1. Stereochemistry
Chapter 6
Classic Terminology
•
Confusion arises regarding terms such as “optically active” and “chiral
center”.
•
“Optically Active”: ability of a collection of molecules to rotate polarized
light. At one time almost synonymous for chiral, but such use is
discouraged.
samples containing chiral molecules may not be optically active or may
not rotate plane polarized light to any measurable extent.
•
“Chiral Center/Chiral Carbon”: defined as an atom, or specifically
carbon, that has four different substituents/ligands attached to it.
“Chiral Carbon” also referred to asymmetric carbon.
Problem is that “asymmetric carbons” and “chiral centers/carbons” can
exist in molecules that are neither asymmetric nor chiral.
Moreover, molecules can exist in enantiomeric forms without having
“chiral centers”.

2. Modern Terminology
•
Much of the confusion that arises from classic terminology can be eliminated
with the introduction of the term “stereogenic center” (or “stereocenter”)
as an organizing principle in stereochemistry.
•
An atom or grouping of atoms is considered to be a stereogenic center if
the interchange of two substituents attached to it can produce a new
stereoisomer.
•
A non-stereogenic center is one in which the exchange of any pair of
substitutents does not produce a stereoismer.
•
•
Stereogenic center is a broader term than “chiral center”.
•
In dealing with chiral molecules that lack defined “chiral centers”, many have
adopted terms such as: “planar chirality” (such as biphenyl) and “axial
chirality” (such as allene). These molecules lack stereogenic centers, but
rather have stereogenic units. Terms have yet to be clearly defined.
Stereogenic unit: an atom or grouping of atoms such that interchange of a
pair of attached substituents produces a new stereoisomer. (broader
concept than stereogenic center)
Examples
•
•
Two prototypes of organic stereochemistry:
•
If we interchange substituents at C2 of 2-butanol, we obtain a Stereogenic
stereoisomer, the enantiomer.
Center
•
Consider molecules with more than one stereogenic
center... for example tartaric acid.
Molecule containing carbon with four different substituents,
WXYZ - such as 2-butanol.
•
Begin with meso-tartaric acid (contains internal mirror
plane), if we exchange two substituents at either C2 or C3
we obtain new stereoisomer: R, R or S, S.
•
While meso compounds are achiral, they contain stereogenic
centers.
•
CWXYZ center does not guarantee a chiral molecule, but
the group is always a stereogenic center.
•
Typically a compound with n stereogenic centers will have
stereoisomers and 2n-1 diastereomers.
2n
•
The 2n rule quickly creates complexity in molecules with
multiple stereogenic centers.
•
Epimers are stereoisomers that differ only in their
configuration at one stereocenter.
Interconverting two substituents
produces a new stereoisomer
H3C
H
OH
H3C
OH
H
H
H
CH3
H
H
CH3
(R)-2-Butanol
Stereogenic
Center
HO2C
H
HO
(S)-2-Butanol
Interconverting two substituents
produces a new stereoisomer
H
OH
CO2H
meso-Tartaric acid
HO2C
H
HO
OH
H
CO2H
(R,R)-Tartaric acid

3. R, S and Cahn-Ingold-Prelog System
w>x>y>z
•
•
For tetracoordinate carbon and
similar systems, the Cahn-IngoldPrelog system provides a
nomenclature that unambiguously
indicates the configuration of the
stereocenter.
Substituents on the atom are
ranked in order of priority.
•
C
(z)
OH
(w)
H
(z)
OH
HOH2C
(w)
(y)
(S)-Glyceraldehyde
CO2+H N
3
(x)
(y)
L-Glyceraldehyde
(x)
CHO
H
HOH2C
H
CH2OH
If priority of substituent groups
decreases going clockwise around
the stereocenter, then designate it
R.
•
HO
View stereocenter with lowest
priority group directed back…
into the page.
•
CHO
CHO
(z)
CO2-
(x)
CO2(x)
HC
H3C ! NH3+
C! H
CH3
(y)
(w)
H
(z)
NH3+
H3C
If counterclockwise, designated S.
L-Alanine
(w)
(y)
(S)-Alanine
Order of prioirity
functional grouips
common in
biomolecules
SH > OH > NH2 > COOH > CHO
> CH2OH > C6H5 > CH3 > 2H > 1H
Prochiral Center
Tetrahedral centers
•
•
CO2-
Two chemically identical substituents on a
tetrahedral carbon may be geometrically
distinct.
Two such atoms are referred to as being
prochiral.
•
Designated as pro-R or pro-S based
on same criteria as R and S.
•
Faces are designated as re face or si
face.
C! Hb
CH3
(pro-R) H
b
CO2-
H3C
Property of prochirality also applicable to
planar carbon centers.
•
Ha
Ha
Hb
CO2-
H3C
Ha
(pro-S)
Triganol planar centers
CH3
H
H3C
O
re face
H
O
si face

