M. U.

en Química, Universitat de València

44606 - Advanced Organic Chemistry
Prof. Pablo Gaviña

Unit 2

Stereochemistry, stereoselectivity
and stereoelectronic effects

Recommended textbooks:
- Francis. A. Carey, Richard J. Sundberg, Advanced Organic Chemistry. Part A: Structure
and Mechanisms, 5th Edition, Springer.
- F. A. Carroll, Perspectives on Structure and Mechanism in Organic Chemistry, 2nd Ed.,
2010, Wiley

1
- Basic concepts of isomerism and stereoisomerism
- Symmetry of organic molecules. Elements of symmetry.
- Reasons of chirality in organic molecules. Stereogenic elements. Nomenclature.
- Diastereoisomerism.
- Prostereoisomerism and prochirality: topicity and its descriptors.
- Conformational analysis. Stereoelectronic effects.
- Influence of configuration and conformation on the reactivity of organic
molecules.
- Stereoselectivity and stereospecifity of organic reactions.

2
 General concepts of isomerism and stereoisomerism

Qualitative elementary composition: C, H, O

Quantitative chemical composition: C 66.66%, H 11.11%, O 22.22%
Empirical formula: (C4H8O)n
Molecular mass: 72, n = 1
Molecular formula: C4H8O
Constitution of the molecule: Nature and bonding of its atoms.
Structure: Constitution and stereochemistry (configuration and conformation)
Isomers:
-Constitutional
-Stereoisomerism
-Configurational isomers
-Conformers (C4H8O)n

3
 CONSTITUTIONAL ISOMERISM AND STEREOISOMERISM

Isomers are chemical compounds that have the same molecular formula but differ in the
constitution or arrangement of their atoms in space.

ISOMERS

Constitutional NO Same connectivity? YES Stereoisomers

isomers

Same functional NO Interconvertible by rotation YES

NO YES
groups? about single bonds?

Functional Positional Configurational conformational

isomers isomers isomers isomers
H H H
OH OH Non-superimposable YES OH H HOH
NO H
mirror images? Et
H H Et
O
OH Diastereomers Enantiomers OH
H HOH
H H
H Et HH Et
OH OH H
H
Et Me H Et
Me

see IUPAC rules on stereochemistry (1974 recommendations)

4
 Equilibrium between constitutional isomers: TAUTOMERISM

There are compounds whose macroscopic behaviour can not be defined in terms of a
single constitution.

Example: proton tautomerism

O O
H3N C O H3N C O
CH CH
H2O
CH2 CH2

H
L-histidine N N

N N
H 4 : 1

Other examples: ketone-enol, enamine-imine,nitroso-oxime tautomerism

Valence tautomerism. Ex: 1,3,5-cyclooctatriene

5
 CONFIGURATIONAL ISOMERISM: ENANTIOMERS

Enantiomers are a pair of stereoisomers in which one is the non-superimposable mirror

image of the other.
Compounds that have the property of not being superimposable with their mirror image
are called chirals. The enantiomers show chirality.

At the EXPERIMENTAL level, the enantiomers show:

Identical chemical composition
Identical physical properties except interaction with polarized light
Identical chemical properties (in an achiral environment)
Optical activity, α ≠ 0
Identical specific rotation [α] , but with opposite signs
RACEMATE OR RACEMIC MIXTURE
Equimolar mixture of the two enantiomers. α = 0
ENANTIOENRICHED MIXTURE
Non-equimolar mixture of the two enantiomers
Enantiomeric excess (ee) = enant. max % - enant. min %

6
 Optical activity: the ability of a chiral molecule to rotate
the plane of plane-polarized light Optical rotation

α
Polarized light
Polarimeter Rotated plane
oscillating in
only one plane
Observer
Unpolarized light

Movable analyzer

Sample cuvette containing

optically active molecule

Polarizer Optical rotation, α: Rotation (in degrees) of the plane

of polarization, as measured by a polarimeter.
Light source T = temperature, ºC
Specific rotation λ = wavelength of the light used. Usually
T α the sodium D line (589 nm)
(intensive property characteristic of a [α ] λ =
l·c α= Measured rotation in degrees
specific enantiopure chiral compound) l= cuvette length (dm)
c= Sample concentration (g /ml)
[α ] observed
Enantiometric excess % (ee.)= ·100 = % main enant. - % lesser enant
[α ] pure enantiomer
7
 SYMMETRY OF ORGANIC MOLECULES. SYMMETRY ELEMENTS

Proper rotation axis of order n: Cn (rotation)

