chiral center
no chiral center
CSUMB
ESSP 311 Organic Chemistry I
Ronald W. Rinehart, Ph.D.
Chapter 7 Stereochemistry
Chapter 7: Stereochemistry
I. General Terms
A. Stereoisomers: Isomers having the same constitution but
differ in the spatial arrangement of their atoms.
B. Objects which are nonsuperimposable upon their mirror image are
CHIRAL. (Left hand vs right hand).
1. Objects which are superimposable on their mirror
image are identical. A molecule with a plane of
symmetry or center of symmetry is superimposable
on its mirror image and ACHIRAL. 2. Example of a
molecule with a plane of symmetry: CHCl(CH3)2
3. Example of a molecule with a center of
symmetry: C4H4Cl2Br2
C. Stereogenic (Chiral) Center
1. A tetrahedral carbon atom with four different substituents has a stereogenic (or chiral) center.
a) Example: CHClCH3OH
2. Ring carbons can be chiral:
|
|
|
|
chiral center |
no chiral center |
3. With only 1 chiral center: a molecule is
always chiral (it has a nonsuperimposable mirror image.)
4. With 2 or more chiral centers: a molecule may or
may not be chiral.
(Meso compounds: not chiral).
5. A molecule can be chiral without a chiral center.
a) Two examples of this are allenes and
spiranes:
|
Allenes: |
Spiranes: |
|
|
|
D. ENANTIOMERS.
1. Mirror image, nonsuperimposable isomers are referred to as enantiomers.
|
|
|
2. Enantiomers are identical to each other with respect
to:
a) IR spectroscopy
b) NMR
c) Many Physical Properties: melting
point, boiling point, density, refractive index, solubility
3. Enantiomers are not necessarily identical in
chemical behavior (especially in biological systems due in
part to how enzymes work) AND are
opposite in OPTICAL ACTIVITY.
II. Analyzing Stereoisomers
A. Fischer Projections
1. Fischer projections are two-dimensional
representations of three-dimensional compounds.
a) They are made by drawing 2 crossing
lines at right angles.
b) The intersection of the two lines
represents a carbon atom.
c) The groups on the horizontal line
are coming out of the plane of the paper towards you.
d) The groups on the vertical line
are going away from you.
e) Below are 3 Fischer projections, two of
which are identical and the last representing a different
compound. Convince
Yourself: Make Models........
|
|
f) Fischer projections are a great
help in thinking in 3-D when models are not available.
` It is definitely worth the
investment of time and energy in learning this tool.
B. Using Fischer Projections.
1. Often times it is necessary or helpful to analyze a
compound by drawing the Fischer projection and
then manipulating the drawing so that you
can look at the compound from different points of view.
a) Some manipulations are allowed and
others are not allowed.
b) This type of analysis is helpful in
determining if two compounds are identical or stereoisomers.
2. You may turn the projection 180o.
Turning the projection 180o results in a projection of the exact
same substance.
|
|
3. 90o turns are not allowed
when you are trying to look at the Fischer projection of a specific compound
in a different way.
a) In drawing the structure after a 90o
turn, you have actually drawn the formula for the
enantiomer if the original projection was one of a chiral
compound.
4. You may hold any 1 group steady and rotate the other three:
|
|
5. Practice Problems.
a) Analyze compounds A, B, and C. Which are
identical? Which are enantiomers?
|
|
b) How are the following pairs of compounds (represented by the Fischer Projections) related?
|
|
|
|
|
|
|
|
III. Optical Activity
A. Review of Electromagnetic Radiation
1. "Side-view" of light: wavelike properties,
perpendicular oscillating electric and magnetic fields
with crests, troughs, nodes
2. "Straight-on view" of light: normal light can have
crest/trough plane in any direction;
polarized light has single plane in which
electrical “vibrations” can occur.
B. The Polarimeter.
1. Components.
|
|
2. Specific Rotation
|
|
3. Practice Problem. 6.0 grams of (-)-2-butanol was
dissolved in a solvent to produce 40 mL of solution.
This solution was placed into a 200 mm
polarimeter tube. The observed rotation was 4.05 degrees
counterclockwise at 25oC.
a) Calculate the specific rotation for this compound.
b) From this information can you tell
which enantiomer was analyzed? The "right hand" version or
the left hand (R or S?
See next section!)
