Stereochemistry

Atactic Polypropylene

random stereochemistry of methyl groups attached

to main chain (stereorandom)
properties not very useful for fibers etc.
formed by free-radical polymerization
 Isotactic Polypropylene

stereoregular polymer; all methyl groups on

same side of main chain
prepared by coordination polymerization under Ziegler-
Natta conditions
 Syndiotactic Polypropylene

stereoregular polymer; methyl groups alternate

side-to-side on main chain
prepared by coordination polymerization under
Ziegler-Natta conditions
Reactions involving stereoisomers:
(a) the conversion of an achiral molecule into a chiral
molecule, with the generation of a chiral center.
n-butane + Cl2, hv  sec-butyl chloride + etc.
achiral chiral
*
CH3CH2CHClCH3

CH3 CH3
H Cl Cl H
C2H5 C2H5

(S)-(+)-sec-butyl chloride (R)-(-)-sec-butyl chloride

product is optically inactive  racemic modification

(b) reaction of a chiral molecule where bonds to the chiral
center are not broken.

* *
CH3CH2CHClCH3 + Cl2, hv  CH3CH2CHClCH2Cl
+ etc.
A reaction that does not involve the breaking of a bond to a
chiral center, proceeds with retention of configuration about
the chiral center.
If a compound can be synthesized by such a reaction from a
compound of known configuration, then the configuration is
known in the product.
 * *
CH3CH2CHCH2OH + HCl CH3CH2CHCH2Cl + H2O
CH3 CH3

It is known from X-ray crystallography that (-)-2-methyl-1-butanol is the (S)-isomer.

When pure (-)-2-methyl-1-butanol is reacted with HCl, the product is dextrorotatory.
Since no bonds to the chiral center were broken in the reaction, the (+)-1-chloro-2-methyl
butane is now known to be the (S)-isomer.

CH3 CH3
H CH2OH + HCl H CH2-Cl
C2H5 C2H5
(c) reactions like (b) in which a second chiral center is
generated:
* * *
CH3CH2CHClCH3 + Cl2, hv  CH3CHClCHClCH3
+ isomers

CH3 CH3 CH3

H Cl H Cl H Cl
+
CH2 H Cl Cl H
CH3 CH3 CH3

(S)- (R,S)- (S,S)-

diastereomers in unequal amounts

(d) reactions of chiral compounds with optically active
reagents.
Enantiomers have the same physical properties and cannot
be separated by normal separation techniques like
distillation, etc.
Enantiomers differ in reaction with optically active reagents.
Enantiomeric acids or bases can be reacted with an optically
active base or acid to form salts that are diastereomers.
Since diastereomers have different physical properties
they can be separated by physical methods. The salts
can then be converted back into the free acids or bases.
Resolution – the separation of enantiomers.
(+)-HA + (-)-Base  [(-)-baseH+,(+)A-] +
(-)-HA [(-)-baseH+,(-)A-]
(enantiomers) (diastereomers, separable)

[(-)-baseH+,(+)-A-] + H+  (+)-HA + (-)-baseH+

[(-)-baseH+,(-)-A-] + H+  (-)-HA + (-)-baseH+

A racemic modification is converted by optically active

reagents into a mixture of diastereomers which can then be
separated. (resolved)
 Resolution of Enantiomers
Reaction Using Diastereomers to Separate Enantiomers
this nitrogen lone
pair is basic
Me
(R)--methylbenzylamine

this hydrogen H2 N O Me
O is acidic
Me
(S)-2-chloroproprionic acid Me O H3N
OH
Cl
Cl
The R,S-diastereomer of the salt
this nitrogen lone
pair is basic
Me
(R)--methylbenzylamine
this hydrogen O Me
is acidic H2N
O Me
O H3N
(R)-2-chloroproprionic acid Me
OH Cl

Cl The R,R-diastereomer of the salt

separate

O O Me
O Me
acidify
Me Me
Me
OH O H3N
O H3N
Cl Cl
Cl
(R)-2-chloroproprionic acid O
acidify
Me
OH

Cl (S)-2-chloroproprionic acid
 (e) a reaction of a chiral compound in which a bond to a
chiral center is broken.
In a reaction of a chiral compound in which a bond to a chiral
center is broken, the stereochemistry depends on the
mechanism of the reaction.

