Determination of Molecular Stereochemistry Using Chiroptical Spectroscopic Methods Vanderbilt Chemistry
Prasad L. Polavarapu Department of Chemistry Vanderbilt University Nashville TN 37235 USA
Presented to Synthetic community/ Chemical-Biology training program February 15, 2011 Food for thought Vanderbilt Chemistry How would you determine: (A). the absolute configuration of: (1). Bromochlorofluoromethane, CHFClBr
(2). Molecules that are chiral solely due to isotopic substitution
(3). Diastereomers of Natural Products
(B). The secondary structures of peptides/proteins Vanderbilt Chemistry ORD ECD Optical Electronic Circular Rotatory Dichroism dispersion Chiroptical Spectroscopic Vibrational methods Circular Vibrational Raman Dichroism Optical Activity VCD VROA
Enantiomers of chiral molecules give oppositely signed chiroptical spectra and thus enable distinguishing enantiomers Optical Rotation: Experimental Measurement
Vanderbilt Chemistry Chiral sample
monochromator detector Analyzer Linear polarizer
Specific Rotation: []= /c l is observed rotation c is concentration in g / mL l is path length in dm Specific Rotation & Molecular structure Vanderbilt Chemistry “Experimental determination of the absolute configuration of bromochlorofluoromethane is a challenge”. Wilen SH, Bunding KA, Kascheres CM, Weider MJ. J Am Chem Soc 1985; 107:6997-6998 Lack of a reliable method to correlate observed Specific rotation with molecular structure prevented optical rotation from becoming a structural tool for the most part of twentieth century. This status has changed now due to advances in quantum chemical theories and ever changing computer technology Vanderbilt Chemistry -1 2 2 Static method of Amos G’=-(4/h){[1/( ns- )]Im{,snm,ns}} Chem. Phys. Lett. 1982; 87: 23-26 -1 = -(1/3) [G’xx+ G’yy+ G’zz] -1 lim G’=-(h/) Im (s/F)|(s/B) 0 [] = 13.43 x10-5 2/M CPHF method implemented (in deg.cc.dm-1.g-1) in CADPAC program
Molecule Pred Expt (R)-methyloxirane 2 14 (S)-methylthiirane -50 -51 (R,R)-dimethyloxirane 70 59 (S,S)-dimethylthiirane -248 -129
Using specific rotation at 589nm and Raman optical activity, absolute configuration of bromochlorofluoromethane was assigned as (S)-(+)/(R)-(-). Hecht L, Costante J, Polavarapu PL, Collet A, Barron LD. Angew. Chem. 1997; 36: 885-887; Calculations were done at Hartree-Fock level of Chem. Eng. News, 1997 theory using 6-31G*/DZP basis sets for 11 molecules Advanced theoretical methods Time dependent density functional theory for specific rotation
Vanderbilt Chemistry (1). K. Yabana, G. F. Bertsch, Application of time-dependent density functional theory to optical activity, Phys. Rev. A 60 (1999) 1271-1279; (2). J. R. Cheeseman, M. J. Frisch, F. J. Devlin, P. J. Stephens, Hartree-Fock and Density functional theory ab initio calculation of optical rotation using GIAOs: Basis set dependence, J. Phys. Chem. A.104 (2000) 1039-1046; (3). S. Grimme, Calculation of frequency dependent optical rotation using density functional response theory, Chem. Phys. Lett. 339 (2001) 380-388 (4).K. Ruud, T. Helgaker, Optical rotation studied by density functional and coupled-cluster methods, Chem Phys Lett. 352 (2002) 533-539. (5). J. Autschbach, S. Patchkovskii, T. Ziegler, S. J. A. van Gisbergen, E. J. Baerends, Chiroptical properties from time- dependent density functional theory. II. Optical rotations of small to medium size organic molecules, J. Chem. Phys.117 (2002) 581-592. Advanced theoretical methods Coupled cluster theory for specific rotation Vanderbilt Chemistry (1). K. Ruud, T. Helgaker, Optical rotation studied by density-functional and coupled-cluster methods, Chem Phys Lett. 352 (2002) 533-539. (2). Ruud K, Stephens PJ, Devlin FJ, Taylor PR, Cheeseman JR, Frisch MJ. Coupled cluster calculations of optical rotation, Chem. Phys. Lett. 2003; 373:606-614. (3). Tam MC, Russ NJ, Crawford TD, Coupled cluster calculation of optical rotatory dispersion of (S)-methyloxirane, J. Chem. Phys. 2004; 121:3550-3557. (4). Pedersen TB, Sanchez de Meras AMJ, Koch H. Polarizability and optical rotation calculated from the approximate coupled cluster singles and doubles CC2 linear response theory using Cholesky decomposition. J. Chem. Phys. 2004; 120: 8887-8897. (5). Kongsted J, Pedersen TB, Strange M, Osted