offers a unique chance of working in a field where the advancement of theory lays the ground for the studies of new and more complex systems, and where the interplay between theory and experiment is a necessity. Furthermore, the QM theory behind chiroptical properties is challenging, both from the purely theoretical and the computational point of view. Chiroptical properties arise formally from a mixture of electric, magnetic and vibrational responses and require the evaluation not only of energetic parameters, but also of the response of the molecular system to the electric and magnetic components of the radiation. In the particular case of vibrational optical activity, both the electronic and nuclear components of the system have to be treated accurately, as they both contribute to the phenomenon to the same extent. There is therefore an ongoing interest in developing new computational methods that would allow, on the one hand, to describe electron correlation in large molecular systems (the use of DFT has surely increased the range of the currently affordable systems, but it‘s predictive powers remains an area of lively scientific debate), and, on the other hand, to treat nuclear motion in an appropriately accurate manner (which requires going beyond the harmonic approximation). A consistent handling of the dependence of ROA spectra on the frequency of the incident light, allowing for a uniform description of off-resonance, pre-resonance and resonance ROA, is a related challenge.
Another aspect of chiroptical spectroscopy that calls for cooperation between theoretical and experimental chemists is the investigation of the effects of the molecular environment. Chiroptical measurements are only rarely carried out for systems that can be regarded as isolated [3]. More commonly, the experiments are performed on solvated system. Solvent effects can be very important, and there have been reports that not only the order of magnitude, but also the sign of the properties can change with the polarity of the solvent. Accounting for solvent effects in the calculations is therefore crucial, especially in the determination of absolute configurations, and much effort has been put into this topic in recent years.
A related topic is the application of chiroptical techniques to systems interacting with surfaces or nanostructures (small metal clusters). Such interactions can increase the Raman scattering cross sections (so called surface-enhanced Raman scattering, or SERS) enormously and some enhancement is also observed in IR spectra (surface-enhanced IR, or SEIRA). This takes place also in the case of chiroptical vibrational spectroscopies. Thus, in parallel to the development of the above-mentioned SERS and SEIRA techniques, their chiral counterparts have started to be developed, so that we can at present speak of SEROA and SEVCD. However, if the computational modeling of “conventional” vibrational optical activity techniques is already well advanced, the modeling of surface-enhanced chiroptical techniques is still on its infancy, with a unified theoretical framework still not being available in the case of SEROA, although proposals have been put forth [4]. The main difficulty in this case is the intrinsic difficulty of coupling an accurate description of the chiroptical property with a sufficiently accurate description of the surface (or the metal cluster) in order to yield a reasonable physical description of the system, while at the same time keeping the whole system computationally tractable. We also consider the progress in this field to be impeded by scarce interactions between theoretical chemists and specialists in surface spectroscopy. Therefore, one of the main goals of the proposed workshop is to stimulate the exchange of expertise between theoreticians and experimentalists in order to highlight the needs of the experimental sciences and how the current state-of-the-art computational techniques can help to fulfill them. Also, the presentation of the most novel challenges in the experimental methodology would hopefully stimulate theoreticians to push the development of novel strategies/models for meeting tthemfrom experiment.
Still in the same context, another very challenging topic in this field is the extension of the new bidimensional (2D) techniques to chiral systems, leading to the development of bidimensional chiroptical spectroscopies. Multidimensional vibrational spectroscopy provides detailed insight into the anharmonic nature of molecular vibrations, including the coupling of the different normal modes in a molecule. Multidimensional spectroscopies, both in the electronic and vibrational domain, can be made to be surface and interface specific, and thus represent powerful techniques for understanding molecular structure and reactivity at these symmetry-breaking regions, and would allow for in vivo characterization of for instance molecular interactions with cell membranes, allowing for a much needed insight into how to design drugs that penetrate cell membranes in an efficient manner. Multidimensional spectroscopy also holds great promise as a non-invasive microscopy technique since it a high degree of focality in combination with low-energy radiation, ensuring deep penetration depth. We believe the additional information that would be possible to extract when considering multidimensional chiroptical spectroscopies to be large and of a novel character, but the successful development of such new experimental techniques will require a theoretical understanding of what is being observed experimentally and correlating experimental observations to molecular structures and interactions through modeling.