CH3 CH3
CH3CH2CHCH2-Cl + Cl2, hv CH3CH2CCH2-Cl + isomers
* *Cl

(S)-(+)-1-chloro-2-methylbutane racemic-1,2-dichloro-2-methylbutane
optically inactive mixture
Cl-Cl 2 Cl.

C2H5
CH3
CH2-Cl + Cl. .
CH3
+ HCl
C2H5 CH2-Cl
H

Cl-Cl

CH3
sp2 hybridized flat free radical
C2H5 CH2-Cl

CH3 Cl
C2H5 CH2-Cl + C2H5 CH2-Cl
Cl CH3
Problem:
“Altogether, the free radical chlorination of (S)-(-)-1-chloro-2-
methylbutane gave six fractions of formula C5H10Cl2. Four
fractions were found to be optically active, and two fractions
optically inactive. Draw structural formulas for the compounds
making up each fraction. Account in detail for optical activity or
inactivity in each case.”
 CH2Cl
H3C H Cl2, hv
C5H10Cl2 + HCl
CH2
CH3

(S)-(-)-1-chloro-2-methylbutane six fractions:

four optically active
two optically inactive
 CH2Cl CHCl2
H3C H Cl2, hv H3C H
CH2 CH2
CH3 CH3
A
No bonds to the chiral center
are broken, configuration is
retained. Product is optically
active
 CH2Cl CH2Cl CH2Cl
H3C H Cl2, hv H3C Cl Cl CH3
+
CH2 CH2 CH2
CH3 CH3 CH3
B
A bond is broken to the chiral center.
Stereochemistry depends on the
mechanism. Here, the intermediate
free radical is flat and a racemic
modification is formed. This fraction
is optically inactive.
 CH2Cl CH2Cl
H3C H Cl2, hv ClH2C C H
CH2 CH2
CH3 CH3
C
The product no longer has
a chiral center. It is achiral
and optically inactive.
 CH2Cl CH2Cl CH2Cl
H3C H Cl2, hv H3C H H3C H
+
CH2 H Cl Cl H
CH3 CH3 CH3

D E

No bond is broken to the chiral center

and a new chiral center is formed. The
products are diastereomers and each
fraction is optically active.
 CH2Cl CH2Cl
H3C H Cl2, hv H3C H
CH2 CH2
CH3 CH2Cl
F
No bonds to the chiral center
are broken, configuration is
retained. Product is optically
active
 CH2Cl
Cl2, hv CHCl2 CH2Cl CH2Cl
H3C H
H3C H H3C Cl Cl CH3
CH2
CH2 CH2 CH2
CH3
CH3 CH3 CH3
(S)-(-)-1-chloro-2-methylbutane
A B

CH2Cl CH2Cl CH2Cl

ClH2C C H H3C H H3C H
CH2 H Cl Cl H
CH3 CH3 CH3

C D E

CH2Cl
H3C H optically active
CH2 optically inactive
CH2Cl

F
 Reactions that Generate Chirality Centers
(Hydrogenation, syn)

CH3 CH3 H H
H2, Pt/C
CH3 CH3
CH2CH3 CH2CH3 CH2CH3 CH2CH3

CH2CH3 product is meso

H CH3
H CH3
CH2CH3
 Bromination
Trans is formed exclusively [No Meso is formed (cis)]

Br2

Br Br Br Br
R R S S
racemic mixture
Bromonium Ion is Opened Equally from Both Sides

Br2

-
+  Br Br Br Br
Br Br R R S S
racemic mixture

Br Br

Br Br
 trans alkene + anti addition = MESO

CH2CH3 H Br2 CH2CH3 Br

H
H
H CH2CH3 Br CH2CH3

CH2CH3 CH2CH3
H H
meso
Br Br
 cis Alkene + anti addition =
racemic mixture

Br
CH2CH3 CH2CH3
H H
a Br b
CH2CH3 Br Br CH2CH3
CH2CH3 CH2CH3 H H
Br2
CH2CH3 CH2CH3
H H Br H H Br
a b

CH2CH3 HCH CH H CH2CH3

H 2 3 CH CH
2 3 H
R R S S
Br Br Br Br
 Brominations often Generate Asymmetric Centers