A, Hansen AE, Mikkelsen KV, Pawlowski F, Jorgensen P, Hattig C. “Coupled cluster calculations of optical rotation of S-propylene oxide in gas phase and solution”, Chem. Phys. Lett. 2005; 401:385-392 Absolute configuration of Bromochlorofluoromethane Vanderbilt Chemistry Optical rotatory dispersion in bromochlorofluoromethane (S)-(+)-CHFClBr Predicted with 4 in C H 6 12 B3LYP/aug-cc-pVTZ 3 neat liquid For (S)-CHFClBr 2 H 1 Specicic Rotation B3LYP/aug-cc-pVTZ 0 C 350 450 550 650 F Br nm) Cl Experimental data from: Canceill J, Lacombe L, Collet A., J Am Chem Soc 1985; 107: 6993-6996. Hecht L, Costante J, Polavarapu PL, Collet A, Barron LD. Angewandte Chemie 1997; 36: 885-887 P. L.Polavarapu, Angewandte Chemie Int. Ed 41(23),4544-4546 (2002). Summary for Optical rotatory dispersion Vanderbilt Chemistry
Remarkable advances in calculation of specific rotations. ORD can now be calculated through resonant regions using sophisticated levels of theory
Optical rotation at a single wavelength should never be used for establishing Molecular structure “Protocols for the analysis of theoretical optical rotations”, P. L. Polavarapu, Chirality 2006; 18: 348-356 However need a significant culture change in reporting Experimental solution phase optical rotations Vanderbilt Chemistry
Errors are not usually reported for optical rotation measurements in liquid solutions
Significant errors can arise from (a). Preparing solutions with smaller amount (~mg) of samples (b). Preparing smaller volume (~ mL) solutions (c). Measuring small (<0.01) optical rotation values
Optical rotation measurements of organometallic compounds: Caveats and recommended procedures. Dewey MA, Gladysz JA. Organometallics 1993, 12, 2390-2392. Electronic Circular Dichroism (ECD) Vanderbilt Chemistry
Excited electronic state
AL-AR
First Vibrational excited state 1 Ground electronic state Vibrational ground state 0
ECD technique is more than 100 yrs old
Gained a new life, in the last decade, with the advent of reliable quantum chemical theories Measurement of Electronic Circular Dichroism
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Circularly Polarized light sample Detector Visible light source
Experimental Theoretical Dipole Strength Absorbance 2 D01=|<0||1>| A= - log(I/I0) Circular Dichroism Rotational Strength R01=Im[<0||1>•<1|m|0>] A=AL-AR A typical ECD spectrum
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(aS)- 3,3'-diphenyl-[2,2'-binaphthalene]-1,1'-diol ECD and Molecular Structures… the Old Way Vanderbilt Chemistry Empirical rules: Octant rule etc [Lightner, D. A.; Gurst, J. E. Organic Conformational Analysis and Stereochemistry from Circular Dichroism Spectroscopy, John Wiley & Sons: New York, 2000.]
Exciton coupling model [Harada, N.; Nakanishi, K. Circular Dichroism Spectroscopy: Exciton coupling in Organic Stereochemistry; University Science Books: Mill Valley, CA, 1983.; ]
Semi-classical models: Devoe’s Polarizability model [Superchi, S.; Giorgio, E.; Rosini, A. Structural determinations by circular dichroism spectra analysis using coupled oscillator methods: An update of the applications of the DeVoe polarizability model, Chirality, 2004, 16, 422-451] ECD and Molecular Structures… the Modern Way Vanderbilt Chemistry
th For i electronic transition, calculate rotational strength, Ri. o o o Ri Im s i i m s Corresponding absorption intensity as dipole strength, D =|< | | >|2 i s i 8 2 m D or dimensionless oscillator strength, f . f e i i i i 3e 2 h 3298.8 i Ri 40 Peak intensity of Lorentzian band: i,0 10 22.94 i 2 ( ) i Lorentzian band intensity distribution: i i,0 2 2 ( i ) i Early Quantum chemical calculations with Random phase approximation: Hansen AE, Bouman TD, Natural chiroptical spectroscopy: Theory and computations, Adv Chem Phys 1980;44:545–644. Hansen AE, Voigt B, Rettrup S, Large-scale RPA calculations of chiroptical properties of organic molecules: Program RPAC, Int J Quantum Chem 1983;23: 595–611. Modern Quantum chemical calculations: Density functional theoretical method for ECD Vanderbilt Chemistry Autschbach, J.; Ziegler T.; van Gisbergen SJA.; Baerends EJ. Chiroptical properties from time-dependent density functional theory. I. Circular dichroism spectra of organic molecules, J. Chem. Phys. 2002; 116: 6930-6940.