4. E, Z System and Olefins
Lower
Priority
•
•
Stereochemistry and olefins.
•
Divide double bond in half (lengthwise)
and compare the two halves.
•
•
•
Use the same priority rules as used in
Cahn-Ingold-Prelog.
Higher
Priority
O
Cl
H3C
H
CH3
Higher
Priority
Lower
Priority
If the two high priority groups are on the
same side of the double bond, then the
double bond is said to be Z (zusammen).
(Z)-3-chloromethyl-3-penten-2-one
If the two high priority groups are on
opposite sides... then the double bond is
E (entgenen)
O
Cl
H3C
H
H3C
If there is an H atom at each end of the
olefin, can also use traditional cis and trans
nomenclature.
(E)-3-chloromethyl-3-penten-2-one
Fischer Projections and Stereochemistry
R
H
HO
CHO
CH2OH
CHO
H
CHO
OH
•
•
•
•
•
D and L stereochemical assignments are older
nomenclature, used prevalently in the life sciences
S CHO
to refer to the stereochemistry of biomolecules.
HO
OH
CH2OH
D-Glyceraldehyde
D and L and Fischer Projections
•
H
HO
Configuration of groups around a carbon
CH2OH
H
stereocenter can be related to glyceraldehyde.
L-Glyceraldehyde
Designate:
(+) isomer -> D-glyceraldehyde.
(-) isomer -> L-glyceraldehyde.
All α-amino acids from proteins have the L
stereochemical configuration (glycine being achiral,
is an exception.).
CH2OH
CHOD-Glyceraldehyde
CHO
HO
H
H
OH
CH2OH
CH2OH
CHO
CHO
H
HO
CH2OH
H
CH2CHO
OH
CHO
HO
H
H
OH
L-Glyceraldehyde
CH2OH
L-Glyceraldehyde
CH2OH
D-Glyceraldehyde
CO2-
CHO
HO
H
+H N
3
H
CH2OH
R
Monosaccharide Stereoisomers!
Fischer Projections: way of drawing molecules in
which horizontal lines represent bonds coming out
of the plane of the page and vertical lines represent
bonds projecting behind the plane.
L-Glyceraldehyde
L-!-Am ino acid
Enantiomers
CHO
CHO
H
In carbohydrates with multiple sugars are centers,
HO
• The L stereogenic the mirror
L/D assigned based only on the configuration of the
H
images of their D isomer
H
tetrasubstituted C at the bottom, farthest from the
counterparts.!
D isomer
carbonyl group.
OH
HO
H
H
OH
HO
OH
HO
H
OH
H
H
CH2OH
CH2OH
D-Glucose
L-Glucose
Epimers
L isomer

5. Helical Descriptions - M and P
•
Many chiral molecules lack a conventional center that
can be described using R/S or E/Z.
•
These molecules can typically be viewed as helical (may
have propeller or screw shape).
•
A descriptor can be assigned based on the sense of the
twist of the molecule....
•
Sight down the axis of the “helix” and consider “near”
vs. “far” substituents.
•
Determine highest priority “near” group and highest
priority “far” group.
•
Sighting down the axis... if going from the highest
priority near group to the highest priority far group
involves a clockwise rotation, then we have a righthanded helix, designated P (plus).
•
Conversely, sighting down the axis... if going
from the highest priority near group to the
highest priority far group involves a
counterclockwise rotation, then we have a
left-handed helix, designated M (minus).
•
In case of molecules with more propeller-like
conformations, M/P most easily assigned
through use of a screw/bolt analogy.
Distinguishing Enantiomers
•
Enantiomers are distinguishable only
when placed in a chiral environment.
•
All methods to separate or
characterize enantiomers are based
on this principle.
•
Enantiomeric excess (EE
%) defined as:
EE% = 100% x (Xa-Xb)
Where Xa and Xb
correspond to the mole
fraction of enantiomer a
and b, respectively.