CH3 CH3 Br2 CH3 CH3 CH3 CH3

H H H H
H H Br Br Br Br
S S R R
racemic mixture

CH3 CH3 Br CH3 CH3

H Br2 H
H H H
H CH3 Br CH3 Br Br
S R
meso
Asymmetric Center is Generated
Racemic Mixture Formed

Br
H-Br H
H

a) (R) Br b) (S)
a)
H Br
H

Br b)
 Enantiomeric Excess (Optical Purity)

observed rotation
rotation of pure enantiomer x 100 = enantiomeric excess (e.e.)
o
observed rotation = +109
109.0
e.e. = 123.0 x 100

= 88.6% e.e.
H H
88.6% (+)
(S)-(-) Limonene (R)(+) Limonene 11.4% racemic
o o
[=  [] = +123.0 actually 94.3% (+)
from lemons from oranges
 Calculate % Composition 30

The specific rotation of (S)-2-iodobutane is +15.90.

Determine the % composition of a mixture of (R)-
and (S)-2-iodobutane if the specific rotation of the
mixture is -3.18.
Sign is from the enantiomer in excess: levorotatory.

3.18
o.p. = X 100 = 20%
15.90

2l = 120% l = 60% d = 40%

 Asymmetric Induction

PPh2
RuCl2
PPh2

CH3 H CH3
H2
OH OH
Ru(BINAP)Cl2
96% e.e.

Noyori and Knowles shared Nobel Prize in Chemistry, 2001

 Preparation of (L)-Dopa
for Treatment of Parkinson’s

HO

HO NH2
C=C
H CO2H
H2
Rh(DIOP)Cl2

CO2H
HO CH2C enz. HO CH2CH2NH2
H
NH2
HO HO
l-(-) Dopa Dopamine
cannot cross blood-brain
barrier
 Stereospecific & stereoselective reaction

Stereospecific reaction: one stereoisomer of the reactant

gives one stereoisomer of the product, while a different
stereoisomer of the reactant gives a different stereoisomer of
product. Stereospecific reaction is a special, more restrictive
case of a stereoselective reaction.
Stereoselective reaction: one in which a single reactant can
give two or more stereoisomeric products, and one or more of
these products is preferred over the others-even if the
preference is very small.
Regioselective reaction: when more than one site reacts,
this reaction is one where an excess of one of the possible
products results.
stereospecific

stereoselective

stereoselective
 inversion

Br Ph
Ph Me anti elimination
H Ph
Syn addition H
Ph
-Ot-Bu

Br
Ph Me
anti elimination
Ph H
Ph Ph
H
-Ot-Bu

anti elimination
 Nu:
Rm Rm
Rm Rm OH OH
Rs Nu: Rs Rs
O Nu
Rs R O R
Rl Nu Rl R
Rl R
preferred
Rl major minor

Rl

R O
Rm Rs

Regioselective reaction

Markovnikov addition
Stereochemical Terminology

Absolute configuration. A designation of the position or order of arrangement of the ligands

of a stereogenic unit in reference to an agreed upon stereochemical standard.

Achiral Not chiral. A necessary and sufficient criterion for achirality in a rigid molecule is the
presence of any improper symmetry element (Sn including σ and ί).

A chirotopic. The opposite of chirotopic. See “ chirotopic” below.

Anomers. Diastereomers of glycosides or related cyclic forms of sugars that are specifically
epimers at the anomeric carbon (C1 of an aldose, or C2, C3, etc., of a ketose).

Anti. Modern usage is to describe relative configuration of two stereogenic centers along a
chain. The chain is drawn in zigazg form, and if two substituent s are on opposite sides of the
plane of the paper, they are designated anti. See also “syn”, “antiperiplanar”, and “
anticlinal”.

Anticlinal. A term describing a conformation about a single bond. In A-B-C-D, A and D are
anticlinal if the torsion angle between them is between 90 and 150 or -90 and -150. See Figure
2.7.

