Transcript Document

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:
right
z
clockwise
Changing
Time
Fixed
atTime
Fixed
Position
The instantaneous electric field
vectors of right- and leftcircularly polarized light beams
propagating along z.
counterz clockwise
left
 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

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 contrarotating electric vectors will change with position
and cause rotation of the plane of polarization.
 
l L
(n  n R )

“earlier” angles
further on
at a
certain
point

same instant
at a further
point, ER
having
moved
faster
(less time
for rotation)

right
left
For an animation see
Google Images
(Google ‘circularly polarized light’ and open the
www.enzim.hu site).
SUM(higher n) to the
 Light waves move more slowly
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
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.
  n
transition at ~ 290 nm
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
C
O
C
O
*
C
O
C
O
C
O
x
z
y
mix
n
*  n
rotation of charge
(interacts weakly with light’s
magnetic field, m)
dXZ
n
dXZ  n
linear displacement
of charge
(interacts with light’s
electric field m)
mixed by chiral
environment
 + dXZ)  n
helical motion
of charge
(simultaneous interaction 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
2mo lN
2
 
Im n m j  j m n 

2
2
3
 jn  
jn
electric magnetic
sum over all excited states
mixing
mixing
Might we be able
guess
reliably
which
excited states, j,
Noto
one
excited
state
dominates.
dominate the sum,
and athus
to understand
optical
rotation?
To get
steady
value Wiberg
had
sum >1500
excitations!
No, because thetoformula
involves
products between
almost-mutually-exclusive properties.

J. Phys. Chem. A, 2008, 112, 2415-2422
a mathematical
thatneed
avoids
the summation has allowed
HowSince
many 1997
excited
states does one trick
actually
to consider?
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).
When the mterm is large, the m term is small, and vice versa.
Forget intuitive understanding!
Because all products are small, contributions can be
relatively important even when neither individual term is
large,
orofthe
factor
with s
(frequencies)
Calculated specific
rotation
twisted
2,3-hexadiene
as a function
of the numberisofsmall.
excited states considered.
Racemization (R)
(RS)
CH3
O
HO
planar
achiral!
(R)-Lactic Acid
CH3
C
(S)-Lactic Acid
OH
CH3
CH3
HOMO
HO
HO
H
H :B
CH3
HO
O
COOH
COO
H
easy
C
H
HO
*
COOH
LUMO
OH
harder
(occasional)
CH3
O
HO
C
OH
dianion
very rare
Epimerization (R,R)
COOH
COOH
H
HO
OH
H
COOH
(R,R)-Tartaric Acid
(R,S)

H
OH
H
OH
COOH
meso-Tartaric Acid
Change at One Center of Two (or many)
Racemization
Resolution (R)
+
(S)
1) Pasteur “Conglomerate”
Chiral-Resolved Seeding
Chiral-Resolved Poison
(RS)
Lengthening Rate
Depends on Width
Metastable
(in  solution)
“Critical”
Nucleus
Crystal
at
Equilibrium
Average
Average
Crystal
Interior
Molecules
more
stable
than
in
solution
molecule
molecule
in Equilibrium with
Surface
Molecules less stable thanless
in solution
more
stable
stable
Saturated Solution
Average Molecule same asthan
solution
than in solution
in solution
Resolution
cont.
(R)
+
(S)
(RS)
1) Pasteur Conglomerate
Chiral-Resolved Seeding
Chiral-Resolved Poison
Influence nucleation
2) Temporary Diastereomers
Chromatography with Chiral-Resolved Support
Compound with Chiral-Resolved Mate
C 6 H5
C
C
C
C 6 H5
C10 H7
OCOCH2 COOH
van’t Hoff
Prediction
1874
Brucine
Kohler
Walker
Tishler
1935
“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
144-146°C
[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
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.
“Left-handed” reagent “slaps” H onto
the front face of the C=O group.
Wolfson, et al., Org. Commun. (2008)
H
CH2
^
Nature can
“The compound
The yeast may have oxidized the alcohol
we want to get.”
before
reducingand
the aldehyde,
and then
be
Subtle
Surprising
reduced the ketone back to the alcohol.
as in Levene’s preparation of (R)-Butane-1,3-diol
“I confuse
“What
did
I dosometimes.”
wrong?”
“It’llmyself
reduce
this.”
H O H catalyst
HO
O H
O
“What Levene did was to
CH
CH
CH32 C
3 3C C
reduce it with yeast & sugar.”
H
H
H
[add H2 to get optically active product!]
“enolate”
“A reaction that Prof. McBride will talk about
later on called the ‘aldol’ reaction…”
CH2
^
The yeast may have oxidized the alcohol
before reducing the aldehyde, and then
reduced the ketone back to the alcohol.
HO
CH3 C
H
or
HO
CH2 C
CH3 C CH C
CH3 C CH2
HO
O
H
H
H
H C
CH
C CH
(S)
3(R)
2
H
What happens Enantiospecific reduction
H
OH
O
HO
H
to the (S)?
of (R) by yeast/sugar
CH3 C CH2 C H
CH3 C CH2
H
H
H
O
O
O
C
H
OH
C H
H
End of Lecture 30
Nov. 15, 2010
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J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0