6. Symmetry and Stereochemistry
•
Stereochemistr y and symmetr y are
intimately connected.
•
•
Basic Symmetry Operations:
•
Two types of symmetry operation:
A symmetry operation is a transformation of
a system that leaves an object in an
indistinguishable position.
Proper Rotations (Cn): rotation around an
axis by (360/n)° that has the net affect of
leaving the object unchanged.
Proper
rotations are physically possible.
Improper Rotations (Sn): involve a rotation of
(360/n)° combined with reflection across a
mirror plane, perpendicular to the axis of
rotation. Improper rotations are not
physically possible.
•
•
S1 = a mirror plane.
C1 = identity operation.
Symmetry and Stereochemistry
•
Stereochemistr y and symmetr y are
intimately connected.
•
•
Basic Symmetry Operations:
•
Two types of symmetry operation:
A symmetry operation is a transformation of
a system that leaves an object in an
indistinguishable position.
Proper Rotations (Cn): rotation around an
axis by (360/n)° that has the net affect of
leaving the object unchanged.
Proper
rotations are physically possible.
Improper Rotations (Sn): involve a rotation of
(360/n)° combined with reflection across a
mirror plane, perpendicular to the axis of
rotation. Improper rotations are not
physically possible.
•
•
S1 = a mirror plane.
C1 = identity operation.

7. Chirality and Symmetry
•
•
For rigid molecules, a necessary and sufficient criterion for chirality is an absence of any Sn axes.
•
When a chiral molecule
is subjected to an
improper rotation, it is
converted to its
enantiomer.
•
Chiral molecules need
not be asymmetric - just
cannot have any
improper axes.
•
Chiral compounds can
have one or more proper
axes of rotation.
The presence of an Sn axis renders an object achiral (due to presence of internal mirror
plane).
Symmetry Arguments
•
Symmetry argument: a statement from first principles that depends only on
the symmetry of the system, not its exact nature.
•
Two important features must always be remembered:
The most compelling symmetry arguments are based on an absence of
symmetry.
If two objects cannot be interconverted by a symmetry operation, then they
are expected to be different, essentially in all ways.
•
Must be careful about using symmetry arguments to declare that two objects
are equivalent.... no law that molecules will adopt a conformation that results in
highest symmetry.
•
Symmetry arguments tell us nothing about magnitude.

8. Focusing on Carbon
•
•
Consider the desymmetrization of methane (CH4).
•
In CX3Y, we now have two different valence angles: X-C-Y and X-C-X. this
reduction in symmetry leads to dipole moment, molecular property not
present in CX4.
•
In CX2Y2, we now have three different valence bond angles: X-C-Y, X-C-X
and Y-C-Y.
•
These systems no longer correspond to regular tetrahedra.... still tend to
refer to them as being “tetrahedral”.
•
Full desymmetrization (CWXYZ) gives four bond lengths and six diostinct
valence bond angles... and chirality.
Things get more interesting when all four substituents on C are different
(CWXYZ).
Topicity Relationships
Convenient to describe relationships between
regions of molecules....

9. Topicity: Homotopic, Enantiotoptic and Diastereotopic
•
If two groups cannot be intereconverted by a symmetry operation, they are expected
to be different.
•
This principle is applicable not just to molecules in their entirety but is also applicable
to groups/regions within molecules.
•
When groups can be interconverted by means of a symmetry operation, then they are
chemically identical.
•
•
Yet, depending on the nature of the symmetry operation, they can act differently.
•
They can be either constitutionally heterotopic or stereoheterotopic.
When identical groups or atoms are in inequivalent environments, they are said to be
heterotopic.
Constitutionally heterotopic: connectivity of the groups or atoms is different in
the molecule.
•
-
Stereoheterotopic: groups or atoms have different stereochemical relationships in
the molecule.
Homotopic: groups/atoms are interconvertible through a Cn operation. CH2 in
propane is an example
Topicity: Homotopic, Enantiotoptic and Diastereotopic
•
Diastereotopic (special case of stereoheterotopic): absence
of a symmetry operation that results in two otherwise
i de n t i c al at om s/grou p s ( su c h as p rot on s) b e i n g
interconverted (the molecule that already contains at least
one defined stereogenic center).
•
Example: the protons on C3 of 2-butanol.
•
Enantiontopic (special case of stereoheterotopic):
two
atoms/groups that are equivalent based on a symmetry
element (mirror plane, S1), but this equivalence is destroyed
by the presence of a chiral influence. In the absence of a
chiral influence/element, the groups are equivalent.
•
Example: CH2 of ethyl chloride.
•
Topicity becomes important when dealing with trigonal
centers (such as carbonyls and alkenes). The faces of the
trigonal center can be enantiotopic or diastereotopic.
Ha Hb
R
HO H
Ha Hb
Cl
Equivalent unless
in a chiral
environment.

