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Stereochemistry
This is study of the 3 dimensional arrangement in space of molecules.
HO2C H H H
trans isomer cis isomer
The cis isomer (maleic acid) is toxic, whereas the trans isomer (fumaric
acid) is an essential metabolite for plants and animals.
Chirality
Chirality means handedness.
Achiral objects have mirror images that are identical to the object.
H H H H Cl H H Cl
Cl Cl Cl Cl H Cl Cl H
cis isomer is achiral trans isomer is chiral
CH3 CH3
H H
H3CH2C Br Br CH2CH3
A A
B B
D C C D
Such a carbon is called a chiral carbon atom (asymmetric carbon atom or
stereocenter), and is usually denoted with an asterix (*).
H H
Cl Cl
(Note that the absence of a mirror plane does not imply chirality).
The (R) and (S) assignments are designated via the Cahn-Ingold-Prelog
Convention.
I > S > O > N > 13C > 12C > Li > 3H (T) > 2H (D) > H
(b) In the case of the same atoms being bound directly to the chiral carbon,
we go to the next atoms along the chain.
-CH2Br > -CHCl2 > -C(CH3)3 > -CH(CH3)CH2F > -CH(CH3)2 > -CH2CH3
(c) Double and triple bonds are treated as if each bond were to a separate
atom. (Imagine that each bond is broken and that the atoms at both ends
were duplicated).
1
1
*C 2 C*
4 3 3 2
(R) enantiomer
1 1
2 * C*
C 2 3
3 4
(S) enantiomer
Example:
Consider the naturally occurring amino acid, alanine, and its enantiomer.
(1) (1)
NH2 NH2
(2) (2)
*C CO2H HO2C
C*
H CH3 H3C H
(4) (4)
(3) (3)
unnatural natural
alanine alanine
(1) (1)
NH2 NH2
C* C*
H3C CO2H HO2C CH3
(3) (2) (2) (3)
Optical Activity
Enantiomers have the same Boiling points
Melting points
Density.
Almost all their physical properties are identical, but one exception is their
effect on plane polarized light.
Note: There is no relationship between (R) and (S) and the direction of the
rotation of plane polarized light. (R) does not mean d and (+).
(R) and (S) are just names from the CIP convention. (+) and (-) are
experimentally observed physical properties.
Specific Rotation ()
Specific rotation of a compound is measured on an instrument called a
polarimeter.
[] = obs / c.l
Rotation depends on the temperature and the wavelength of the light used.
Standard conditions are at 25C and using the D line of the sodium
spectrum.
Nature (enzymes) is still the best chemist for enantiomerically pure products.
The receptor sites for sense of smell can distinguish between enantiomers
since:
CH3 CH3
O O
H3C H H CH3
CH2 H2C
(+)-carvone (-)-carvone
caraway seed spearmint
Absolute Configuration
The absolute configuration of a molecule is the detailed stereochemical
picture including how the atoms are arranged in space.
Any reaction that uses optically inactive reactants and catalysts cannot
produce a mixture that is optically active. Any chiral products formed will
be formed as a racemate.
This is demonstrated by the hydrogenation of 2-butanone:
H
CH3CH2
CH3 O-H
(R)-2 butanol
H H equal
CH3CH2 amounts
C O (racemate)
CH3
H H (S)-2 butanol
CH3 O-H
CH3CH2
H
There is no energy difference for the attack from the top or bottom face, and
there is no energy difference in the (R) or (S) products.
Therefore although chiral products are produced, the products are formed in
equal amounts a racemic mixture.
The optical purity is defined as the ratio of the observed optical rotation of
the mixture to the rotation of a pure enantiomer. It is usually expressed as a
percentage.
Example: (+) 2-butanol has a +13.50 specific rotation. A bottle on the shelf
contains 2-butanol, which gives a specific rotation of +9.54.
If the ring was flat and planar, then an internal plane of symmetry would
exist, and this molecule would therefore be achiral.
H H
Br Br
But the ring is not planar, it is puckered into a chair conformation, with one
Br axial, and one equatorial.
H H
Br Br
H H
Br Br
Conformational Enantiomerism
Certain molecules are so bulky or strained that they cannot easily convert
from one chiral conformation to its mirror image conformation (the opposite
of cis-1,2-dibromocyclohexane).
Molecules can become locked or stuck in one conformation which cannot
equilibrate.
(S) (R)
Br Br
Br Br
X
I I
I I
This is more common for strained ring systems and /or bulky substituents.
Allenes
This is a class of compounds that contain a C=C=C bonding unit.
Figure 5-18
H H
C C C
H H
The middle C is sp, and the outer two Cs are sp2 hybridized.
The two contiguous bonds must lie perpendicular to each other for p
orbital overlap thus the ends of an allene are perpendicular.
H CH3 H3C H
C C C C C C
H3C H H CH3
Enantiomers
Fischer projections
We have already seen 3 dimensional representations using wedges,
Sawhorse and Newman projections.
These become less convenient for molecules with many chiral carbon atoms,
and we typically use Fischer Projections.
Fischer Projections
A A A
D
B
= B C = B C
C
D
D
View
Fischer projections are drawn with a cross, with the chiral atom at the center
of the cross.
The horizontal lines represent wedges (bonds) coming out of the plane of
paper.
The vertical lines represent dashed lines (bonds) going into the plane of the
paper.
(Bow-tie convention).
Fischer projections that differ by a 180 rotation are the same enantiomer,
since the vertical lines are still back, and the horizontal lines are still
forward.