H3C CH3
A 360°/ n rotation about the axis produces a structure
indistinguishable from the original. C2, 2σv
H H
Plane of symmetry: σ (reflection)

An imaginary plane that divides an object in two halves, so H CH3

that one half is the mirror image of the other.
H3C C2, σh
H
Center of symmetry or center of inversion: i (inversion)

Point located in the center of the object so that any straight line
that passes through it joins two elements of the object equal to H Cl
each other, opposite and equidistant F D
D F
Improper rotation axis: Sn (rotation + reflection)
Cl H i (S2)
It is equivalent to carrying out two consecutive symmetry operations:
a rotation about a Cn axis followed by reflection through a plane
perpendicular to that axis. It can be easily demonstrated that σ = S1
and i = S2
8
 SYMMETRY AND CHIRALITY

Chirality is a property that depends on symmetry.

Mathematically it can be shown that every object that has an improper rotation axis Sn is
achiral. Since a center of symmetry (i) and a plane of symmetry (σ) are respectively
equivalent to S2 and S1, a molecule will be chiral only when it has no plane or center of
symmetry or any improper rotation axis Sn with n > 2.

On the other hand, a molecule can have a proper rotation axis (Cn) and be chiral.
C2 C2

H3C H
CH3
S4 H N
H
H
N N H3C CH3
H H

3,4,3’,4’-tetramethylspirane-
Ión 3,4,3',4'-tetrametilespiro-
Enantiómeros (1,1')-bipirrolidinio ion
(1,1’)-bipyrrolidine
Enantiomers Aquiral, ópticamente inactivo
(quirales)
(chiral) Achiral, optically inactive

9
 Conformationally flexible molecules

CH3 CH3
Example:
H H
CH3 H3C
H H

as
ti c
cis-1,2-dimethylcyclohexane

én
id
id

é
n ti
ca
s
CH3 CH3
CH3 H3C
H H
H H

In the chair conformation the molecule is chiral and has a non-superimposable mirror image.
However, this conformation is in balance with an inverted chair that turns out to be identical to
its mirror image (50% of each chair's population, since they are identical in energy). Therefore
cis-1,2-dimethylcyclohexane is experimentally an optically inactive substance. In fact, the
conformational equilibrium involves going through a highly energetic conformation with a
plane of symmetry (achiral). In conformationally fluxional molecules, if there is one
conformation that is achiral, then the molecule as a whole is achiral.
10
 CAUSES OF CHIRALITY IN ORGANIC MOLECULES: ELEMENTS OF
CHIRALITY

The cause of CHIRALITY in a molecule is the presence of one or more CHIRALITY ELEMENTS
OR STEREOGENIC ELEMENTS
CHIRALITY CENTER (OR STEREOGENIC CENTER)
CHIRALITY AXIS
CHIRALITY PLANE
Molecules with one stereogenic element are necessarily CHIRAL
Molecules with two or more stereogenic elements can be CHIRAL or ACHIRAL (meso
compounds)

11
Chirality elements: chirality center (chiral center)

-Tetrahedral carbon. The enantiomers in which the chiral center is a carbon

tetrasubstituted with four different substituents are the most numerous.
c
c c

b
X C b b C
a
d a a d

-Amines and ammonium salts. In principle the amines substituted by three different
groups are chiral, but the energies of activation for the inversion are so low that the
separation of the enantiomers can not be carried out. The ammonium salts with four
different substituents are chiral and resolvable

c c CH3
N

N b b N N
H3C
d
a a
d Base
BaseofdeTräger
Träger
Sterically hindered
chiral
inversion 12
- Sulfoxides and sulfonium salts. The sulfoxides that contain two distinct groups
on the S are chiral, as well as the sulfonium salts with three different groups.

Activation energies for

O configuration inversion
S
S CH3
Ph Ea
CH2Ph CH2CH3 X X
Ph R c c
a b a
b
[α]D = +25.2º
N 5 Kcal/mol, inversion at r.t.
P 30 Kcal/mol
As 40 Kcal/mol
-Phosphines. The activation barriers for S 35 Kcal/mol
the pyramidal inversion of the phosphines
are much higher than those of the amines
and for this reason numerous chiral
phosphines have been prepared.

CH3CH2CH2 P [α]D = +35º

H3C
13
-Chiral molecules with a chiral center but without chiral atom.
Derivatives of adamantane are among them.
b b

c c
a a

d d

Nomenclature

It uses the descriptors R and S and follows the Cahn-Ingold-Prelog (CIP) priority rules.

The non-bonded electron pair gets the H

lowest priority.