Diedrich C.; Grimme S. Systematic Investigation of Modern Quantum Chemical Methods to Predict Electronic Circular Dichroism Spectra, J. Phys. Chem. A. 2003, 107, 2524-2539;
Pecul M.; Ruud K.; Helgaker T. Density functional theory calculation of electronic circular dichroism using London orbitals, Chem. Phys. Lett. 2004; 388: 110-119;
Stephens PJ, McCann DM, Devlin FJ, Cheeseman JR, Frisch MJ. Determination of the absolute configuration of [3(2)](1,4) barrelenophanedicarbonitrile using concerted time-dependent density functional theory calculations of optical rotation and electronic circular dichroism. J Am Chem Soc 126 (2004) 7514-7521. Modern Quantum chemical calculations: Coupled Cluster theoretical method for ECD Vanderbilt Chemistry Pedersen TB.; Koch H.; Ruud K. Coupled cluster response calculation of natural chiroptical spectra, J. Chem. Phys. 1999; 110: 2883-2892;
Crawford TD.; Tam MC.; Abrams ML. The current state of ab initio calculations of optical rotation and electronic circular dichroism spectra. J. Phys. Chem. 2007, 111, 12057-12068 Molecular stereochemistry:
(+)-P-Ni3[(C5H5N)2N]4Cl2 Vanderbilt Chemistry
Daniel W. Armstrong, , F. Albert Cotton, Ana G. Petrovic, Prasad L Polavarapu, and Molly M. Warnke Inorg. Chem. 2007, 46, 1535-1537 Electronic circular dichroism and Molecular Stereochemistry
(+)-P-Ni3[(C5H5N)2N]4Cl2 Vanderbilt Chemistry
450 BHLYP/LANL2DZ
0 Experimental
Ni3[(C5H5N)2N]4Cl2 -450 200 400 600 800
(+)-P- absolute configuration was also confirmed using ORD and VCD Daniel W. Armstrong, , F. Albert Cotton, Ana G. Petrovic, Prasad L Polavarapu, and Molly M. Warnke Inorg. Chem. 2007, 46, 1535-1537 Summary for ECD Vanderbilt Chemistry Remarkable advances in calculation of ECD using sophisticated levels of quantum chemical theory
ECD and ORD are not independent methods(can be transformed into each other using Kramers-Kronig transform)
But that does not mean redundancy •ECD in the UV-Vis range cannot be measured in solvents such as DMSO but ORD can still be measured in DMSO in the long wavelength region. •Experimental ORD may show more sensitivity than what can be deduced for accessible experimental ECD spectrum •If ECD is predicted correctly and ORD is not (or vice versa) then that reflects on the inadequacy of theoretical level used. But ………………. Vanderbilt Chemistry How would you determine:
(A). The absolute configurations of:
(1). Diastereomers of natural products that have same signed ORD and ECD?
