Results from symmetric and non-symmetric energy sharing (e, 2e ...
Are mirror images identical symmetric)chemistry.creighton.edu/~mhulce/ORGANIC/321... · Molecules...
Transcript of Are mirror images identical symmetric)chemistry.creighton.edu/~mhulce/ORGANIC/321... · Molecules...
Are mirror images identical
(symmetric),
or different
(asymmetric)?
Left hand mirror Right hand the left and right hands are
nonsuperimposable
A molecular case: the amino acid alanine
Symmetric or asymmetric?
Molecules with the same constitution that differ only by the relative positions of their atoms in space:
1 stereoisomers!
Molecular stereoisomers that are nonsuperimposable mirror images are called
1 enantiomers
• An enantiomer possesses the property of molecular chirality.
Enantiomers
• Usually have 4 different functional groups bonded to an sp3-hybridized atom. That atom isreferred to as a
1 Stereogenic center1 Stereocenter1 Chiral center
• Have identical physical properites save for one: they cause exactly opposite rotations ofplane-polarized light and so are said to exhibit optical activity.
1 A clockwise rotation is
° (+) ° dextrorotatory ° d
1 A counterclockwise rotation is
° (-) ° levorotatory ° l
Light: electromagnetic radiation
Electric field
Electric wave
MagneticMagnetic wave field
Oscillating orthogonal electric and magnetic fields of a beam of light
Plane-polarized light and its consequences
1st polarizing 2nd polarizingfilter filter
observer sees maximum light
source plane- polarized light
observer sees no light
plane- polarized light
Polarimeter: An instrument to measure optical activity
[ α ]ECD = 100 α
cl
% e.e. = *[(+)-enantiomer] - [(-)-enantiomer]* x 100 [(+)-enantiomer] + [(-)-enantiomer]
% e.e. = α x 100 [ α ]EC
D
Defining a physical constant: Specific rotation
" = the observed rotation of plane-polarized light in degreesc = the concentration in g / 100mLl = the pathlength (always 1 dm)
Enantiomeric purity (% e.e.):
Note: a 50 : 50 mixture of enantiomers has no ". It appears to be achiral. Such mixtures are called racemates.
SO WHAT?
Is molecular chiralty important?
Consider:• Gloves• Smells• Drug-receptor interactions
Different stereoisomers like enantiomers interact with one another in different ways!
Stereochemical theory of odor
H
O
H
O
H H
(S)-(+)-CARVONE (R)-(-)-CARVONE
smells like caraway seeds smells like spearmint gum
(R)-(+)-LIMONENE (S)-(-)-LIMONENE
smells like citrus fruit smells like turpentine
Some drugs that exist as enantiomers and why this matters
(-)-ibuprofen (+)-ibuprofen [α]D
25 = - 20.6E (c 1.00, ethanol) [α]D25 = + 58.5E (c 2.00, ethanol)
Advil, Motrin
OTC for arthritis, fever; general anti-inflammatory analgesic
(+)-enantiomer is the active isomer
(-)-enantiomer is inactive
the enzyme 2-arylpropionyl-CoA epimerase converts (-)-enantiomerto the (+)-enantiomer
(Zhao, X.; Eur. J. Med. Chem. 2006, 41, 1352-1358; Piccolo, O.; J. Org. Chem. 1985, 50, 3945-3946.)
O
OH
O
OH
Some drugs that exist as enantiomers and why this matters
(-)-thalidomide (+)-thalidomide [α]D
25 = - 64.6E (DMF) [α]D25 = + 64E (DMF)
teratogen antiemetic
enantiomers are interconvertable (undergo racemization) in vivo
racemate is immunomodulator used to treat
erythema nodosum leprosum
(in combination with dexamethasone) newly diagnosed multiple myeloma
actinic prurigo
(Ellis, G.P.; West, G.B. Progress in Medicinal Chemistry, Elsevier: New York, 198, p 170)
N
O
H
O
N
O
O
N
O
H
O
N
O
O
Some drugs that exist as enantiomers and why this matters
(-)-ketamine (+)-ketamine [α]D
25 = - 91.88E (c 2.00, H2O) [α]D25 = + 92.48E (c 2.00, H2O)
analgesic racemate used to induce general anesthesia
(+)-enantiomer (Ketanest S) is more potent
(-)-enantiomer is more hallucinogenic: may cause nightmares
(Marrietta, M. P.; Way, W.L.; Castagnoli, N. Jr.; Trevor, A.J. J. Pharmacol. Exp. Ther. 1977, 202, 157-165.)
N
Cl
O
HN
Cl
O
H
N
H
N
H
(+)-methamphetamine(-)-methamphetamine
The Alan Baxter story
2002 Salt Lake City Winter Olympics bronze medalist in downhill skiing (slalom)
failed IOC routine drug test: + for methamphetamine
source of + : Vicks nasal spray
U.S. version contains the legal enantiomer of methamphetamine:
(decongestant) (crank)
IOC test did not differentiate between enantiomers
Baxter cleared, but lost his medal – now IOC explicitly bans both enantiomers
2006 Turin Winter Olympics Baxter finishes 16th
The R,S system of naming chiral centers:
• Use the Cahn-Ingold-Prelog “Priority Rules”
1. Rank the priorities of the 4 atoms attached to the chiral center, according toatomic number.
2. If 2 or more atoms attached are identical, rank the atoms attached to those atoms, two bonds away from the chiral center. Priority of the entire substituent isdetermined by the first point of difference. The highest priority substituent isassigned a 1, the next, 2, then 3, and the lowest, 4.