10. Topicity: Pro-R/Pro-S and Re/Si
•
Describing “tetrahedral” carbon atoms:
It is useful to be able to identify enantiotopic
hydrogens.
-
If replacement of an H with a D would result in
an R stereogenic center, then then it is denoted
as pro-R.
-
If replacement of an H with a D would result in
an S stereogenic center, then then it is denoted
as pro-S.
-
A carbon atom with enantiotopic hydrogens is
said to be a prochiral center.
•
-
Enantiotopic groups need not be H... thus pro-R/
S not limited to H’s.
Describing trigonal “planar” faces:
-
Re: if priority of substituents are in a clockwise
direction.
-
Si: if priority of substituents are in a
counterclockwise direction.
Chirotopicity
•
The terms enantiotopic and diastereotopic
describe the relationship between a pair of atoms
or groups within a molecule.
•
Can be useful to describe the local environment
of a single atom, group or location in a molecule.
•
Chirotopic: atom or point in a molecule that
resides in a chiral environment.
•
Achirotopic atom or point in a molecule does
not reside in a chiral environment.
•
Two examples:
-
Rotamers of meso-1,2-dibromoethane
Chiral acetal

11. Reaction Stereochemistry
•
In (R)-3-chloro-2-butanone, the two
faces of the carbonyl are diastereotopic,
and the carbonyl is expected to be
nonplanar.
•
In carbonyls where the two faces are
inequivalent, the carbonyl cannot be
planar (based on symmetry argument).
•
Cannot predict magnitude of deviation
from planarity.
Reaction Stereochemistry
•
Consider reactivity of three carbonyls:
-
Acetone: reaction with an achiral reagent such as LiAlH4
produces the same product regardless of which face is involved
with the reaction. The faces are homotopic.
-
2-butanone: the carbonly is enantiotopic and reaction with an
achiral reagent results in an enantiomeric product.
-
(R)-3-Chloro-2-butanone:
the faces of the carbonyl are
diastereotopic, and reaction with an achiral reagent yields a
diastereomeric product.
-
Symmetry properties of transition states cane be evaluated enantiotopic vs diastereotopic- impacts reaction kinetics.
•
•
•
What if a chiral reagent is used...
•
General rules:
1.
Homotopic groups cannot be differentiated by chiral reagents
2.
Enantiotopic groups can be differentiated by chiral reagents
3.
Diastereotopic groups are differentiated by achiral and chiral
reagents.
Acetone: reduction with chiral reagent yields a singly product.
2-butanone: expect enantiotopic faces of carbonyl to differentially
react with chiral reagent (chiral reducing agent).