(2). Molecules that are chiral solely due to isotopic substitution
(B). Secondary Structures of Peptides and Proteins confidently Diastereomeric Natural Products O O H
COOCH3
COOCH3 HO Vanderbilt Chemistry
Garcinia acid dimethyl ester (GADE) Hibiscus acid dimethyl ester (HADE)
Garcinia acid is extracted from Hibiscus acid is extracted from the dried rind of the fruit of the Rosella plant G.cambogia (tamarind fruit) ECD ORD
ECD and ORD may not be able to discriminate diastereomers New Chiroptical Spectroscopic methods (A). Vibrational Circular Dichroism (VCD) (B). Vibrational Raman Optical Activity (ROA) What are the advantages? Vanderbilt Chemistry (1). All (3N-6) vibrations of a chiral molecule can exhibit VCD/ROA For a 10 atom molecule, there will be 24 vibrations Thus, unlike in ECD, no chromophore is needed to observe VCD/ROA (2). Chiral hydrocarbons do not exhibit measurable ECD/ORD spectra, but they do give large VCD/ROA spectra
(3). Through isotope labeling, site specific structure can de determined
(4). VCD is a ground electronic state property. Thus, quantum chemical predictions of VCD are more reliable and less time consuming (5). Some of the literature ECD interpretations of absolute configurations and protein secondary structures are now being corrected in light of VCD studies (6). Some of the literature crystal structure determinations of absolute configurations are now being corrected in light of VCD studies Vibrational Circular Dichroism (VCD) Vanderbilt Chemistry
Excited electronic state
First Vibrational excited state 1 Ground electronic state AL-AR Vibrational ground state 0 Measurement of Vibrational Circular Dichroism
Vanderbilt Chemistry Circularly Polarized light sample
Detector
Infrared First measured in 1974 light source
Infrared circular dichroim of C-H and C-D stretching vibrations: Observations Holzwarth G.; Hsu EC.;Mosher HS.; Faulkner TR; Moscowitz A J Am Chem Soc 1974, 96: 252-253 Remarkable developments in instrumentation and theory have occurred in 1980s and 1990s Measurement of Vibrational Circular Dichroism: Fourier Transform instruments Vanderbilt Chemistry
S MI Detector Polarizer Sample
BS Fixed Mirror PEM Lens
Moving Mirror
FT LA Filter IAC IDC FT 1. Liquid samples Routine 2. Gas samples Samples with high vapor pressure 3. Films (dried solutions) became possible recently A typical VCD spectrum [(+)-vanol]
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VCD magnitudes are of the order of 10-4 absorbance units
100 times smaller than ECD magnitudes Density functional theoretical method Vanderbilt Chemistry
J. R. Cheeseman, M. J. Frisch, F. J. Devlin, P. J. Stephens, Ab initio calculation of atomic axial tensors and vibrational rotational strengths using density functional theory, Chem. Phys. Lett. 252 (1996) 211-220.
Computer Programs:
Freeware: DALTON program [www.kjemi.uio.no/software/dalton/ ]
Commercial: Gaussian 09 [www.gaussian.com]; Turbomole [www.turbomole.com]; ADF [www.scm.com] Diastereomeric Natural Products O O H
COOCH3
COOCH3 HO Vanderbilt Chemistry
ECD ORD
VCD can discriminate diastereomers better than ECD/ORD Diastereomeric Natural Products O O H
COOCH3
COOCH3 HO Vanderbilt Chemistry
VCD is much more powerful than ECD/ORD for discriminating diastereomers Summary for VCD Vanderbilt Chemistry
VCD provides an independent reliable approach from ECD/ORD for molecular structure determination
Are there any disadvantages of VCD ? (1). Higher concentrations than those needed for ECD/ORD VCD measurements require ~1-20 mg/100 L (2). Sample should be soluble in IR transparent solvents
(CCl4, CHCl3, CD2Cl2, CD3CN, D2O, DMSO-d6 etc) Natural products whose structures have been determined/confirmed using VCD
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Carboxylic acids (1-4) Monoterpenes (5-14) Alkaloids Cinchonidine Schizozygane alkaloids (15-19) Iso-schizozygane alkaloids (20-21) Tropane alkaloids (22-28) Natural products whose structures have been determined/confirmed using VCD