Et
O
H N S Me
CH2Ph Ph
Ph
Me S Ph
R
Et S
14
CIP rules for assigning priorities

There are 5 rules that are applied hierarchically until a decision is reached. We will only
consider the first two.

1.- (a) The higher the atomic number, the higher priority.
(b) A duplicated atom corresponding to an atom closer to the root (the central atom of
the hierarchical tree) has a higher priority than a duplicated atom whose original atom is
farthest from the root (it is used to prioritize between two cyclic substituents )

2.- When two substituents on the chiral center are identical in everything except for its
isotopic distribution, the isotope of greater mass has preference over that of smaller mass.

How do these rules apply?

-Each rule is applied exhaustively to all atoms or groups of atoms that are compared.
-Each rule is applied following a hierarchical diagram. The atoms directly attached to the
stereogenic center are considered first. If there are two identical atoms attached to the
stereocenter, we advance to the next position simultaneously by the two chains, until
reaching the first point of difference.
- If branches appear, we will always follow the branch that starts from the highest priority
atom.
15
Duplicated atoms and ghost atoms

They are introduced to be able to apply the CIP rules to molecules with multiple bonds,
saturated cycles, aromatic rings or atoms with non-bonded electron pairs.

- Double and triple bonds

They are considered as if they were single but doubling or tripling the atoms. Each real
atom and "duplicated atom" becomes tetravalent by adding "ghost atoms" (imaginary
atoms with atomic number = 0)
0 00 0 00
(C) (C)
C O C O C C C C

(O) (C) 0 0 0(C) (C) 0 0 0

0 0
0 0 0 0

- Saturated cycles

The saturated rings are "opened" and considered as if they were branched chains. The
exploration continues until we get back to the starting atom that is considered as a
"duplicated atom" to which "ghost atoms" are added to complete the tetravalence.

2 2 3 1
1 CH2 1 CH2 CH2 (C) 0 0 0
CH CH 3 2 1
CH2 CH2 CH2 (C) 0 0 0
3
16
- Aromatic heterocycles

Each duplicated atom is assigned an average atomic number that it would have if the original
atom had double bonds in all possible positions.
(6) (6)
(6.33)
(6.5)
(6)

N N N N N N N N
(6) (6)
(6) (7)
(6.5)

- Non-bonded electron pairs

They are assigned an atomic number of zero (less than an atom of H)

Application of 2nd rule: Only when it isn’t possible to get a decision while using rule # 1, what
means exhaustively ignoring the isotopic differences, then we can consider the isotopes. The
greater atomic mass, the higher priority.

-CH CH
Example: 2CD2CH3
> 2CH2CH3

But…
CH F CD
2CH2 > 2CH3

17
Interesting example of the application of CIP rules via using of a hierarchical tree:

FH2CFHC CHFCH2Cl

CH CH
CH2CH2Br
IH2CH2C
HO H

IV

III
H H Cl
H F
H F II
H H H
C C C
F C H
I H
H C C C
C H
H
C
C
HO H

18
An interesting example of the application of sub-rule 1b: priority in duplicate atoms

Determine the absolute configuration of the following compound:

HO H
d
a

19
 Chirality elements: chirality axis

Allenes.
The molecular model of an allene of the type CHX = C = CHX shows that the substituents at
the ends are perpendicular to each other.
The allenes of this type lack plane of symmetry, center of inversion or any axis Sn (n> 2),
therefore they are chiral and can be resolved in enantiomers.
The allenes do not contain a chiral center and their chirality comes from a chiral axis which
in this case is the axis C = C = C.

X H H
X
C C C C C C

H X X H

a a
A stereogenic axis can be related to a
stereogenic center in which two of the c b

substituents had moved in the d a

direction of the axis. b b

a,b,c andy ddare
a,b,c different
diferentes aayand b are different
b diferentes
center of chirality
centro de quiralidad eje axis of chirality
de quiralidad

20
Nomenclature:To use the descriptors Ra and Sa. To carry out the assignment, the molecule is observed
along the stereo axis. Priorities 1 and 2 are assigned to the two substituents of the carbon closest to the
observer following the CIP rules, and then priorities 3 and 4 are assigned to the substituents of the furthest
carbon. The substituents ordered 1, 2, 3 and 4 describe the four vertices of a distorted tetrahedron. This
tetrahedron is observed by placing substituent 4 away from the observer and sequence 1, 2 and 3
determines whether the system is R or S.