Antiperiplanar. A term describing a conformation about a single bond. In A-B-C-D, A and D

are antiperiplanar if the torsion angle between them is between +150° to -150° . See Figure
Apical, axial, basal, and equatorial. Terms associated with the bonds and positions
of ligands in trigonal bipyramidal structures.
Asymmetric. Lacking all symmetry elements (pointing group C1). All asymmetric
molecules are chiral.
Asymmetric carbon atom. Traditional term used to describe a carbon with four
different ligands attached. Not recommended in modern usage.
Atactic. A term describing the relative configuration along a polymer backbone. In
an atactic polymer, the stereochemistry is random-no particular pattern or bias is
seen.
Atropisomers. Stereoisomers ( can be either enantiomers or diastereomers) that can
be interconverted by rotation about single bonds and for which the barrier to rotation
is large enough that the stereoisomers can be separated and do not interconvert
readily at room temperature.
For example, the multi-substituted styrene species below can be resolved and is
CH3 Cl
optically stable in boiling butanol. CH 3

CO2H
H3C CH3
Br
Chiral. Existing in two forms that are related as non-congruent mirror images. A
necessary and sufficient criterion for chirality in a rigid molecule is the absence of any
improper symmetry elements.

Chiral center. Older term for a tetracoordinate carbon or similar atom with four
different substituents. More modern, and preferable, terminology is “stereogenic center”
(or “stereocenter”)
Chirotopic. The term used to denote that an atom, point, group, face, or line resides in a
chiral environment.

Cis. Describing the stereochemical relationship between two ligands that are on the same
side of a double bond or a ring system. For alkenes only, Z is preferred.

Configuration. The relative position or order of the arrangement of atoms in space that
characterizes a particular stereoisomer.

Conformers or conformational isomers. Stereoisomers that are interconverted by rapid

rotation about a single bond.

Constitutionally heterotopic. The same groups or atoms with different connectivities.

D and L. An older system for identifying enantiomers, relating all stereocenters to the sense of
chirality of D- or L-glyceraldehyde. Generally not used anymore, except for biological
structures such as amino acids and sugars.

Diastereomers. Stereoisomers that are not enantiomers.

Diastereomeric excess (de). In a reaction that produces two diastereomeric products in
amounts A and B, de = 100% (|A – B|) / (A + B).

Dissymmetric. Lacking improper symmetry operations. A synonym for “chiral”, but not the
same as “asymmetric” .

Eclipsed. A term describing a conformation about a single bond. In A-B-C-D, A and D are
eclipsed if the torsion angle between them is approximately 0°.

Enantiomers. Molecules that are related as non-congruent mirror images.

Enantiomeric excess (ee). In a reaction that produces two enantiomeric products in amounts
A and A´ , ee = 100% (|A – A´|) / (A + A´).

Epimerization. The interconversion of epimers.

Epimers. Diastereomers that have the opposite configuration at only one of two or more
stereogenic centers.

Erythro and threo. Descriptors used to distinguish between diastereomers of an acyclic

structure having two stereogenic centers. When placed in a Fischer projection using the
convention proper for carbohydrates, erythro has the higher priority groups on the same side of
the Fischer projection, and threo has them on opposite sides.

Exo. In a bicyclic system, a substituent that is on a bridge is exo if it points toward the smaller
of the two remaining bridges. See also “endo” .

E, Z. stereodescriptors for alkenes (see discussion in the text).

Gauche. A term describing a conformation about a single bond, In A-B-C-D, A and D are
gauche if the torsion angle between them is approximately 60°(or -60°). See section 2.3.1.

Geminal. Attached to the same atoms. The two chlorines of 1,1-dichloro-2,2-difluoroethane

are geminal. See also “vicinal”.

Helicity. The sense of chirality of a helical or screw shaped entity ; right (P) or left (M).
Heterochiral. Having an oppsite sense of chirality. For example, D-alanine and L-
leucine are heterochiral. See also “homochiral”.
Homochiral. Compounds that have the same sense of chirality at their individual
stereocenters are called “homochiral”.
• For example, the 20 natural amino acids are homochiral – they have the same
arrangement of amino, carboxylate, and side chain groups.
• For example, L-alanine and L-cysteine are homochiral, in spite of the former being
S and the latter R configuration. R-2-aminobutane and R-2-butanol are also
homochiral.
CHO CHO CO2H
H OH HO H H2N H
CH2OH CH2OH CH2OH

D-glyceraldehyde L-glyceraldehyde L-serine

CH2OH CHO
O OH
HO H HO H
H OH H OH CO2H CO2H
H OH HO H H2N H S H2N H
R
CH2OH CH2OH CH3 CH2SH

D-fructose L-Idose L-alanine L-cysteine

Isotactic. A term describing the relative configuration along a polymer backbone. In
an isotactic polymer, all stereogenic centers of the polymer backbone have the same
sense of chirality.