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Tropane alkaloids(22-28) Montanine-type alkaloids (29-30) Iridoids (31-34) Meroditerpenoids (35-38) Verticillane diterpenoids(39) Sesquiterpenes (40-46)
Compounds 40-43: P. J. Stephens, D. M. McCann, F. J. Devlin, A. B. Smith, J. Nat. Prod. 2006, 69, 1055-1064. Natural products whose structures have been determined/confirmed using VCD
Vanderbilt Chemistry Halogenated sesquiterpenes (47-51) Endoperoxides (52) Furochromones (53-56) Eremophilanoids (57-59) Eudesamanolides (60) Presilphiperfolanes (61-63) Longipinane derivatives (64-66) Cruciferous phytoalexins (67-73) Natural products whose structures have been determined/confirmed using VCD
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Furanones (74-80) Furanocoumarins (81) Klaivanolide (82) Pheromones(83-84) Norlignan(85-86) Taxol Ginkgolides Peptides (pexiganan, cyclosporins) Axially chiral natural products Dicurcuphenol B (87) Dicurcuphenol C (88) Gossypol (90) Cephalochromin (91) Vanderbilt Chemistry
Vibrational Raman Optical Activity (VROA) Measurement of Vibrational Raman Optical Activity (VROA)
Vanderbilt Chemistry Excited electronic state
Virtual state Incident light Scattered light IR-IL First Vibrational excited state 1 Ground electronic state Vibrational ground state 0 sample
laser
First Measured in 1973 IR-IL L. D. Barron, M. P. Bogaard and A. D. Buckingham, JACS. 95, 603 (1973) Quantum Chemical predictions of ROA Vanderbilt Chemistry
Hartree-Fock Numerical differentiation approach using Amos’ static method for G tensor Advances in Quantum mechanical predictions Vanderbilt Chemistry
Numerical differentiation methods Hartree-Fock Numerical differentiation with Dynamic method and London orbitals T Helgaker, K. Ruud, K. L. Bak, P. Jorgensen, J. Olsen. Farad Disc 1994, 99,165-180 2000s Density functional numerical differentiation method K. Ruud, T. Helgaker, P. Bour, J. Phys. Chem. A. 106, 7448 (2002)
Analytical methods 2000s Time-dependent Hartree–Fock schemes for analytical evaluation of the Raman Intensities, Quinet, O.; Champagne, B. J. Chem. Phys. 2001, 115, 6293-6299. TDHF Evaluation of the Dipole−Quadrupole Polarizability and Its Geometrical Derivatives, Quinet, O.; Liegeois, V.; Champagne, B. J. Chem. Theory Comput. 2005, 1, 444-452 An analytical derivative procedure for the calculation of vibrational Raman optical activity spectra, Liegeois, V.; Ruud K.; Champagne, B. J. J. Chem. Phys. 2007; 127, 204105. Absolute configuration of
Bromochlorofluoromethane Vanderbilt Chemistry Comparison of experimental ROA of (-) CHFClBr with predictions for (R)-CHFClBr Experiment B3LYP/6-311++G(2d,2p) -1 4 -1 4 Freq(cm ) zx10 Freq(cm ) zx10 HF(or MP2)/DZP 3022 -0.7 3173 -0.3 1305 -2.4 1321 0.5 1206 -2.8 1212 -1.0 1062 -4.5 1065 -0.2 774 -5.1 744 -4.9 662 5.9 634 3.2 427 10.2 417 1.1 315 -2.1 305 0.0 218 -1.9 218 -0.3 The Absolute Configuration of Bromochlorofluoromethane. P L. Polavarapu, Angewandte Chemie, 41(23),4544-4546 (2002).
Absolute Absolute Configuration of Bromochlorofluoromethane configuration of from Experimental and Ab Initio Theoretical Vibrational F Br Raman Optical Activity. Hecht L, Costante J, Polavarapu PL, CHFClBr is Collet A, Barron LD. Angewandte Chemie 1997; 36: 885-887 Cl (S)-(+) Absolute configuration of chirally deuterated neopentane: 2 2 2 (R)-[ H1, H2, H3]-neopentane Vanderbilt Chemistry
Boltzmann population weighted Spectrum
Absolute configuration of chirally deuterated neopentane, J. Haesler, I. Schindelholz, E. Riguet, C. G. Bochet & W. Hug, Nature 446, 526-529 (2007) Summary for ROA Vanderbilt Chemistry
ROA provides an independent and reliable approach to determine Chiral molecular structures
Well suited for biological molecules in aqueous solutions How Can You Benefit From These New Developments
Vanderbilt Chemistry There are three independent methods, fully developed and ready to be used.