12. Stereospecifc vs. Stereoselective Reactions
•
•
Describe the stereochemical outcomes of reactions.
-
To determine if a reaction is stereospecific look at the product ratios from
different stereoisomers.
-
In stereospecifc reactions, a common intermediate cannot be involved in the
reaction mechanism for the two stereoisomeric reactants.
•
Stereoselective reactions: a single reactant can give multiple stereoisomeric
products, favoring production of one or more of them.
•
Alternatively... can be stereoselective when two stereoisomers of the starting
material give the same stereoisomeric product ratio.
•
•
•
Diastereoselective... products are diastereomer... stereospecific reaction.
Stereospecific reaction: one stereoisomer of the reaction gives one stereoisomer
of the product, while a different stereoisomer gives a different stereoisomer
product.
Enantioselective.... preferentially forming one enantiomeric product over another.
Regioselecive: Site where a reaction could occur, and difference in the reactivity
of various sites in the molecule, when more than one site can react.
Symmetry and Time Scale
•
When considering the symmetry of any system, we must always
include a time scale.
•
Symmetry arguments and stereochemistry are much easier if
we treat all molecules as rigid geometric objects.
•
Real molecules are in motion and the motion is fast compared
to the observation time scale.
•
Must include motion in our consideration of stereochemistry.
•
•
When considering the CH3 of 2-butanol:
•
The methylene protons, under the same conditions, do not
interconvert.... thus are diasterotopic.
•
If temperature could be lowered to freeze rotation of CH3
group, then the 3 H atoms would each be unique. (reflected in
computational models)
•
At room temperature rapidly rotating... thus all 3 H atoms
interconvert...
Generally safe to three CH3 H’s as equivalent.
Ha Hb H H
H
HO H

13. Symmetry and Time Scale
•
•
Symmetry and time scale are tightly coupled.
•
Tri-substituted amine is classic example:
The pyrimidal form is chiral, but the two
enantiomers interconvert rapidly by
pyrimidal inversion.
•
•
Time scale is important for all stereochemical concepts.
Typically, if a molecule can adopt a reasonable conformation
that contains a symmetry element, then it behave as if it has
that symmetry element.
R2
R3 N R1
R3 N R
1
R2
Even stereogenic tetracoordinate carbon can undergo
inversion/exchange at high enough temperatures and long
enough time scales.
Symmetry and Time Scale
•
Many chiral molecules where enantiomeric forms can be
interconverted by rotation about a single bond.
•
If the rotation that interconverts a pair of enantiomers is slow
at ambient temperature (or at readily accessible and maintained
temperatures), then the enantiomers can be separated and
used.
•
Substituted binaphthol provides a classic
example. More sterically crowded variant on
biphenyl model of a chiral molecule that lacks a
“chiral center”.
OH
Atropisomers:
stereoisomers that can be
interconverted by rotation around single bonds,
and for which the barrier to ration around the
bond is so high that the stereoisomers do not
rapidly interconvert at RT and can be separated.
•
HO
•
trans-cyclooctene is another example...
hydrocarbon chain must loop over either
face of the double bond, with enantiomers
arising based on the position of the loop
relative to the double bond.
Binaphthol
trans-Cyclooctene

14. Symmetry and Time Scale
•
•
Facile rotation does not guarantee interconversion of conformational isomers.
Triarylborane: correlated rotation of the rings - the two-ring flip - is facile at RT, with
three different two-ring flips possible depending on which ring does the “non-flip”.
a
c
B
b
B
b
a
B
c
All two-ring flips are rapid, but in highly substituted systems, not all possible
conformations can interconvert.
As long as only two-ring flips can occur, we have two sets of rapidly interconverting
isomers, but no way to completely go from one set to another.
•
Situation is termed residual stereoisomerism. We have two separate stereoisomers, each
of which is a population of rapidly interconverting isomers.
Topological and Supramolecular Stereochemistry
•
Preparation and characterization of molecules with novel
topological features.
•
Supramolecular chemistry has produced a number of structures
with novel topologies such as catenanes and rotaxanes.
•
Mathematical definition of topology - concerns studies of the
features of geometrical objects that derive solely from their
connectivity patterns.
•
Metric issues, numerical values such as bond lengths and angles,
are unimportant in topology.
•
Consider two-dimensional topology as the study of geometric
figures that have been drawn on a rubber sheet.
You can stretch and bend and flex the sheet without changing the
topology of a figure drawn on the sheet.
Thus a circle, triangle and square are topologically equivalent.
All three are essentially just a closed loops.
•
Applicable to three-dimensional structures.... with additional
requirements:
-
Cannot break a line or allow lines to cross.
Cannot destroy a vertex.