The increasing interest in the field of 2D vibrational techniques is demonstrated by the emphasis this topic has recieved recently in the literature. In fact, after the appearance of a review by M. Cho in Chemical Reviews in 2008 [5], an entire issue of The Accounts of Chemical Research has been published in 2009 [6] on these topics, followed by numerous publications in the following years.Research on 2D vibrational techniques has been so far mostly limited to 2D-IR spectroscopy. However, 2D optical spectroscopic methods using circularly polarized (CP) light beams have been theoretically proposed and reported for the measurement of the nonlinear optical activity of chiral molecules in isotropic media [5-11]. It has also been suggested that 2D CP-IR photon-echo spectroscopy can be a better tool for protein structure determination than 2D IR spectroscopy [6]. However, such techniques are far from being standard, and the extraction of structural information from the spectroscopic signals requires once again a close collaboration with computational chemists. The development of QM strategies for computing 2D signals have received so far very limited attention, being limited to date to very few attempts to simulate some parameters of 2D-IR spectra [see e.g. 12-15]. Very few attempts has been made to date to simulate a complete 2D vibrational chiroptical spectrum from fully ab initio data [16], in part due to a lack of awareness and in part due to the computational complexity of the problem. Therefore, another aim of the present workshop is to promote the understanding of such new experimental techniques by theoreticians, and on the other hand to give theoreticians the opportunity to promote the potentials of their (static and/or time-independent) methods, and in this was create a common ground for jointly developing this field of research.

References

[1] Polavarapu PL. Renaissance in chiroptical spectroscopic methods for molecular structure determination. Chem Rec 2007; 7: 125–136.
[2] Blanch E. et. al., Biochemistry 2003; 42: 4665.
[3] J.Sebestik and P.Bour, J.Phys.Chem.Lett. 2011; 2: 498
[4] B.G.Janesko and G.E.Scuseria, J.Chem.Phys. 2006; 125: 124704
[5] Cho M Coherent Two-Dimensional Optical Spectroscopy Chem. Rev. 2008; 108: 1331-1418.
[6] “Coherent Multidimensional Optical Spectroscopy” Acc. Chem. Res. 2009, volume 42, issue 9, Pages 1207-1469.
[7] Rhee H; Choi J-H, Cho M Infrared Optical Acivity: Electric Field Approaches in Time Domain Acc. Chem. Res. 2010; 43: 1527-1536.
[8] Choi J-H, Cho M Two-Dimensional Circularly Polarized IR Photon Echo Spectroscopy of Polypeptides: Four-Wave-Mixing Optical Activity Measurement.
[9] Choi, J.-H.; Cheon, S.; Lee, H.; Cho, M. Phys. Chem. Chem. Phys. 2008, 10, 3839–3856.
[10] Abramavicius, D.; Mukamel, S. J. Chem. Phys. 2006, 124, 034113.
[11] Jeon J; Yang S; Choi J-H; Cho M Acc. Chem. Res. 2009; 42: 1280-1289.
[12] Moran, A.; Mukamel, S. Proc. Nat. Acad. Sci. U.S.A. 2004, 101,506
[13] Ham, S.; Cha, S.; Choi, J.-H.; Cho, M. J. Chem. Phys. 2003, 119, 1451.
[14] Gorbunov, R. D.; Kosov, D. S.; Stock, G. J. Chem. Phys. 2005, 122, 224904.
[15] Biancardi, A; Cappelli, C.; Mennucci, B.; Cammi, R. J. Phys. Chem. B 2010, 114, 4924–4930.
[16] Donaldson, P.M. et al., J.Chem.Phys. 2007, 127, 114513.