IV. The Cahn-Ingold-Prelog R-S Notational System
A. Rules.
1. Identify the chiral center and the attached
substituents. Rank the substuents in order of their
precedence (atomic numbers, etc: see
text.) highest = 1, lowest = 4
2. Point the lowest ranking substituent away
from you.
a) Note whether the "order number" of
the three highest substituents increases clockwise
(the R isomer) or counterclockwise (S).
b) Or with Fischer projections, perform the
allowed moves and place the lowest priority group at the
top (or bottom) of the projection,
then determine the direction of rotation for the other three groups.
i) Again, clockwise rotation
corres ponds to the R isomer, counterclockwise to S.
|
|
B. Practice Problems.
1. Assign the absolute configuration (R or S) for each
of the following:
|
|
|
|
|
|
|
|
2. Draw the following molecules:
a) (S)-2-chlorobutane
b) (S)-3-methylhexane
c) (R)-alanine, CH3CH(NH2)CO2H
C. Relative Configuration
1. Prior to 1951, while it was known that chiral
molecules existed as enantiomers, it was unknown
which form was responsible for positive and
negative optical rotations. a) One could
know, however, relative configuration:
|
|
|
|
Compound I: (+)-3-buten-2-ol |
Compound II: (+)-2-butanol |
i) Since the chiral center for
compounds I and II is unchanged in this reaction, both I and II
have the same
RELATIVE configuration.
ii) At this point we do not
know if the configuration is R or S.
iii) It took x-ray
crystallography in 1951 to finally give us this information.
b) A case in point: In the 1890's Emil
Fischer knew that two forms of glyceraldehyde existed:
(+) and (-).
i) He had no idea which
structure corresponded to (+) or (-) so he guessed!
ii) (He had a 50:50 chance of
being correct.) It turned out that he guessed correctly, which is
nice since 50 years worth
of drawings of stereoisomers in various journals, etc (based
on his guessed assignment of structures) would have been wrong!
|
|
|
|
D-(+)-glyceraldehyde |
L-(-)-glyceraldehyde |
|
Fischer guesses this structure is the dextrorotatory one |
|
|
D- refers to the –OH group at C-2 being on the |
L- refers to the –OH group at C-2 being on the |
|
(+) means the compound is dextrorotatory |
(-) means the compound is levorotatory |
|
In
the old days, the symbols d- and l- were used to
indicate dextro- and levorotatory compounds, |
|
V. Compounds with Two Chiral Centers.
A. Enantiomers.
1. Like our previous examples, compounds with two
chiral centers can exist as enantiomers.
2. Examples:
|
|
B. Diastereomers.
1. Compounds I and II above are mirror image,
nonsuperimposable isomers (enantiomers). 2. What is
the relationship between compounds I & III; I & IV; II & III;
and II & IV?
a) While they are stereoisomers, they are
NOT mirror images (and therefore not enantiomers.)
b) They are diastereomers.
C. Meso Compounds.
1. A meso compound is a compound with two
or more chiral centers, but its mirror image is identical to
itself.
2. How to recognize a compound as meso: the
top half of a molecule mirrors its bottom half in a Fischer
projection. [look for a plane of molecular
symmetry in other representations]
D. Practice Problems.
1. For structures I through IV below,
define the relationships between the following given pairs
(identical/meso, enantiomers, diastereomers,
not stereoisomers.)
|
|
a) I and II are:
b) III and IV are:
c) I and III are:
d) II and IV are:
e) I and IV are:
2. State the relationship between the
following two structures:
|
|
3. Draw structures for the following:
a) (2R, 3S)-2,3-dibromobutane.
b) (2R, 3R)-2,3-dibromobutane.
c) (1R, 2S)-1,2-dichlorocyclopropane.
4. Assign the absolute configurations for the two chiral centers of structures II and III of problem 1 above.
II: III:
VI. Reactions That Produce Stereogenic (Chiral) Centers.
A. General Principle.
1. Optically active products cannot be formed from
optically inactive substrates and reagents since either
a) both enantiomers form at the same rate
or
b) meso compounds form.
B. Production of 1 Chiral Center.
1. Example.
|
|
|
|
Optically inactive substrate/reagents |
Optically inactive product: Racemic mixture |
a) Explain why (on a mechanistic level) the
product is a mixture of both R and S isomers.
Answer. The reaction goes through the bromonium ion. Actually, two different
bromonium ions can
form depending on how the Br2 initially encounters the alkene:
|
|
When the water molecule attacks the more
substituted carbon on the bromonium ions I and II,
both R and S isomers of the
product are formed. (I yields the S isomer.)