15. Topological and Supramolecular Stereochemistry
•
With few exceptions, all stereoisomers are topologically
equivalent.
•
Distortions are possible with almost every molecule allowing the
stereoisomers to interconvert.
•
Consistent with definition of stereoisomers: molecules with the
same connectivities but different spatial arrangement of atoms.
•
There are stereoisomers that have different topologies...
•
Topology deals with graphs – objects that consist of edges and
vertices.
•
In considering molecular topologies, we are considering chemical
graphs in which edges are bonds and vertices are atoms.
Simplest systems that can produce topological stereoisomers?
•
Since they are not non-congruent mirror images, it is possible to
call them topological diastereomers.
•
•
•
Knots are relatively common in biochemistry.
•
Conventional stereoisomers referred to in terms of geometric or
Euclidian isomerism.
Just need a cyclic structure.
Molecular realizations of the circle and trefoil knowt would be
examples of topological stereoisomers.
Topological stereoisomers vs. conventional diastereomers:
Topological isomers (circle & trefoil knot models) cannot be
interconverted without breaking or crossing any bonds, but
conventional stereoisomers can be interconverted by distorting
stereocenter(s) of the molecule without breaking or crossing any
bonds.
Enantiomorphous Trefoil Knots
•
•
•
Topological Stereoisomers
Loops and Knots

16. Topological Chirality
•
•
Is there topological chirality?
•
No general rule for proving that a knot is chiral. Can
be proved to be achiral simply by finding a way to
draw the knot such that it is itself achiral.
•
Failure to find an achiral presentation is not sufficient
to determine a knot to be chiral.
Enantiomorphous Trefoil Knots
Trefoil knots provide a simple example of topological
chirality.... enantiomorphs.
Nonplanar Graphs
•
We can draw a two-dimentional representation
for the overwhelming majority of organic
molecules, with no bonds crossing each other.
•
Such two-dimensional presentations are known
as planar graphs.
•
If you cannot represent the connectivity of a
system without crossing some lines, you have a
nonplanar graph.
•
Graph theory dictates that all nonplanar graphs
will conform to one of two prototypes:
•
•
K5 = simply five vertices, maximally connected
K3,3 = contains two sets of three vertices, with
every vertex of one set connected to every
vertex of the other set.
K5
K3,3

17. Achievements in Topological and
Supramolecular Stereochemistry
•
Recent efforts have produced chemical structures that
successfully realize many interesting and novel topologies,
including the synthesis of a trefoil knot using Sauvage’s Cu+/
phenanthroline templating strategy.
•
Another seminal advance in the field was the synthesis and
characterization of a “Möbius strip” molecule. A Möbius
strip can be thought of as a closed ribbon with a twist.
•
First Möbius strip molecule generated in 1980’s based on
tetrahydroxyethylene ethers. Ring closure results in mixture
of products (w/and w/out twist).
•
•
Structure without the twist represents K3,3 topology.
•
Other types of isomerism that really don’t fit any preexisting categories are perhaps best regarded as
supramolecular stereoisomerism.
Facile synthesis of complex catenanes and rotaxanes using
preorganization strategies has led to the consideration of a
number of novel stereochemical situations.
Achievements in Topological and
Supramolecular Stereochemistry
•
Rotaxanes and catenanes can often exist in
different forms that are stereoisomers, but
with some unique properties.
•
The provided rotaxane exists in two
forms, in which the macrocycle can be
electrochemically driven from one position
to the other.
•
A catenane in which one of the rings
contains two different building blocks can
exist in two forms, differing in the
orientation of the rings.
•
Similar supramolecular stereoisomerism
arises in “container compounds” when the
container has two distinguishable poles...
an unsymmetric guest orient in isomeric
positions.
•
Represent stereoisomers – structures
with the same connectivities but differing
arrangements of the atoms in space.
•
They are not enantiomers, and therefore
must be diastereomers that interconvert
by the translation/reorientation of one
component relative to the other.

18. Achievements in Topological and
Supramolecular Stereochemistry
a [3] catenane comprised of two distinct ring
types. diastereomers arise based on the position of
the “odd” ring. [topological diastereomers]
More subtle topological
isomerism can arise in a [2]
catenane in which the two
rings have directionality.
Sauvage, et al. generated
such a [2] catenane by using
of Cu+/phenanthroline
templating.
Even more subtle
topological isomerism can
arise in a [2] catenane in
which one of the two rings
has directionality.
The two enantiomers
can interconvert
through rotation of the
1,5-dihydroxy naphthyl
group and translating
the other macrocycle.
Stereochemical Issues in Polymer Chemistry
•
Many unnatural polymers of considerable commercial
importance have one stereocenter per monomer (such
as polypropylene and polystyrene).
•
These unnatural systems usually start with a simple
achiral monomer, with the stereogenic centers being
generated during polymerization.
•
•
Often, no control over the chiral sense of the polymer.
Isotactic
Polymer stereochemistry is denoted by tacticity:
-
Isotactic: same configuration at all stereocenters.
Syndiotactic: alternating stereocenter configuration.
Atactic: random mixture of stereocenter
configurations.
•
Control over polymer stereochemistry is a major
research area in both academic and industrial
laboratories.
•
Polymers with different stereochemistries often have
very different properties.
•
Another stereochemical issue is helicity... some
polymers can adopt helical conformations.
Syndiotactic
Atactic

