chem 125 lecture 29 11/12/08 this material is for the exclusive use of chem 125 students at yale and...
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Chem 125 Lecture 2911/12/08
This material is for the exclusive use of Chem 125 students at Yale and
may not be copied or distributed further.
It is not readily understood without reference to notes or the wiki from the lecture.
Pasteur's"Bargain-Basement"Moldy Racemic Acidfrom 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 ReactionsHave Different Rates
React Racemate withResolved Chiral Reagentor Catalyst (e.g. Enzyme)
Nature's WayPrepare only one Enantiomer
Use resolved starting material
Or resolved reagent/catalyst
Eisai - 7389Purchase 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 alkylation1 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?
COOH
COOH
H
OH
HO
H
COOH
COOH
OH
H
H
HO
COOH
COOH
H
OH
HO
H
COOH
COOH
OH
H
H
HO ?
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 (1824-1907)
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 (1791-1867)
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 www.enzim.hu site).
From P.W. Atkins, Physical Chemistry (OUP)
)( RL nnl
−=λπθΔ
θΔ
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!€
R j ← n( ) = Im n μ j • j m n( ) .
)( RL nnl
−=λπθΔ
€
Δθ =2μolN
3h
ω2
ω jn2 −ω2
Im n μ j • j m n( )j≠n
∑ πc/λ
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.
n←∗π transition at ~ 290 nm
linear displacement of charge(electric)
helical motionof charge
(both)
n
π*
n
π* n transition is magnetic dipole-allowed, electric dipole-forbidden. Electric dipole character is induced by mixing of the oxygen dYZ orbital into
the π orbital:
€
R π ∗+ λ dYZ( ) ← n( ) = Im n μZ π ∗+ λ dYZ( ) π ∗+ λ dYZ( ) mZ n( )
This generates a ZmZ component (from .m) of the rotational strength:
C O
C O
C O
C O
C OC O
rotation of charge(magnetic)
π* n dXZ n π + dXZ) n
x
z
y
Quantum-Chemical Calculations
€
Δθ =2μolN
3h
ω2
ω jn2 −ω2
Im n μ j • j m n( )j≠n
∑
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 Chiralityto Life on Mars:
Lord Kelvin’s LegacyDavies Auditorium
Becton Center5:00 PM Today
Who Cares?Living Things
Food & Drug Administration
Drug Companiestheir Lawyers & USPTO (Patent Office)
"Chiral Switch"
Pain Reliever
COOH
Isobutyl
PropionicAcidPhenyl
Ibuprofen (Advil, Motrin)
(S) Active Pain Reliever
(R) Inactive
Sold as racemate
Sedative
Thalidomide
(S) Sedative
(R) Teratogen
Sold as racemate (1957-62)
N
N
OOO
O
H
(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"
omeprazole1
2
34
5
6 12
34
5
67
8
9
BenzimidazolePyridine
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 OB 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. 1989 fromX-ray of Ohishi et al. 1989
(S)-Omeprazole - Stereopair View
left eye right eye
(S)-Omeprazole - Stereopair View
from X-ray ofOhishi et al. 1989
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 29Nov. 12, 2008