2. If a chiral substrate is optically active, the
product may or may not be optically active, depending
upon the reaction and/or reaction
conditions.
a) Reaction of (R)-2-butanol and
HCl: Formation of a racemic mixture.
i) The product mixture is
optically inactive.
|
|
|
(R)-2-butanol à (R S)-2- chlorobutane |
ii) In the above reaction
paths are equivalent (due to the planar nature of the carbocation).
iii) The resulting product is
optically inactive: a racemic mixture.
b) Reaction of (R)-2-butanol and SOCl2: Formation of an optically active product.
|
|
|
(S)-2-butanol à (R)-2-chlorobutane |
i) Since only the R
isomer is created, the product is optically active.
ii) Notice that the starting
material was optically active.
iii) Since the chiral center
has changed from S to R in going from reactant to
product, we say
that an inversion of
configuration has occurred. To see why, review the mechanism for
this reaction in the
chapter 4 outline.
C. Production of 2 Chiral Centers.
1. This principle is also true for reactions resulting
in two or more chiral centers.
2. The reaction of cis-2-butene:
|
|
a) Product from path a: (2S,3S)-2,3-dibromobutane.
b) Product from path b: (2R,3R)-2,3-dibromobutane.
c) Paths a and b are equivalent: A
racemic mixture is produced.
3. The reaction of trans-2-butene:
|
|
a) Product from path a: (2S,3R)-2,3-dibromobutane.
A meso compound.
b) Product from path b: (2R,3S)-2,3-dibromobutane.
A meso compound.
c) Both products above are identical.
VII. The Resolution of Racemic Mixtures
A. Difficulties in the Separation of Enantiomers
1. Enantiomers are difficult to separate since their
physical and chemical properties are for the most part
identical.
2. Pasteur was able to separate the R and S isomers of
tartaric acid with tweezers and a microscope due to
the difference in structures of their
respective isomers.
a) Pasteur actually separated the (+)
isomers of sodium ammonium tartrate, which exist as left- and
right-handed crystals.
b) This type of difference is extremely
rare and therefore not a general method of separation.
c) Gerald L. Geison, a science historian
at Princeton University, said "Pasteur was doubly Lucky" not
only because few compounds consist of
enantiomers which form crystals which are different, but
also because the temperature of the
air in Pasteur's lab that day just happened to be the right
temperature for the final step in the
precipitation of the crystals.
i) Pasteur's
discovery led to the birth of stereochemistry.
ii) He reasoned
that the mirror-image relationship between the crystals must be a
consequence of mirror-image shapes of the corresponding molecules, but nothing
was known about the structures of molecules at that time (1848).
d) Jacobus Hendricus van't Hoff (1st Nobel
Prize for Chemistry, 1901) and Joseph Achille Le Bel in the
late 19th century independently
reasoned that asymmetric compounds could be formed from carbon
atoms bonded to four different
groups.
3. Currently research is focussing on methods of
synthesis which produce a single optical isomer.
a) This saves on starting materials and in
costly and/or time-consuming separation methods.
4. Many pharmaceutical drugs on the market are actually
racemic mixtures where one form is the desired
drug and the other form is either inert or
biologically active in a different way.
a) It is probable that racemic drugs will
not be allowed in the near future.
B. The Separation of (+) Amino Acids.
1. Racemic mixtures of amino acids can sometimes
be separated by adding the racemic mixture with a
mixture of yeast and sugar and allowing the
mixture to ferment.
2. The enzymes in the yeast cells are very specific in
their action and will consume only the naturally
occuring form of the amino acid, leaving
the other isomer to be collected.
3. A problem with this method is that the
naturally-occuring isomer is destroyed.
C. Using Acid-Base Properties in Resolution.
1. A common method in the separation of a racemic
mixture is to convert the enantiomers into
diastereomeric compounds.
2. This is accomplished by the reaction of the mixture
with a chiral reagent
(known as the resolving agent.)
a) Most commonly the racemic mixture is a
carboxylic acid and the chiral reagent an amine (or a
racemic mixture of an amine
and a chiral carboxylic acid.)
b) Reaction between the two form
diasteromers of the corresponding salt.
3. Diastereomers are different in their chemical
and physical properties and can therefore be
separated by chemical or physical means.
4. The following is a general scheme of separation:
a) Acid-Base reaction between racemic
acid ("C" for carboxylic acid) and basic chiral amine ("A").
