Chemistry 125: Lecture 30 November 15, 2009 (Optical Activity) Racemization & Resolution Preparing Single Enantiomers After an aside concerning the difficulty of understanding optical rotation, methods of resolution are described. The aldol reaction. For copyright notice see final page of this file

How does Optical Activity work? Slides modified from Chem 125 guest lecture by Laurence Barron 11/12/2008 click

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: The instantaneous electric field vectors of right- and left-circularly polarized light beams propagating along z. right left z clockwise Changing Time at Fixed Position Fixed Time counter-clockwise Chiral molecules respond slightly differently to right- and left-circularly polarized light. A difference in refractive index (wave velocity) leads to optical rotation.

Circular Differential Refraction “earlier” angles further on Circular Differential Refraction at a certain point A molecule can view linearly polarized light as a superimposed sum of right- and left-circularly polarized waves of equal amplitude. (So can we.) A difference in refractive index for the right- and left-circularly polarized beams means a difference in wave velocity. So the phase relation between the two contra-rotating electric vectors will change with position and cause rotation of the plane of polarization. same instant at a further point, ER having moved faster (less time for rotation) For an animation see Google Images (Google ‘circularly polarized light’ and open the www.enzim.hu site). right left SUM Light waves move more slowly (higher n) to the extent that their electric/magnetic fields “feel” the material by mixing the ground-state wave function with excited state wave functions to shift electron density (like walking through mud). From P.W. Atkins, Physical Chemistry (OUP)

The Carbonyl Chromophore transition at ~ 290 nm The Carbonyl Chromophore The carbonyl group is an important source of optical activity in many organic compounds, even though the group in isolation has a plane of symmetry and thus is not chiral/optically active. “Perturbations” from the chiral environment provided by the rest of the molecule reduce the symmetry and induce optical activity in its electronic transitions by allowing orbitals that would otherwise be orthogonal to mix.

* dXZ mix n n *  n dXZ  n  + dXZ)  n The *  n transition is magnetic (m) dipole-allowed, electric (m) dipole-forbidden. The dXZ  n transition is m dipole-allowed, m dipole-forbidden. For transition to a mixed state electric and magnetic contributions reinforce - or cancel (one for right, the other for left, hence slightly different wave velocities, nR ≠ nL) C O * dXZ C O x z y C O mix C O C O n C O n mixed by chiral environment *  n dXZ  n  + dXZ)  n rotation of charge (interacts weakly with light’s magnetic field, m) linear displacement of charge (interacts with light’s electric field m) helical motion of charge (simultaneous inter-action with m and m) For planar molecule * and dXY are orthogonal and cannot give a mixed excited state. But without true symmetry they can mix, so m and m participate together.

Quantum-Chemical Calculations electric mixing magnetic mixing sum over all excited states Since 1997 a mathematical trick that avoids the summation has allowed computing rotation for rigid molecules in the gas phase, often accurately enough to determine absolute configuration from the sign and magnitude, by using opaque ab initio quantum-chemical programs (Gaussian, Dalton). How many excited states does one actually need to consider? Calculated specific rotation of twisted 2,3-hexadiene as a function of the number of excited states considered. J. Phys. Chem. A, 2008, 112, 2415-2422 Might we be able to guess reliably which excited states, j, dominate the sum, and thus to understand optical rotation? No one excited state dominates. To get a steady value Wiberg had to sum >1500 excitations! No, because the formula involves products between almost-mutually-exclusive properties. When the m term is large, the m term is small, and vice versa. Because all products are small, contributions can be relatively important even when neither individual term is large, or the factor with ws (frequencies) is small.  Forget intuitive understanding!

Racemization (R) (RS) :B COOH H H (R)-Lactic Acid planar achiral! HO planar achiral! (S)-Lactic Acid COOH H CH3 HO HOMO p* LUMO H COO CH3 HO harder (occasional) :B dianion very rare easy

Epimerization (R,R) (R,S) D Change at One Center of Two (or many) (R,R)-Tartaric Acid meso-Tartaric Acid Change at One Center of Two (or many)

Racemization Resolution (R) (RS) (S) + 1) Pasteur “Conglomerate” Chiral-Resolved Seeding Chiral-Resolved Poison

Lengthening Rate Depends on Width Metastable (in  solution) “Critical” Nucleus As an “organic” chemist I find it more comfortable to think about the energy of molecules than that of surfaces. Average molecule more stable than in solution Crystal at Equilibrium Interior Molecules more stable than in solution Surface Molecules less stable than in solution Average Molecule same as solution Average molecule less stable than in solution Crystal in Equilibrium with Saturated Solution

Resolution (R) (RS) (S) + cont. 1) Pasteur Conglomerate Chiral-Resolved Seeding Chiral-Resolved Poison cont. Influence nucleation 2) Temporary Diastereomers Chromatography with Chiral-Resolved Support Compound with Chiral-Resolved Mate

van’t Hoff Prediction 1874

Kohler Walker Tishler 1935 Brucine “Alkaloids” organic bases isolated from plants used to make diastereomeric salts with racemic acids

Kohler Walker Tishler 1935 Mole ratio brucine/acid 1.08 42% yield Levo [a]D -28.4° mixed mp 195°C

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

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

Before being slapped Alexander was meso. http://slightlyrelevant.com/2010/09/20/one-last-game-of-civ-4/ Before being slapped Alexander was meso. (at least approximately) Now he is chiral. Was the person who slapped him right- or left-handed? Cf. detective stories in which a stab wound exonerates a right-handed defendant.

Wolfson, et al., Org. Commun. (2008) H “Left-handed” reagent “slaps” H onto the front face of the C=O group. Wolfson, et al., Org. Commun. (2008)

Nature can be Subtle and Surprising CH2 ^ “The compound we want to get.” The yeast may have oxidized the alcohol before reducing the aldehyde, and then reduced the ketone back to the alcohol. Nature can be Subtle and Surprising as in Levene’s preparation of (R)-Butane-1,3-diol H O H “I confuse myself sometimes.” “What did I do wrong?” “It’ll reduce this.” catalyst O C H CH3 H H O C H CH3 O C H “What Levene did was to reduce it with yeast & sugar.” [add H2 to get optically active product!] “enolate” CH2 CH3 “A reaction that Prof. McBride will talk about later on called the ‘aldol’ reaction…”

Enantiospecific reduction of (R) by yeast/sugar CH2 ^ The yeast may have oxidized the alcohol before reducing the aldehyde, and then reduced the ketone back to the alcohol. or O C H CH3 CH2 CH2 O C H CH3 CH O C H CH3 CH2 O C H CH3 (R) (S) OH C H CH2 O CH3 What happens to the (S)? Enantiospecific reduction of (R) by yeast/sugar CH3 CH2 O C H OH

End of Lecture 30 Nov. 15, 2010 Copyright © J. M. McBride 2009, 2010. 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). 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