Chemistry 125: Lecture 29 Preparing Single Enantiomers and the Mechanism of Optical Rotation Within a lecture on biological resolution, the synthesis of single enantiomers, and the naming and 3D visualization of omeprazole, Professor Laurence Barron of the University of Glasgow delivers a guest lecture on the subject of how chiral molecules rotate polarized light. Mixing wave functions by coordinated application of light’s perpendicular electric and magnetic fields shifts electrons along a helix that can be right- or left-handed, but so many mixings are involved, and their magnitudes are so subtle, that predicting net optical rotation in practical cases is rarely simple. Synchronize when the speaker finishes saying “…very fond of racemic and tartaric acid.” Synchrony can be adjusted by using the pause(||) and run(>) controls. For copyright notice see final page of this file

Pasteur's "Bargain-Basement" Moldy Racemic Acid from Thann Pharmacy (probably apocryphal anecdote via L. F. Fieser ~1960) Penicillium glaucum had "eaten" (R,R) Purified  l-(S,S)-Tartaric Acid ??? (Remember the smell of carvones!)

React with One Enantiomer Diastereomeric Reactions Have Different Rates React Racemate with Resolved Chiral Reagent or Catalyst (e.g. Enzyme)

Nature's Way Prepare only one Enantiomer Use resolved starting material Or resolved reagent/catalyst

Eisai Purchase 5 stereocenters. Make the rest. 1 by chiral Simulated Bed Chromatography. 2 by allyl silane additions. 2 by asymmetric dihydroxylations. 2 by oxy-michael reactions. 3 by asymmetric Ni/Cr reactions. 1 by Jacobsen epoxidation. 1 by conjugate reduction. 1 by enolate alkylation 1 by ketal formation Best regards, Frank Only One Chiral Separation Specific or general selective reactions that preferentially form one isomer. In starting materials 19 Stereocenters

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

Molecular Chirality and Optical Rotation Laurence Barron

Chirality pervades much of modern science: from the physics of elementary particles, through organic stereochemistry, to the structure and behaviour of the molecules of life, with much else besides (nonlinear optics; nanotechnology; materials, electrical engineering; pharmaceuticals; astrobiology; origin of life; etc.). Chirality Means Right- or Left-Handedness ‘Rassi-maid’ by Hans Erni

Lord Kelvin ( ) Originally William Thomson. First introduced the word chirality into science. Best known for inventing the absolute (Kelvin) temperature scale. River Kelvin

I call any geometrical figure or group of points chiral, and say that it has chirality if its image in a plane mirror, ideally realized, cannot be brought into coincidence with itself. (Lord Kelvin, Baltimore Lectures, 1904) Lord Kelvin’s Definition of Chirality Mirror-image chiral molecules (enantiomers) show optical rotation of equal magnitude but opposite sign. (Louis Pasteur, 1848)

Natural Optical Rotation  Isotropic collections of chiral molecules (e.g. a sugar solution) show natural optical activity phenomena such as optical rotation.  Mirror-image enantiomers generate equal and opposite optical rotation angles.  Not to be confused with magnetic optical rotation (the Faraday effect).

Magnetic Optical Rotation  A static magnetic field B parallel to the incident light beam induces magnetic optical rotation in collections of achiral molecules (the Faraday effect, 1846). Reversing the magnetic field direction reverses the sense of optical rotation. Michael Faraday ( ) B

Symmetry and Optical Rotation “The magnetic rotation has neither right-handed nor left-handed quality (that is to say, no chirality). This was perfectly understood by Faraday and made clear in his writings, yet even to the present day we frequently find the chiral rotation and the magnetic rotation of the plane of polarised light classed together in a manner against which Faraday’s original description of his discovery contains ample warning.” Lord Kelvin (Baltimore Lectures, 1904)  Chiral phenomena such as natural optical rotation are characterized by time-even pseudoscalar observables. The quantum states of the system must have mixed parity and definite reversality like  ( L ) and  ( R ).  Magnetic optical rotation is not a chiral phenomenon (the observable is a time-odd axial vector). The quantum states must have definite parity and mixed reversality like  ( J,M ) and  ( J,-M ).

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

Circular Differential Refraction  Linearly polarized light can be described as a coherent superposition of right- and left-circularly polarized waves of equal amplitude.  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 site). From P.W. Atkins, Physical Chemistry (OUP)

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.

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 / 

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

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

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. (S)-(  )-thalidomide (R)-  )-thalidomide (teratogenic) (sedative)

Tetelman Lecture From Cosmic Chirality to Life on Mars: Lord Kelvin’s Legacy Davies Auditorium Becton Center 5:00 PM Today

Who Cares? Living Things Food & Drug Administration Drug Companies their Lawyers & USPTO (Patent Office) "Chiral Switch"

Pain Reliever Isobutyl Propionic Acid Phenyl Ibuprofen (Advil, Motrin) (S) Active Pain Reliever (R) Inactive Sold as racemate

Sedative Thalidomide (S) Sedative (R) Teratogen Sold as racemate ( ) (S)  (R) 0.12 / hr(R)  (S) 0.17 / hr (S) eliminated 0.24 / hr (R) eliminated 0.08 / hr in vivo racemization (human) 10,000 birth defects ?

O 5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl}1H-benzimidazole Gastric Proton Pump Inhibitor (Acid Reflux) World's largest selling drug in 2000 ($6.2B) "Omeprazole" "Prilosec" omeprazole Benzimidazole Pyridine

OTC ?

O 5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl}1H-benzimidazole "Nexium" O Gastric Proton Pump Inhibitor (Acid Reflux) World's largest selling drug in 2000 ($6.2B) "Omeprazole" "Prilosec" "esomeprazole" (racemate) (S)

N N O O O S T E R E O B I N O C U L A R S T E R E O N N O O O

Stereoviewing

from X-rayof Ohishi et al (S)-Omeprazole - Stereopair View left eye right eye

(S)-Omeprazole - Stereopair View from X-ray of Ohishi et al right-eye view left-eye view Central frame perceived in stereo How it should look when you stare dreamily into the distance “through” the stereo-pair above until the blue lines “swim” together and superimpose.

End of Lecture 29 Nov. 12, 2008 Copyright © J. M. McBride Some rights reserved. Except for cited third-party materials, and slides 7-20 used by Prof. Barron, 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