(+)C + (+)A à (+)C/(+)A + (-)C/(+)A
racemic acid + chiral amine à
diastereomeric salts
b) After separation of the diastereomers,
treatment with acid or base to reform the enantiomers
(+)C and
(-)C:
(+)C/(+)A + HCl à (+)C + (+)AH+ Cl−
(−)C/(+)A + HCl à (−)C + (+)AH+ Cl−
5. An example of this process is illustrated in the attempted resolution of (+)-lactic acid using ethylamine.
|
|
What is the relationship of these two salts?
ENANTIOMERS: a racemic ammonium salt; NOT separable.
6. Here is the same example but using (R)-1-phenylethylamine as the resolving agent.
a) In this first step the two
diastereomeric salts are formed.
i) The two salts can be
separated by some technique such as fractional crystallization.
|
|
b) Once the diastereomeric salts are
separated, they are each individually treated with mineral acid
(such as HCl).
i) This results in the
isolation of the two pure enantiomers of lactic acid and the recovery of the
resolving agent (as
its hydrochloride salt).
VIII. Stereoregular Polymers
A. Review of Polymers
1. Polymers are large compounds which consist of
monomeric units connected together.
2. The simplest polymer is polyethylene.
3. Compounds such as DNA, proteins, starches, and
cellulose are polymers.
4. The examples below will consider polypropylene.
B. Types of Stereochemical Arrangements in Polypropylene
1. Isotactic.
a) In this stereochemical arrangement, all
of the methyl groups are oriented on the same side of the
polymer chain.
|
|
2. Syndiotactic.
a) In this case the methyl groups alternate from one side to the other with respect to the polymer chain.
|
|
b) Both the isotactic and syndiotactic arrangements are known as stereoregular polymers.
c) Use of Ziegler-Natta types of catalysts results in the synthesis of either types of polymers.
3. Atactic.
a) In this type of arrangement the methyl groups are randomly arranged along the polymer chain.
b) Atactic polypropylene forms from free-radical synthetic methods.
c) Due to the irregular structure of this form, polymer chains of this type do not pack efficiently.
i) This minimizes van der Waals attractions which exist between the polymer chains.
ii) This results in lower melting points and lower densities than are observed in stereoregular chains.
IX. Stereogenic Centers Other Than Carbon
A. Silicon
1. Silicon is a Group IVA element.
2. When bonded to four different groups, Si is chiral.
a) Several organosilicon compounds have
been resolved into their enantiomers.
B. Nitrogen
1. Nitrogen is a Group VA element and forms a
trigonal pyramidal molecule when it bonds to
three different groups.
2. The lone pair can be considered as a
fourth group in amines.
3. Enantiomeric molecules are possible in principle,
but rapid inversion even at room temperature results
in racemization. However, if the
nitrogen is at a bridgehead position in a small bicyclic system, this
inversion may not be possible, and
enantiomers can be observed. Look at the structures of brucine
and strychnine, both of which
have been used as resolving agents.
|
|
B. Phosphorus
1. Phosphorus is also a Group VA element.
2. Phosphorus bonded to three different groups (phosphines)
can be optically active.
a) This is because inversion is slow in
comparison to amines.
b) Ea for the inversion of
amines is on the order of 24-40 kJ/mol, as opposed to an
Ea of 120-140 kJ/mol
for phosphines.
C. Sulfur
1. Tricoordinate sulfur compounds are chiral when
sulfur bears three different groups.
2. An example of a compound of this type is (S)-(+)-butyl
methyl sulfoxide.
|
|
3. In using the Cahn-Ingold-Prelog rules for
establishing absolute configuration, the lone pair is given the
lowest priority.
X. Enantiomeric Drugs
A. Importance of Chirality: Through the Looking Glass
"Perhaps looking-glass milk isn't good to
drink," says Alice to her kitten.
1. Just as Alice could not read the backwards-written
"Jabberwocky" poem without a mirror, nor would
she have been able to digest the
enantiomeric proteins and sugars in the looking-glass milk.
a) The enzymes responsible for the
digestion of foods and the catalysis of other biochemical reactions
are protein molecules with
asymmetric shapes.
b) For example, enzymes which are
responsible for the breakdown of D-glucose in glycolysis would
not be able to act on L-glucose.
c) Cell-surface receptors are also
handed.
2. Drugs which exist in enantiomeric forms are each
different with respect to their biochemical action in
the body.