3 3 3
3
2 CH3
H3C H
C C C CH3 H 1 2 4
1 2
H CH3
H 1 2
4 1
4 Sa 4 Sa
1 3
H3C 4 2
H
Observing by either of the two ends of the chiral
H
CH3 axis, the same configuration is obtained.
Sa 2 4 3 1 Sa

When another double bond is presented, as in the cumulene abC = C = C = Cab, all the
substituents are back in the same plane and the molecule only has geometric
isomerism (cis / trans)
H3C CH3 H CH3

C C C C C C C C

H cis H H3C trans H

21
Alkylidene, cycloalkanes, spiranes and other rigid cyclic compounds

CH3
COOH H Cl
H H

H3C H3C
H HOOC COOH

Cl
alkylidenecyclohexane spirane adamantane

Nomenclature. The Ra and Sa notation for these compounds is determined following the
same standards indicated for the allenes.

Important: If we use the

CH3 H3C representation of Fischer to
Cl Cl assign the configuration, the
substituents closest to the
H3C CH3 observer (1 and 2) have to be in
the horizontal plane
Cl Cl

4 4
CH3 2 CH3
1 2 1
Cl CH3 Ra Sa H3C Cl
Cl Cl
3 3
22
Biphenyls: Atropoisomerism
The biphenyl molecule can rotate around the bond that binds two aromatic rings. This
rotation is becoming more difficult when ortho-hydrogens are substituted by other groups.
When the substituents at 2.2 'and 6.6' are bulky enough, rotation is impeded and a chiral
axis appears. This type of isomerism is called atropoisomerism (a = without, tropos =
rotation).
a a a a The chiral axis appears
when a ≠ b and leads to a
pair of enantiomers
3

P 1 2
b b
b b Sa
4

Nomenclature. The Ra and Sa notation for these compounds is determined following

the same standards indicated for the allenes.
You can also use the nomenclature P (plus) and M (minus) that is used for substances
with helical geometry. A molecule will have helicity P if the main groups of both ends of
the axis rotate clockwise away from the observer (and M if they rotate in the opposite
direction)

For the molecules with chirality axis, it is: Ra = M

Sa = P
23
 Elements of chirality: plane of chirality

It appears in molecules that contain a group of atoms in a plane, from which the rest of the
molecule protrudes, as long as the rotation of the plane is impeded.

Ansa compounds and cyclophane

O
paracyclophanes
R

H2C CH2 H2C CH2 H2C CH2

(CH2)n

H2C CH2 H2C CH2 H2C CH2

O R R
Plano de simetría
Symmetry plane
Ansa compound Achiral
Aquiral enantiomers
enantiómeros

Annulenes Trans-Cyclooctene
p CH3
2 H
3
1

H
aquiral
Achiral Rp
(E)-cyclooctene
(E)-cicloocteno
24
Nomenclature: The descriptors Rp and Sp are used following these rules:
1. Among the atoms directly attached to the chiral plane (but outside the plane), the one
with the highest priority (CIP) is selected as the “pilot atom”.
2. From the atom of the chiral plane attached to the pilot atom, a path is traced by the
atoms of the chiral plane always following the highest priority atoms.
3. If contemplating from the pilot atom the path 1,2,3 follows a clockwise pattern the chiral
plane is designated R. If the pattern is counterclockwise, it is S.

(CH2)n p
p H
H2C CH2 2
2 3
1O O 1

3 H
Br
Rp Rp

25
 Elements of chirality: helicity

The existence of enantiomers in some molecules is best defined in terms of helicity. A helix can
be right (if its rotation away from the observer is clockwise) or left (anti-clockwise). The right
and left helices that have the same shape are mirror images (enantiomers).

Nomenclature: The chirality of the helixes is denoted by the symbols P for the right
helixes (from the Latin plus) and M for the left helixes (from the Latin minus)

4,5-substituted phenanthrene and helicenes. The steric interactions in these systems cause
that the aromatic rings are not coplanar. The molecules adopt a helical geometry.

H3C
CH3

CH2COOH

CH3
M
Fenanthrene
P
Helicene
26
Topological chirality in catenanes and rotaxanes

The introduction of directionality in mechanically interlocked molecules (catenanes and

rotaxanes) can generate what is known as topological chirality.