Meso. A term describing a achiral member of a collection of diastereomers that also

includes at least one chiral member.

Opitcally active. Rotating plane polarized light. Formerly used as a synonym for
“chiral”, but this is not reconmmended.
Racemic mixture or racemate. Comprised of a 50:50 mixture of enantiomers.

Relative configuration. This refers to the configuration of any stereogenic

center with respect to another stereogenic center. If one center in a molecule is
known as R, then other centers can be compared to it using the descriptors R*
or S*, indicating the same or opposite stereochemistry, respectively.

Resolution. The separation of a racemic mixture into its individual component

enantiomers.

Scalemic. A synonym for “non-racemic” or “enantiomerically enriched”. It has

not found general acceptance, but is used occasionally.

S-cis and s-trans. Descriptors for the conformation about a single bond, such
as the C2-C3 bond in 1,3-buadiene, or the C-N bond of an amide. If the
substituents are synperiplanar, they are termed s-cis (“s” for “single”); if they
are antiperiplanar, they are termed s-trans.
 Stereogenic center. An atom at which interchange of any two ligands produces a
new stereoiosmer. A synonym for “stereocenter”.
Stereogenic unit. An atom or grouping of atoms at which interchange of any two
ligands produces a new stereoisomer.
stereogenic stereogenic
HO center F center
F
HO Cl Cl
CO2H Cl P Cl P
H CO2H
NH2 H2 N Cl F
H F
swap swap Cl
two ligands two ligands

swap
stereogenic two ligands stereogenic
swap
centers
CH3 Cl center
OH2
two ligands CH3 H3C H2O Cl Cl Cl
H C C C Ru Ru
C C C H Cl H2O Cl
H3C H2O
H OH2
H OH2
Stereogenic
H3C CH3 H CH3 centers
swap HO CO2H HO
two ligands CO2H
H H
H H H3 C H
stereogenic H OH
centers HO2C swap HO2C
OH ligands H
S,S-tartaric acid meso-tartaric acid
Syn. Modern usage is to describe the relative configuration of two stereogenic centers along a
chain. The chain is drawn in zigzag form, and if two substituents are on the same side of the
plane of the paper, they are syn. See also “anti”, “synperiplanar”, and “synclinal”.

Synclinal. A term describing a configuration about a single bond. In A-B-C-D, A and D are
synclinal if the torsion angle between 30° and 90° (or -30° and -90°). See Figure 2.7.

Syndiotactic. A term describing the relative configuration along a polymer backbone. In a

syndiotactic polymer, the relative configuration of backbone stereogenic centers alternate
along the chain.

Synperiplanar. A term describing a conformation about a single bond. In A-B-C-D, A and D

aresynperiplanar if the torsion angle between them is between + 30° and –30°. See Figure 2.7.

Tacticity. A generic term describing the stereochemistry along a polymer backbone. See
“atactic”, “isotactic”, and “syndiotactic”.

Trans. A term describing the stereochemical relationship between two ligands that are on
opposite sides of a double or a ring system. For alkenes only. E is preferred.

Vicinal. Attatched to adjacent atoms. In 1,1-dichloro-2,2-difluoroethane, the relationship of

either chlorine to either fluorine is vicinal. See also “geminal”.
Anomers. Diastereomers of glycosides or related cyclic forms of sugars,
which are specifically epimers at the anomeric carbon (C1 of an aldose, or
C2, C3, etc of a ketose).
OH OH
O HO O OH
HO H
HO HO
HO HO
OH H

anomer -anomer
of glycose of glucose
Epimers. Diastereomers that have the opposite stereochemistry at only one
of two or more stereogenic centers.
OH H