3. Drugs such as antibiotics produced by fermentation
processes consist of a single enantiomer since the
metabolic processes of microorganisms are
based on chiral enzymes.
a) Chiral drugs made synthetically without
the use of enantiomeric reagents or catalysts result in a
racemic mixture.
4. Because human enzymes and cell surface receptors are
chiral, the following may be observed for the
two enantiomers of a racemic drug:
a) They may be absorbed, activated, or
degraded at different rates.
b) They may have equivalent pharmacological
activity.
c) They may have unequal pharmacological
activity.
d) One may be active and the other inactive
or toxic.
i) One enantiomer of ethambutol
is used to treat tuberculosis; the other causes blindness.
ii) One enantiomer of naproxen
is used to treat arthritis; the other causes liver poisoning.
iii) The R form of
thalidomide was a sedative used to treat morning sickness in pregnant women;
the S form is
believed to have been responsible for birth defects.
e) They may have different kinds of
activity.
i) One enantiomer of limonene
smells like lemons, the other like oranges.
ii) (S)-(+)-ketoprofen
is an analgesic and anti-inflamatory; (R)-(-)-ketoprofen shows activity
against bone loss in periodontal disease (one company hopes to put it in a
toothpaste).
f) In the case of ibuprofen the undesired
(R)-isomer is converted by the body into the active
(S)-(+)-ibuprofen.
5. Research is currently focusing on the synthesis of single enatiomers.
a) Sometimes naturally-occuring enzymes are
used to catalyze the synthesis since enzymes are so
specific in their action, as in the
synthesis of vitamin C and aspartame (using bacterial enzymes).
i) The use of
naturally-occuring enzymes has limitations, among them is that not all target
molecules have natural
enzymes available for their production.
b) Synthetic catalysts sometimes hold
advantages over enzymes:
i) They are often more sturdy.
ii) They can catalyze
reactions not known to occur in nature.
iii) The chiral catalyst may be
modified to produce the other enantiomer.
iv) Once the reaction is
complete, products can be easier to isolate.
6. A new drug, nafarelin, may be effective in the
treatment of endometriosis.
a) It was synthesized by the replacement
of the amino acid residue glycine with the enantiomer of the
naturally-occuring (L)-alanine.
7. Some drug proteins have short half-lives in the body since enzymes degrade the drug.
a) Drug manufacturers are experimenting
with the replacement of specific amino acids in the
molecule's weak points with
sturdier enantiomers.
i) The degradation enzymes will
not bind to the mirror-image amino acid, thus preventing the
breakdown of the
drug at that location of the molecule.
8. The use of single enantiomer pesticides may have several advantages.
a) Single enantiomer pesticides are more
potent than the racemates.
i) This will allow farmers to
apply less pesticide into the fields.
ii) It has been been estimated
that in some cases the use of the single enantiomer pesticide would
require only 1/4 as
much pesticide as the racemate.
b) Richard Schmitt of the EPA's Office of
Pesticide Programs says "Frequently, the enantiomer that is
removed is not active against
the target pest but may be active against fish, mammals, or people. It is
definitely an advantage to have
less of those chemicals out there in the environment."
9. Single enantiomers may also find application outside
of biological systems.
a) Since a molecule's handedness affects
light and electric fields, single enantiomers may lead to new
materials for optical and
optoelectronic technologies.
B. Structures of Some Enantiomeric Compounds
|
Estrone |
3-chloro-1,2-propanediol |
||
|
|
|
|
|
|
(+) estrogenic hormone |
(-) inactive |
(R) toxic |
(S) antifertility activity |
|
contergan |
barbiturate drug |
||
|
|
|
|
|
|
(S) extreme teratogen |
(R) not teratogen |
(R) sedative/hypnotic |
(S) causes cramps |
|
benzo[a]pyrene metabolite |
glucose |
||
|
|
|
|
|
|
(+) extreme carcinogen |
(-) allegedly not carcinogenic |
major calorie source |
starve to death on this |
Many thanks to Rod Oka of
MPC for generously sharing his "Lecture Companion" outline,
reproduced here
in extensively modified form by permission, with
web references and other goodies added by me.
Structures drawn using ACDLabs ChemSketch™, CS ChemOffice ChemDraw™, and
MDL IsisDraw™ .
Polarimeter diagram drawn with MS Excel™, my favorite program. Specific rotation
equation done with MDL IsisDraw™ .