+
catenanes

achiral
aquiral aquiral
achiral achiral
aquiral

aquiral
achiral aquiral
achiral quiral
chiral chiral
quiral
enantiómeros
enantiomers

rotaxanes

aquiral
achiral achiral
aquiral

Chiral (two
quirales (dos enantiomers)
enantiómeros)
27
Compounds with topological chirality are chiral, although they may lack classical chirality
elements (stereogenic centers, axes or planes). Therefore they can exist as a pair of
enantiomers.
Achiral catenane Achiral rotaxane

Sauvage, Dietrich-Buchecker,
Tetrahedron Lett. 1983, 24, 5091 Stoddart et al.
Tetrahedron Lett. 1991, 32, 6235

Chiral catenane Chiral rotaxane

28
Nomenclature. a) Rotaxanes

The chirality can be described through the combination of an axial vector and a polar vector
that generates a screw movement that turns to the right or to the left

derecha
Right Left
izquierda
configuration (R)-
configuración (R)- configuración(S)-
configuration (S)-

The directionality (→) of the axial (axis) and polar (ring) vectors is based on the CIP rules and
is marked by the direction from the highest priority atom to the next priority (a → b) by the
shortest path . If the combination of both vectors results in a "screw" that rotates to the
right: (R); if it turns to the left: (S).

achiral thread achiral ring H H

H H
N N N N
atom with highest
CIP priority
O O O O
O O O
O O O S
N N
S H H
N N
H H
atom with second O O O O
highest CIP priority HN S N HN S N
axle directionality atom with second O H O H
highest CIP priority
atom with highest
CIP priority
ring directionality

Left
For catenans, the polar vector of one of the rings is considered, configuration (S)-
while the other is considered as "open" and assigned an axial
vector. And the same rules are applied.
29
 DIASTEREOISOMERS

AT EXPERIMENTAL LEVEL: TWO DIFFERENT SUBSTANCES

Identical chemical composition
Different physical and chemical properties
Optically active or not
If they are optically active: [α] is different

At MOLECULAR LEVEL: TWO DIFFERENT MOLECULES

Identical connectivity

They are not mirror image

CAUSES OF DIASTEROISOMERISM

Restrictions of rotation in unsaturated systems: Alkenes and imines

Restrictions of rotation in cyclic systems

Molecules with more than one stereogenic element (center, axis or plane)

30
 DIASTEREOISOMERS: MULTIPLE BONDS

ALKENES IMINES
1 1
1 1 1 2
2 CH3 H3C 2
H3C CH3 H3C H N N

2H H 2 2 H CH3 1 1 Ph CH2CH3 1 Ph CH2CH3

2 2
cis-2-buteno
Cis-2-butene trans-2-buteno
trans-2-butene (E)-N- (Z)-N-
(Z)-2-butene (E)-2-butene
(E)-N-(1- (Z)-N-(1-
(Z)-2-buteno (E)-2-buteno (1 phenylpropylene)
fenilpropiliden) (1 phenylpropylene)
fenilpropiliden)
methylamine
metanamina methylamine
metanamina

OXIMES
The twist restrictions of the double
1
2 1
2 bonds C = C and C = N give rise to
OH HO
N N the appearance of geometric or cis-
1 Ph CH2CH3
trans isomerism.
1 Ph CH2CH3
2 2
anti-oxima de la propiofenona sin-oxima de la propiofenona
Propiophenone anti-oxime Propiophenone syn-oxime
(Z)-oxima de la propiofenona
Propiophenone (E) - oxime
(E)-oxima de la propiofenona Propiophenone (Z) - oxime

31
 DIASTEREOISOMERS: CYCLIC COMPOUNDS

EXAMPLE: dimethylcycloalkanes

H3C CH3 CH3

H3C CH3 H3C
cis
H H H
H H H
aquiral
achiral aquiral aquiral
achiral
achiral

CH3 H CH3 H CH3

H
trans H
H CH3 H CH3 CH3
E quiral quiral aquiral
chiral E chiral achiral
H CH3
H CH3

CH3 H CH3 H
quiral
chiral quiral
chiral

The geometric restrictions of the cyclic compounds favor the appearance of geometric
isomerism (cis-trans). The resulting geometric isomers (diastereomers) can be chiral or
achiral.

32
 DIASTEREOMERS: COMPOUNDS WITH MORE THAN
ONE STEROGENIC ELEMENT

2 stereogenic centers: 2,3,4- 2 stereogenic centers: tartaric

dihydroxybutanal acid
enant. E

CHO CHO CO2H CO2H

H OH HO H H OH HO H
H OH HO H HO H H OH
CH2OH CH2OH CO2H CO2H

diast. diast. diast.

