1. Chemistry 125: Lecture 29 November 13, 2009 “Absolute” Configuration X-ray and CIP Nomenclature Preparing Single Enantiomers Determination of the actual atomic arrangement in tartaric acid in 1949 motivated a change in stereochemical nomenclature from Fischer’s 1891 genealogical convention (D,L) to the CIP scheme (R,S) based on conventional group priorities. Methods of resolution are described. 3D visualization of omeprazole. The chemical mode of action of omeprazole is expected to be insensitive to its stereochemistry, making clinical trials of the proposed virtues of a chiral switch crucial. For copyright notice see final page of this file PRELIMINARY

2. d-(+)l-(-) How does Optical Activity work? ?

3. Chirality and Circularly Polarized Light  In order to detect molecular chirality, some sort of chiral probe must be used.  Right- and left-circularly polarized light beams are mirror-image chiral systems and so can act as chiral probes:  Chiral molecules respond slightly differently to right- and left-circularly polarized light. A difference in absorption corresponds to circular dichroism; a difference in refractive index leads to optical rotation. The instantaneous electric field vectors of right- and left- circularly polarized light beams propagating along z. right left z z Changing Time at Fixed Position counter- clockwise Fixed Time clockwise

4. Circular Differential Refraction  Linearly polarized light can be described as a coherent superposition of right- and left-circularly polarized waves of equal amplitude. From P.W. Atkins, Physical Chemistry (OUP)  A difference in refractive index for the right- and left-circularly polarized beams means a difference in velocity. So the phase relation between the two contrarotating electric vectors will change, resulting in a rotation of the plane of polarization.  Go to Google Images for animations (Google ‘circularly polarized light’ and open the www.enzim.hu site).

5. A Scattering Picture of Optical Rotation A circularly polarized light wave ‘bouncing’ from one group to the other as it scatters from a simple two-group chiral molecular structure will sample the chirality. The scattered intensity of right- and left-circularly polarized waves will be slightly different for a given handedness of the chiral structure.

6. The Rotational Strength The optical rotation angle is given by Using quantum-mechanical perturbation theory this becomes The molecular quantity responsible for optical rotation (and circular dichroism) is the rotational strength:  and m are electric and magnetic dipole moment operators, respectively, so the optical activity ultimately originates in interference between electric and magnetic dipole transitions during the light scattering process!  c / 

7. The Carbonyl Chromophore The carbonyl chromophore is an important source of optical activity in many organic compounds. The carbonyl group itself has a plane of symmetry so is not chiral/optically active. Optical activity is induced in its electronic transitions via perturbations from the chiral environment provided by the rest of the molecule. transition at ~ 290 nm

8. linear displacement of charge (electric) helical motion of charge (both)   n ** n  *  n transition is magnetic dipole-allowed, electric dipole-forbidden. Electric dipole character is induced by mixing of the oxygen d YZ orbital into the    orbital: This generates a  Z m Z component (from . m ) of the rotational strength: C O C O C O C O C O C O rotation of charge (magnetic)  *  nd XZ  n  + d XZ )  n x z y mix mixed by environment asymmetry

9. Quantum-Chemical Calculations The optical rotation can be calculated using ab initio quantum-chemical programs (Gaussian, Dalton). Often sufficiently good to determine absolute configuration from the sign and magnitude. Calculated specific rotation of 2,3-hexadiene as a function of the number of excited states considered. J. Phys. Chem. A, 2008, 112, 2415-2422 Must sum >1500 excitations to get steady value!

10. Absolute Configuration J. M. Bijvoet van't Hoff Laboratory, Univ. Utrecht (1949-51) Na Rb d-(L)-Tartrate X-ray anomalous dispersion 60 year old Fischer Guess for (L)-Tartrate “The question of nomenclature is beyond the scope of our investigation... The problem of nomenclature now concerns given configurations, and requires a notation which denotes these configurations in an unambiguous and if possible self- explanatory way.” (Bijvoet, 1951)

11. Naming Double Bond Configuration Malic Acid (HO 2 C)CH(OH).CH 2. (CO 2 H) Maleic & Fumaric Acids (HO 2 C)HC=CH(CO 2 H)  cis (on this side of) trans (across) cis or trans? Absolute nomenclature is hard to generalize O O O + H 2 O cis trans (though relative is fine) 

12. Double Bond Configuration Assign groups at either end "priority" by atomic number (or weight for isotopes) at first difference O O (E) ntgegen (Opposed) (Z) usammen (Together) The names trans and cis are "polluted" by previous usage.

13. In Assigning Priority Proceed One "Shell" at a Time (respecting previous decisions) Tie Win Tie Win Cl is high in priority, but irrelevant; the decision is already made. Cl

14. Robinson: "Hello Katchalsky. What are you doing here in Zurich?" from V. Prelog, My 132 semesters of chemistry studies (1981) The 1950s "CIP" Priority Scheme is Conventional R. S. Cahn C. K. Ingold V. Prelog Robinson: "Well then, if it is not wrong, it is absolutely unnecessary." Robinson: "You know, Prelog, your and Ingold's configurational notation is all wrong." Prelog: "Excuse me, Sir Robert, I am only Prelog, and I live here." Prelog: "Sir Robert, it can't be wrong. It is just a convention. You either accept it or not." R. RobinsonR. B.Woodward by permission J. D. Roberts

15. Exercise for Monday: Eadfrith’s Error (Click here & create your very own chiral conventions) (Click here & create your very own chiral conventions) http://www.bl.uk/onlinegallery/themes/euromanuscripts/lindisfarne.html

16. CIP (R/S) Nomenclature for Stereogenic Centers (S) inister (left) 4 3 2 1 1 3 4 2 (2R,3R)- 2,3-dihydroxy butanedioic acid right turn H (R) ectus (right) H H left turn H 1 4 2 3 CH 3 HO D H H D

17. Bloomer Gate

18. Organic

19. :B:B Racemization HOMO  * LUMO (R) (RS) easy harder (occasional) dianion very rare planar achiral! (R)-Lactic Acid H COOH CH 3 HO (S)-Lactic Acid COOH H CH 3 HO H H COO CH 3 HO

20. End of Lecture 29 Nov. 13, 2009 Copyright © J. M. McBride 2009. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0) Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol. Third party materials may be subject to additional intellectual property notices, information, or restrictions. The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0