1. 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

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

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:
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.

4. 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 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)

5. 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.

6. * 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.

7. 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,
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!

8. 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

9. 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)

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

11. 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

12. 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

13. van’t Hoff Prediction 1874

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

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

16. 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)

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

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

19. Before being slapped Alexander was meso.
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.

20. 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)

21. 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…”

22. 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

23. End of Lecture 30 Nov. 15, 2010
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J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0