diast. L-tartaric acid
Ac L-tartàric D-tartaric
Ac D-tartàricacid
D
D
CHO CHO CO2H
H OH HO H
H OH
HO H H OH H OH
CH2OH CH2OH CO2H

enant. Meso-tartaric acid

Ac meso-tartàric

The maximum number of possible stereoisomers is equal to 2n, where n is the number of
stereogenic elements (centers, axes, planes). Some stereoisomers are chiral and therefore
there are two enantiomers. But there are also molecules that even possessing two or more
stereogenic elements are achiral. They are called meso compounds.
33
 OTHER STEREOCHEMICAL NOTATION SYSTEMS

Pseudo-asymmetric carbons

CH2OH CH2OH CH2OH CH2OH

R S S S
HO H H OH H OH H OH

s r
H OH HO H H OH HO H

H OH HO H H OH H OH
R S R R
CH2OH CH2OH CH2OH CH2OH

I II III IV
I and II are a pair of enantiomers. Compounds III and IV are meso forms since both have a plane
of symmetry. They are a pair of diastereoisomers. The nomenclature of these compounds
should reveal the different configuration of carbon 3 (pseudo-asymmetric carbon). For this, the
sub-rule is used, which indicates that the chiral groups R have preference over the S, naming
the corresponding pseudo-asymmetric carbons as s or r.
III = (2R, 3s, 4S)-pentane -1,2,3,4,5- pentaol
IV = (2R, 3r, 4S)-pentane -1,2,3,4,5- pentaol

34
 OTHER STEREOCHEMICAL NOTATION SYSTEMS

D-L: It is used for sugars and amino acids. In the Fischer projection the substituent of the
last stereogenic center is observed. In products D this is to the right, and in the L to the left.

CHO CHO
H OH HO H
HO H H OH CO2H CO2H
H OH HO H H2 N H H NH2
H OH HO H CH3 CH3
CH2OH CH2OH
D-(+)-glucose
D-(+)-glucosa L-(-)-glucose
L-(-)-glucosa L-(+)-alanine
L-(+)-alanina D-(-)-alanine
D-(-)-alanina

Erythro-threo: Relative stereochemistry. Indicates whether two consecutive substituents are

on the same side (erythro) or opposite sides (threo) on a Fischer projection

CHO CHO CHO CHO OH CH2OH CH2OH

H OH HO H HO H H OH CH2OH H2N H H NH2
= +
H OH HO H H OH HO H NH2 H OH HO H
CH2OH CH2OH CH2OH CH2OH Ph Ph

D-erythrose
D-eritrosa L-erythrose
L-eritrosa D-threose
D-treosa LL-threose
L-treosa (d,l)-threo-1-phenyl-1,3-propanediol
(d,l)-treo-2-amino-1-fenil-1,3-propanodiol

35
 OTHER STEREOCHEMICAL NOTATION SYSTEMS

R*,S*: Relative stereochemistry, when the absolute stereochemistry is not

known or is irrelevant.

OH (1R*,2S*-2-amino-1-phenyl-
(1R*,2S*)-2-amino-1-fenil-1,3-
CH2OH 1,3-propanediol.
propanodiol
NH2 Rel-(1R,2S)-2-amino-1-phenyl-
rel-(1R,2S)-2-amino-1-fenil-1,3-
propanodiol
1,3-propanediol

Exo-endo In bicyclic folded systems. The endo substituent is directed towards the interior of
the carbon skeleton while the exo is directed towards the outside.

CH3 CH3 CH3 H

H H H CH3
Cl
exo, exo-2,4-dimetilbiciclobutano
Exo,exo-2,4-dimethylbicyclobutane exo,endo-2,4-dimetilbiciclobutano endo-2-chloroborrnane
Exo,endo-2,4-dimethylbicyclobutane endo-2-cloronorbornano

36
 OTHER STEREOCHEMICAL NOTATION SYSTEMS

Syn-anti: Indicates the relative orientation of the substituents in a linear chain. The main
chain is drawn in a zig-zag pattern.

anti,anti sin,anti sin,anti sin,sin

anti,syn Syn,anti Syn,anti Syn,syn
CHO H OH H OH HO
H OH = HO = =
CHO CH3 CHO CH3
HO H H CHO
H OH
CH3 CH3 OH
threo
treo synsin

Epi: Epimers are diastereomers that differ in the configuration of a single stereogenic
center.
H H
O 9 O
6
O O
O O H H
O O ambrox 9-epi-ambrox
santonina
santonin 6-epi-santonina
6-epi-santonin ambrox 9-epi-ambrox

37
 OTHER STEREOCHEMICAL NOTATION SYSTEMS

s-cis y s-trans: Indicates the conformation around a single bond that has a certain
character of double bond that gives it a torsional barrier.