ECD and ORD VCD ROA
These two should be viewed as one
No need for crystallization, unlike X-ray No need for derivatization with shift reagents, unlike in NMR Experimental measurements done for solutions or for film samples How about………………. Vanderbilt Chemistry
Secondary Structures of Peptides and Proteins Peptides and proteins: ECD has been widely used for determining Secondary structures
ECD spectra-structure correlations Vanderbilt Chemistry
15 -Sheet
y 10
5
0 Molar Ellipticit -5 218 -10 200 220 240 260 Wavelength (nm)
1.5 217 10 222 y 0 0 230 Polyproline II -1.5 -10 200
Molar Ellipticit -20 -3 -turn Molar Ellipticity collagen -30 196 -4.5 190 210 230 250 200 220 240 260 Wavelength (nm) Wavelength (nm) Peptides and proteins: VCD spectra-structure correlations
-Helix -Sheet -Helix + -Sheet Vanderbilt Chemistry 5 6 Ovalbumin 1643 Pepsin 6 BSA 4 4 3 4 2 5 1516 2 5 1628 5 1632 1666 1516 10 10 10 1662
2 A 1 A A 1512 Chymotrypsin 0 Hemoglobin 1640 Trypsin 0 0 -2 -1 1662 1516 -2 1520 -4 -2 1632 1628 1662 1516 -4 -3 -6 1800 1700 1600 1500 1400 1800 1700 1600 1500 1400 1800 1700 1600 1500 1400 -1 Frequency (cm-1) Frequency (cm ) Frequency (cm-1)
5 Polyproline2 II (PPII) 1686 collagen 1670
5 1 0 4 10 AX10
A 0
-turn -5
-1 1662
1636 -10 1800 1700 1600 -2 1850 1750 1650 1550 1450 -1 Wavenumber (cm ) -1 Wavenumber (cm ) Secondary Structures of peptides and Proteins VP1 peptide: Domain IV of Calpain enzyme
Time dependent structural transition of VP1 5 Vanderbilt Chemistry 1624 VP1: GTAMRILGGVI VCD 3 1670 55 0 AX10 AX10
-3 50 1682 1640
VCD band at 1609 indicates 1609 -5 -sheet structure possibly fibril formation 0 0.9 ECD
0.6 1674 CD (mdeg) -50 1620 Double minima indicate -helical structure
AbsorbanceAbsorbance 0.3 1697 -100 195 215 235 255 275 TEM image Wavelenth (nm) 0 1775 1725 1675 1625 1575 Wavenumber (cm-1) Ganesh Shanmugam, Nsoki Phambu, Prasad L Polavarapu, BioPhysChem. Secondary structures of peptides and proteins Vanderbilt Chemistry
Do not bet your life if using ECD !!
Verify your conclusions using VCD/ROA Global Summary Vanderbilt Chemistry Older methods of structural interpretations using ECD and ORD have been replaced with much more reliable modern quantum chemical methods
Two new chiroptical spectroscopic methods, VCD and ROA, have emerged in the last two decades as powerful techniques for chiral molecular structure determination
Combined applications of these methods yield a reliable means of chiral molecular structure determination Coming this year ……August 2011
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Comprehensive Chiroptical Spectroscopy Eds, N. Berova, P. L. Polavarapu, K. Naksnishi, R. W. Woody (John Wiley)
Volume 1: Instrumentation, Methodologies, and Theoretical Simulations
Volume 2: Applications in Stereochemical Analysis of Synthetic Compounds, Natural Products, and Biomolecules
More than 50 chapters and 1000 pages !! Academic Collaborators Vanderbilt Chemistry Sergio Abbate (Italy) Tibor Kurtan (Hungary) Daniel Armstrong (Texas) Tingyu Li (Vanderbilt) Brian Bachman (Vanderbilt) Zsuzsa Majer (Hungary) P Balaram (India) Larry Nafie (Syracuse) Laurence Barron (Glasgow) Koji Nahanishi (Columbia Univ) Nina Berova (Columbia Univ) Bruce Novak (North Carolina) James Birch (UK) Arvi Rauk (Calgary) F. A. Cotton (Texas) Carmelo Rizzo (Vanderbilt) Jeanne Crassous (France) Gabrielle Roda (Italy) Carlo De Micheli (Italy) Kenneth Ruud (Tromso) Jozef Drabowicz (Poland) William Salzman (Arizona) Helmut Duddeck (Germany) Larry Schaad (Vanderbilt) Carl Ewig (Vanderbilt) Volker Schurig (Germany) Joe Gal (Denver) Howard Smith (Vanderbilt) B. A. Hess (Vanderbilt) Gerald Stubbs (Vanderbilt) Ibrahim Ibnusaud (India) William Wulff (Michigan) Coworkers Vanderbilt Chemistry Research Associates Graduate Students Undergraduate students P. K. Bose Darlene Back S. R. Chatterjee G. Chen T. M. Black S. Chawla B. Galabov P. K. Bose P. Chen D. Henderson S. T. Pickard A Dehlavi D. Michalska D. K. Chakraborty J. Goring R. S. Pandurangi T. Chandramouly K. Hammer G. Shanmugam Z. Deng Neha Jeirath K. Srinivasan J. He Sheng Lin J. McBride A.G. Petrovic A. Petrovic R. Reddy P. Zhang A. Schwaab F. Wang S. E. Vick C. Zhao Sheena Walia Acknowledgments Vanderbilt Chemistry Funding over the years
National Institute of Health National science Foundation National center for Supercomputing Applications