3. Position the molecule so that your line of sight is from the chiral center, directlyback to the priority 4 substituent.
4. If priority groups 1, 2, and 3 are arranged clockwise in descending rank, the chiralcenter is assigned the stereodesignator
R
4. If priority groups 1, 2, and 3 are arranged counterclockwise in descending rank,the chiral center is assigned the stereodesignator
S
C X
Y
Z
C X
X C
Y
Z
For comparison purposes, identical atoms must be compared in the same hybridization state:
• The “Phantom atom” Rules
1. For naming purposes, a π bonded atom is considered to replicated by a phantomσ bond to a phantom atom.
2. Rule 1 is applied to both atoms of the π bond.
3. Rules 1 and 2 apply to each π bond of multiply bonded atoms.
4. All other things being equal, phantom atoms rank below real atoms of the sameatomic number.
Cl
H
An example:
Is this an R or an S molecule?
So, it is R.
Cl
HC
CCl
H
H
H H
CC
CCl
H
H H
C HH
C
Cl
H
1
4
1
4
3
2
What ways are there to draw enantiomers?
1. Hatched and wedged line projections (most popular)
are these these enantiomers, or just different hatched and wedged line projections of the same molecule?
2. Sawhorse projections could be used, too:
CH3H
H
CH3
H
H H
H
O
H
O
H H
Remember carvone and limonene?
Do these have R or S configurations?
What ways are there to draw enantiomers?
3. Newman projections
Are these anti-staggered and gauche staggered conformations of the same molecule?
CH3
CH2CH3
H
H H
CH2CH3
H
CH2CH3
CH3
CH3CH2 H
H
CH3
CCH2
H3CBr
H
1
2
3
4
CH3
C
CH2
CH3
Br H
What ways are there to draw enantiomers?
4. Fisher projections
\
a. Orient your point of view so that your body lines up with the parent chain of the molecule andyour line of sight bisects the bond angle formed by the remaining two substituents of the chiralcenter.
b. Draw the molecule as it appears to youusing wedged and hatched lines:
c. The Fisher convention replaces wedged and hatched lines with regular ones.
• The vertical lines of a chiral center are always pointing away from you
• The horizontal lines of a chiral center are always pointing towards you
Two of these Fisher projections of different conformations of the same configuration. Which two?
CH3
CH2CH3
Br H
CH2CH3
CH2CH2CH2CH3
HOHCH2CH3
H
OHCH3CH2CH2CH2
CH2CH3
CH2CH2CH2CH3
OHH
Draw (R)-2,3-dimethylheptane as a wedged and hatched line structure and as a Fisher projection:
A molecule with 2 chiral centers and 4 stereoisomers
2,3-dihydroxybutanoic acid, also called tartaric acid:
• Draw all four R,S isomers of this molecule
O
OH
OH
OH
* *
CH3
O
OH
OHH
OHH
H3C
O
OH
OHH
OHH
CH3
O
OH
HOH
OHH
H3C
O
OH
HOH
OHH
CH3
H OH
H OH
CO2H
CH3
HOH
HOH
CO2H
CH3
H OH
OH H
CO2H
CH3
HOH
OHH
CO2H
(2R,3R) (2S,3S)
(2R,3S) (2S,3R)
enantiomers
enantiomers
diastereomers
A molecule with 2 chiral centers and 4 stereoisomers
OH
OH
CH3
CH3OHH
OHH
H3C
H3C OHH
OHH
CH3
CH3HOH
OHH
H3C
H3C HOH
OHH
CH3
H OH
H OH
CH3
CH3
HOH
HOH
CH3
CH3
H OH
OH H
CH3
CH3
HOH
OHH
CH3
(2S,3R) = meso (2R,3S) = meso
(2S,3S) (2R,3R)
the same
enantiomers
diastereomersdiastereomers
A molecule with 2 chiral centers and 3 stereisomers: one isomer is a meso isomer
Consider with 2 chiral centers and (not counting conformational isomers)
22 = 4 possible stereoisomers, but there are only 3!
O
O
OH
OH
Cl
O
Cl
OHHO
OH
Cl
O
O
OH
OH
OH
O
OHHO
OH
OH
OH
sucralose (Splenda™)400-800 times as sweet as sugar
sucrose
How many chiral centers does Splenda have? nine
What is the theoretical maximum number of stereoisomers can this sugar substitute have?
2n , where n = number of stereogenic groups: 29 = 512
O
O
OH
OH
Cl
O
Cl
OHHO
OH
Cl
Are the configurations of Splenda’s indicated chiral centers R or S?
O
O
OH
OH
Cl
O
Cl
OHHO
OH
Cl
Cl
HC
CO
C
H
OH
CC
OC
O
C
CO
OCl
R
1
2
3
4
3
2
4
1
R