O O

s-trans-butadieno
S-trans-butadiene
s-cis-butadieno
S-cis-butadiene S-trans-propanal
s-trans-propanal S-cis- propanal
s-cis-propanal

O CH3 O H
N N
H H H CH3
s-cis-N-metilformamida S-trans-N methylformamide
s-trans-N-metilformamida
S-cis-N-methylformamide

38
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Concept of prochirality
Prochiral center: achiral center that becomes chiral when two identical substituents on
noted center (atoms or groups of atoms) become different from each other. The concept
also extends to prochiral axes and planes)
Prochiral groups: The two equal groups attached to a prochiral center (the concept also
extends to prochiral axes and planes)

Descriptor pro-R and Pro-S. It is used to differentiate two prochiral groups. To assign a
descriptor, the CIP priority rules are applied and arbitrarily assigning a higher priority to the
prochiral group that we are considering with respect to its equal.

Ha Hb
2
COOH
Cl Ha
H
C C C
1
NH2 H Hb
H
es pro-R
Ha is a Ha is
es pro-Sp
H = pro-R
H = pro-S Hb is
es pro-Sa Hb is
es pro-Rp

Prochiral carbon Prochiral axis Prochiral plane

39
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Prochiral sp2 center

The concept of prochirality can be extended to trigonal carbons (sp2). Addition reactions to
double bonds generate a tetrahedral carbon (sp3). The new carbon can be chiral, and its
configuration will depend on the side the reagent approaches. In this case we talk about
facial prochirality.

Nu OH
O - CH3 H
1. Nu
CH3 H +
enantiomers
enantiómeros
2. H3O HONu

prochiral CH3 H

O
CH3 H
CH3 H epoxydation
epoxidación H CH3
enantiómeros
H CH3 CH3 H enantiomers
H CH3

prochirales O

40
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Re and Si descriptors. They are used to distinguish the two re

prochiral faces of a trigonal atom:
1.- The observer is placed in front of one of the faces of the
3H
trigonal atom. 1
2.- The priority of the bonded groups is established according O
to the rules of Cahn-Ingold-Prelog, and the direction of 2
CH3
rotation is observed.
3.- If the substituents describe a clockwise trajectory, the face
is the Re-face and if counterclockwise, the Si-face.
si

In the case of molecules with carbon-carbon double bonds, the notation must be applied
independently for each prochiral carbon.
si re
re
3H 3
3 2 H
H C C
1 prochiral 2 prochiral 2
carbon CH2 carbons 1 Br Br 1
CH3 1
2
re si
si
41
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Prostereoisomerism: Descriptor pro-Z and Pro-E. It is used to refer to two pro-stereogenic

groups located on a trigonal carbon sp2. The CIP-sequence rules are applied and of the two
equal groups, the highest priority is assigned to the group that we are considering.

HO2C H pro-Z

H3C H pro-E

ATTENTION: The replacement of a pro-R group by a different group does not necessarily
mean that a carbon with an R configuration will be generated. This will depend on whether
the new group maintains the same priority as the replaced group. (The same applies to the
pro-Z and pro-E groups and the Re and Si faces)

42
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Topocity considers the stereochemical relationships between two identical substituents

(atoms or groups of atoms) within a molecule. I.e., it classifies above mentioned
substituents according to their symmetry relation. The word "topic" comes from the
Greek "topos" which means "place"

GROUPS

homomorphic heteromorphic

homotopic heterotopic

constitutionally
stereotopic
heterotopic

enantiotopic diastereotopic

COOH O
CH3
Heteromorphic
HC OH N
Homomorphic CH3
groups
groups
H2C H3C
OH
CH3 43
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Two identical atoms or two groups of constitutionally identical atoms are called
homomorphic. If they are different groups, they are called heteromorphic. The topicity
considers the relationships between two homomorphic groups of a molecule.

Two identical substituents (homomorphic) that occupy equivalent environments, both in

terms of chemical properties and symmetry, are called homotopic.
Br

H H H

CH3
H
Cl Cl CH3

If two identical groups are in different environments (topologically not equivalent) they are
called heterotopic. These can be constitutionally heterotopic or stereotopic.

Br Ha CH3
HO
Cl
OH F Hb H
Cl

Constitutionally stereotopic stereotopic

heterotopic diastereotopic enantiotopic
44
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

The difference between homotopic, enantiotopic or diastereotopic groups can be made

according to two criteria: symmetry and substitution criteria.

Homotopic groups: They are topologically equivalent homomorphic groups.

Criterion of symmetry: Those groups that can be interchanged by a rotation about a
Cn rotation axis giving a structure which is indistinguishable from the original.