H OH

exo-epimer endo-epimer

Endo: In a bicyclic system, a substituent that is on a bridge is endo if it

points toward the larger of the two remaining bridges.
Exo: In a bicyclic system, a substituent that is on a bridge is exo if it points
toward the smaller of the two remaining bridges.
Topicity: relates to the spacial position of an atom or group, in particular with
respect to the spacial position of two different hydrogen atoms, methyl
groups, or other identical pairs of atoms or groups in a molecule, or with
respect to the two faces of a -system.
Homotopic. The relationship between two regions of a molecule that are
related by a proper symmetry operation.
Enantiotopic. The relationship between two regions of a molecule that are
realated only by an improper symmetry operation, typically a mirror plane.
Diastereotopic. The relationship between two regions of a molecule that
have the same connectivity but are bit related by any kind of symmetry
operation.
Heterotopic. The same groups or atoms in inequivalent constitutional or
stereochemical environments.
Homotopic. change Ha H D
to D

Hb Ha
change Hb these are identical
to D
D H

change Ha H D
to D OH
Enantiotopic. Hb Ha
change Hb these are enantiomers
H3 C OH
to D
D H
OH

H D
change Ha CH3
H3C
to D
HO H

Hb Ha
CH3 change Hb these are diastereomers
Diastereotopic. H3C to D
HO H D H
CH3
H3C
HO H
Prochiral. A group is prochiral if it contains enantiotopic or diastereotopic
ligands or faces, such that replacement of one ligand or addition to one face
produces a stereocenter.
prochiral centre chiral centre
Ha Ha
 + Cl 
Hc COOH Cl COOH
-Hc
F F

Pro-R/Pro-S
To distinguish entantiotopic or diastereotopic groups from one another the
terms pro-S and pro-R are used.
The atoms and groups that are identically linked to the prochiral centre[s]
and replacement of one or other of them by another ligand produces a pair of
enantiomeric products. Cl

D
R Hb
Cl +D Ha and Hb are enantiotopic ligands
-Ha Br
Ha Hb Ha = Pro-R
Cl
-Hb Hb = Pro-S
Br +D S
Ha D

Br
Pro-R/Pro-S
The atoms and groups that are identically linked to the prochiral centre[s]
and replacement of one or other of them by another ligand produces a pair of
diastereotopic products.
COOH

D
S Hb

R H
HOOC
COOH Ha and Hb are diastereotopic ligands
+D COOH
Hb
-Ha
Ha Ha = Pro-R; Hb = Pro-S
COOH
HOOC H -Hb
+D R D
Ha
COOH
R H
Citric acid HOOC

COOH
Facial Topicity
Considering a -system, most typically a carbonyl system, which bears two
different substituents, such a system exhibits facial topicity.
Enantiotopic faces
When addition to opposite faces of an sp2 –hybridised atom (carbon)
produces enantiomers, the faces are called enantiotopic faces
R
-
R
OH
Pro-S-faces H3C
(Si face) H
+R- S-enantiomer
H H+
O
H3C H+ H3C OH
-
Pro-R-faces +R H
(Re face) R
-
R
R-enantiomer
Diastereotopic faces
When addition to opposite faces of an sp2 –hybridised atom (carbon)
produces enantiomers, the faces are called enantiotopic faces

O O O
SH
C2H5OH
O H O O
N R H S SPh
S C2H5 C2H5 S S
SPh H
H3C H3C H3C

Re face attack Si face attack

Diastereomers
II. Stereochemistry in Reactions
Rule: optically inactive starting materials can give only optically inactive
products.

A. Stereospecific reactions
different reactant different product
stereoisomers stereoisomers

HO OH Me Et
KMnO4 H C
+ C H (erythro)
H C C H
cis Me Et HO OH
R,S S,R
stereospecific
syn addition enantiomers (racemic)

HO OH Me H
H C C Et (threo)
+
H C C Et
trans Me H HO OH
R,R S,S
II. Stereochemistry in Reactions
A. Stereospecific reactions
Ph Ph
Ph Ph
H3C OTs TsO CH3 tBuOK
or Z
H3C Ph Ph CH3 H3C CH3
H H stereospecific
anti elimination
Ph Ph
Ph CH3
H3C OTs TsO CH3
or E
Ph CH3 CH3 Ph
H3C Ph
H H

H Br HO H
OH-
R S inversion of
configuration
S R
II. Stereochemistry in Reactions
B. Stereoselective reactions
predominance of a single
single reactant
product stereoisomer