CO2H CH3
CH3 CO2H
H OH HO H
(R) (R)
View View
CO2H H
CH3 OH
H OH H3C CO2H
(R) (S)
View View
CO2H CO2H H H
H OH = H OH 90o H3C CO2H = H3C CO2H
H3C OH
CH3 OH
Fischer projections have another rule which helps with the above laws:
The carbon chain is drawn along the vertical line of the projection, with the
most highly oxidized carbon substituent at the top.
(R)-1,2-propanediol
CO2H CO2H
H OH HO H
CH3 CH3
(R) lactic acid (S) lactic acid
Examples:
CH2OH CH2OH CH3
H OH HO H 180o H OH
CH3 CH3 CH2OH
CH3
H OH
CH3
Either translate the Fischer projection into wedges, shading and sticks, and
proceed as previously.
(Normally we rotate the molecule to view down the lowest priority bond,
and then draw the highest to lowest priority arrow, and clockwise = R).
(2) (2)
CHO
CHO
H OH (1)
HO CH2OH
(1) CH2OH
(3) (3)
Diastereomers
Stereoisomers are molecules that have atoms bonded together in the same
order, but differ in how the molecules are directed in space.
Enantiomers are mirror image isomers. All other stereoisomers are called
diastereomers.
H CH3 H H
trans cis
Seen these before. They are not mirror images of each other not
enantiomers.
(3)
CH3
H Br (1) = (S) configuration at C-2
(2)
H Cl
CH3
Enantiomers Enantiomers
We can also say (2S, 3R) is a diastereomer of (2S, 3S) and (2R, 3R), and
(2S, 3S) is a diastereomer of (2S, 3R) and (2R, 3S).
Meso Compounds
Previously we saw all the permutations (4) for a molecule with two chiral
centers.
This follows a general rule that n chiral centers give rise to 2n stereoisomers.
This gives the maximum possible number of stereoisomers that can exist
but often if the molecule is highly symmetrical, some of these stereoisomers
are actually the same compound.
Since diastereomers have different physical properties, they are often easy to
separate by normal practical techniques (distillation, recrystallization,
chromatography, etc).
In a lab it is different.
O H2, Pt H OH HO H
H3C CH2CH3
H3C CH2CH3 H3C CH2CH3
2-butanone (R)-2-butanol (S)-2-butanol
Enantiomers have the same physical properties, but they differ in a chiral (or
handedness) sense, so a chiral (or handed) probe must be used for such a
separation.
The resolving agent is then cleaved off, leaving pure separated enantiomers.
Example: Resolution of 2-butanol.
CO2H
H OH (R,R)-(+) tartaric
HO H acid
CO2H
H+
O CH2CH3 CH2CH3 O
O H H O
H OH CH3 CH3 H OH
HO H HO H
CO2H CO2H
(S)-2-butyl-(R,R)-tartrate (R)-2-butyl-(R,R)-tartrate
H+ H+
CH2CH3 CH2CH3
HO H H OH
CH3 CH3
(S)-2-butanol (R)-2-butanol
CO2H CO2H
H OH H OH
HO H HO H
CO2H CO2H
Acid hydrolysis cleaves each ester back to an optically active alcohol and
carboxylic acid.
Stereochemistry of Reactions
This is the study of what happens when chiral compounds react. Studies with
chiral compounds can reveal a vast amount of information about a reaction
mechanism.
H3C O CH3
_
H O S CH3 HO H
H O
CH3CH2 O CH2CH3
(R)-2-butyltosylate (S)-2-butanol
-O3S CH3
Racemization
Many reactions will display neither clean (total) inversion or clean retention
of configuration. Such reactions are called racemizations.
If all optical activity is lost it is a complete racemization, if some optical
activity remains, it is a partial racemization.
CH3CH2
CH(CH3)2
H3C O-CH2CH3
Br CH3CH2
(R) H3C CH(CH3)2
- + (S)
-Br -H
Inversion
CH3CH2 top
+
H3C C CH(CH3)2
H-O-CH2CH3
(planar) bottom
H3C
-H+ CH(CH3)2
CH3CH2
O-CH2CH3
(R)
Retention
The carbocation is planar, and therefore achiral. The attack of the
nucleophile from the top and bottom faces are equally preferred a
racemate is produced.
Retention of Configuration
This is the least common type of reaction. When a product maintains the
same configuration as the reactant, it proceeds with retention of
configuration.
CH3CH2
H Cl
OH
H3C S O
Cl
-HCl
Cl
CH3CH2 Slow CH3CH2 Cl
H S O H +
O _ S O
H3C H3C O
Fast
CH3CH2
H Cl +SO2
H3C
Retention
The product is not racemized since the slow C-O bond breaking and fast Cl
attack do not allow the cation to achieve a planar (achiral) arrangement.
Reactions that do not Involve the Chiral Atom
Typically, if bonds directly to the chiral atom are not broken or formed
during the reaction, the configuration will remain unchanged.
CH3CH2 _ H CH3CH2 H
-I
- H
H O H I H O
H3C H H3C H
(S)-2-butoxide (S)-2-methoxyethane
The four bonds to the chiral C atom are unchanged, and the configuration is
the same.
Asymmetric Induction
This is the use of an optically active reagent or catalyst to convert an achiral
reactant into a chiral product.
Similar results can be achieved in the lab using chiral catalysts or reagents
(which are usually expensive).
H H2, Pt OH H H H
O
CH3 H CH3 OH CH3
minor major
The two faces of attack are not the same since the methyl group sterically
hinders one face.
The chiral carbon atom communicates its chirality to the new center.