19. Stereochemical Issues in Chemical Biology
•
•
Molecular shape is a crucial concept in chemical biology.
•
Proteins: polymers built through concatenation of α-amino acid monomers with defined
stereochemistries, and peptide bond formation does not result in formation of new
stereogenic centers. Therefore, polymerization of amino acids does not require special
stereochemical control in the bond forming reaction. Proteins and peptides are isotactic.
Despite the apparent diversity and complexity of biomacromolecules, biopolymers are built up
from fairly simple monomers and connecting units.
Amino acid chirality plays a major role in defining the structural and chemical properties of
proteins. Conformation preferences of proteins reflect amino acid stereochemistry.
•
Nucleic Acids: the only stereogenic centers of DNA and RNA are found in the sugar carbons,
with the ribose and deoxyribose being enantiomerically pure. Thus nucleic acids are isotactic.
While the connecting phosphate groups are not stereogenic centers, the two O- groups on
them are diastereotopic.
•
Polysaccharides: The linkages formed between saccaride monomers result in stereogenic
centers. Thus stereochemical control of the polymerization/oligomerization process is
essential.
The anomeric carbon is the site of the stereogenic center. Defined as being α or β based on
orientation of the -OH or glycosidic bond. Stereochemsitry of glycosidic bond has a dramatic
impact on the structural, mechanical and chemical properties of the oligo or
polysaccharide. .... example α-1,4 vs β-1,4
Helicity
•
Helicity is most often associated with polymers,
especially biopolymers.
•
All helicities are chiral, defined by the
handedness of the helix, with right-handed and
left-handed helices being topologically
RNCO
equivalent.
•
•
R O
R O
N
NaCN
DMF, -58°C
N
N
R O
•
•
Isotactic synthetic polymers are similar to
biopolymers in that all the stereocenters are
homochiral.
Synthetic isotactic polymers usually do not
exhibit the strong helical biases associated with
biopolymers.... but in some cases substantial
helical biases can be observed in synthetic
polymers.
H
NaCN
N C
D
DMF, -58°C
O
NCO
D
H
N C
D
NaCN
DMF, -58°C
N
N
R O
O
NCO
R
N
In structural biology, helices are associated with
proteins, DNA and some polysaccharides.
While in simple, prototype helices the right- and
left-handed conformations are enantiomeric, in H
enantiomerically pure isotactic systems the two D
are diastereomeric, with clear thermodynamic
preferences for one conformation over the
other.
O
H
R

20. Helicity
•
A series of polyisocyanates represent
remarkable examples of helical synthetic
polymers.
•
The polyisocyanate backbone contains
contiguous amide groupings reminiscent of RNCO
those of peptides and proteins.
•
•
•
•
Steric clashes between carbonyl O’s and the Rgroups on N in the isocyanate backbone
preclude a planar geometry.
A helical bias is introduced by incorporating
D
defined stereogenic centers in the side chains
(R).
Making the side-chain sterogenic simply through
isotopic substitution results in a large helical
bias.
It has been estimated that the bias for one
helical handedness over the other induced by
the isotopic substitution is on the order of 1
cal/mol/subunit - very small. Thus the large
observed bias reflects cooperativity. (once a
small bias is established it propagates)
O
R O
R O
N
NaCN
DMF, -58°C
N
N
R O
R
N
N
N
R O
R
O
H
NCO
H
NaCN
N C
D
DMF, -58°C
O
NCO
D
H
N C
D
NaCN
H
DMF, -58°C
Sergeants and soldiers principle: the initial chiral
influence is the sergeant that alines all the
soldiers.