OH H
KMnO4 H
OH +
H OH
exo endo
H OH
major minor

Br
KOH
+ +
EtOH
major minor minor
Saytzeff orientation
II. Stereochemistry in Reactions
C. Racemization and epimerization
H Br HO H
- inversion of configuration
OH
DMSO HO H
(SN2)

+ H racemization
H2O 50/50 H OH
(SN1)

HO H H OH
OH- + 12%
H2O racemization
94% 6%
O O
H
CH3 CH3 epimerization
OH- -racemization of one
chiral center in a
diastereomer
CH3 CH3
III. Prochiral Relationships
A. Enantiotopic ligands and centers

H Cl H’s are homotopic ligands.

H H
Cl H

Cl H
H H H’s are heterotopic ligands,
specifically enantiotopic ligands.
H Cl C is a prochiral center.

OH
CH3
O H
C is an enantiotopic center,
H OH has prochiral faces.
H
CH3
III. Prochiral Relationships
A. Enantiotopic ligands and centers
Designation:
1. ligands: assign one ligand a higher priority than the other, but
lower that the remaining ligands (usually D for H and 13C for
12
C)
 pro-R or pro-S
pro-S pro-R D H
S
H H H3C Cl

H3C Cl H D
R
H3C Cl
2. faces: examine rotation of ligands from each face
R  re face or si face
O
re face C
H3C H
si face
III. Prochiral Relationships
B. Diastereotopic ligands and centers
D H
CO2H R,S
HR HS
HO H
CO2H
H D
HO H
CO2H S,S
diastereotopic
ligands HO H

Diastereotopic ligands are chemically different.

triplets doublet of doublets

H H H H
CO2H CO2H
Ph Ph
H H HO H
III. Prochiral Relationships
B. Diastereotopic ligands and centers
Me Et

Ph minor
Me Et re
R OH
Ph Me Et
O si
Ph major

diastereotopic HO R
center

when carbonyl is flanked by

Cram’s Rule: O the S and M groups, the
(empirical)
S M preferred attack is on the
side with the smallest
substituent
Nu- LR
 Silicon

b b
a a
Si d d Si

c c

Silicon, like carbon, forms four bonds in its stable

compounds and many chiral silicon compounds
have been resolved
 Nitrogen in amines

b b
a very fast a
N : : N

c c

Pyramidal geometry at nitrogen can produce a

chiral structure, but enantiomers equilibrate too
rapidly to be resolved
 Phosphorus in phosphines

b b
a slow
P : : P a

c c

Pyramidal geometry at phosphorus can produce a

chiral structure; pyramidal inversion slower than
for amines and compounds of the type shown have
been resolved
 Sulfur in sulfoxides

b b
a slow a
+S : : S+

O_ O_

Pyramidal geometry at sulfur can produce a chiral structure;

pyramidal inversion is slow and compounds of the type
shown have been resolved
 Therapeutic Agents

Non-optically active
Optically active
Drugs (40%)
drugs (60%)
Biological Discrimination
 Relevance of Stereochemistry

EPHEDRAfrom Ma Huong
OH
NHCH3 d-pseudoephedrine and l-ephedrine
* * (R,S) (S,S)
CH3 useful decongenstants

2 asymmetric centers
4 stereoisomers
Biological Activity

(R)(+) Thalidomide (S)(-) Thalidomide

O O H O O H
H N N
H
N O N O

O O
a sedative and hypnotic a teratogen
 O O

NHCH3 NHCH3

Cl Cl

S-(+)-Ketamine R-(-)-Ketamine
2-4 times more potent than Causes spontaneous motor
R-(-)-ketamine in activity and post-emergent
anaesthesia distress
 H H
H3C H3C

CH3 COOH CH3 COOH

H3C H3C

S-Ibuprofen R-Ibuprofen

Inhibits platelet thromboxane Racemizes to the S-form and does

production twice as effectively as not cause G.I. lesions
does the racemate
Enzymatic scheme for inversion of R-ibuprofen to S-ibuprofen.

acyl CoA synthetase hydrolase

R-IBU R-IBU-CoA R-IBU

CoA ATP, Mg++

racemase

S-IBU S-IBU-CoA S-IBU

hydrolase