HA and HB are
homotopic
arehomotópicos
Br y Br son homotopic C2
Br Br Br

H C2 H H
Br Br Br Br Br
inversión de
Inversion of
conformación
conformation

Flat
H H H
Representación moléculas idénticas
Identical molecules
representation
plana Chair shape
forma de silla
45
 Criterion of substitution: If we alternately replace one and the other group with
different atoms, the resulting molecules are identical.
H D
HO OH

Hb Ha
Ha D moléculas
HO OH Identical
idénticas
H
molecules
y H son D
replace HHaA and bHB are HO OH
HA and HB are Replace homotopic
homotópicos
homotopic HA to Cl HB to Cl
Identical Hb D
molecules

Constitutionally heterotopic groups: They are topologically non-equivalent groups because

they present different bonding with the rest of the atoms of the molecule.

Criterion of symmetry: Not related to symmetry.

Criterion of substitution: By alternative substitution them with different atoms they
give two constitutional isomers.
Hb Ha H D H H
HO OH HO OH HO OH

Hd Hc H H H D
y H son constitucionalmente
Ha Replace
sustituimos sustituimos
Ha
c
and Hc are Ha por D
Ha to D Constitutional
isómeros
Replace
Hc por D
heterotópicos Hc to D 46
constitutional heterotopics constitucionales
isomers
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Enantiotopic groups: They are homomorphic groups which are topologically not equivalent.

Criterion of symmetry: They are those that can be exchanged by reflection in a plane of
symmetry (σ) giving a structure indistinguishable from the original.
Prochiral carbon
σ σ
HA HB Prochiral axis
Br Br
Br H O
Br σ
Br
C C C
FA FB H
HOOC
H H H
Cl

Criterion of substitution: If we alternately replace one and the other group with
different atoms, the resulting molecules are enantiomers.
Hb Ha H H H H
HO OH HO OH HO OH

Hd Hc H D D H
y H son enantiotópicos sustituimos sustituimos
HHc
c andd Hd are enantiotopic Replace
Hc por D Replace
Hd por D
Hc by D enantiómeros
enantiomers Hd by D

An atom directly bonded to two enantiotopic groups is a PROCHIRAL center (the concept
extends to prochiral axes and planes). 47
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Diastereotopic groups: They are topologically non-equivalent homomorphic groups.

Criterion of symmetry: They can not be exchanged via symmetry operations.

Criterion of substitution: By alternately replacing them with different atoms, two

diastereomers are obtained.

HO R S OH

H CH3
D
HO S OH
Replace Hc Hc
(sustituimos to por
D D) diastereómeros
diastereoisomers
Hd CH3 HO S S OH
Hc
y H son Cl D
HHc
c and d Hd D CH3
are diastereotopic
diastereotópicos H

Replace HdHd
(sustituimos to por
D D) Cl Ha H H
(Z) Diastereoisomers
diastereómeros

Two enantiotopic or diastereotopic groups H Hb Cl H

are considered PROSTEREOISOMERIC. Ha
y H son
The concept of prostereoisomerism is more Ha and Hbb
diastereotópicos
are stereotopic H D
generic than that of prochirality. (E)

48
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

Topicity in methylene groups (-CH2-): Summary

Prochiral carbon Prochiral carbon

R1 is achiral
R1 and R2 are achiral R2 is chiral

Ha and Hb Ha and Hb Ha and Hb

are homotopic are enantiotopic are diastereotopic

49
 PROCHIRALITY AND PROSTEREOISOMERISM. TOPICITY

BEHAVIOUR OF THE HOMOMORPHIC GROUPS VERSUS CHIRAL OR ACHIRAL

REAGENTS AND IN NMR ACCORDING TO THEIR TOPICITY

Indistinguishable

-Homotopic groups

Distinguishable only by chiral reagents (or solvents)

-Enantiotopic groups

Distinguishable by any reagent and by NMR

-Constitutionally heterotopic groups

-Diastereotopic groups

50
TOPICITY AND NMR: Homotopic and heterotopic constitutional groups

O Hd He
Ha
O Hf
Hb Hc

Ha, Hb
Ha, Hb,and
Hc Hc
sonare homotopic: 2,01
homotópicos: 2,01 ppm
ppm
Constitutionally
Constitucionalm.
heterotópicos
heterotopic Hd, He
Hd, He,and Hf are
Hf son homotopic: 3,67
homotópicos: 3,67 ppm
ppm

O
3.67

O
2.01

3 2 1 0
PPM

51
TOPICITY AND NMR: Diastereotopic groups

CH3 O Ha

CH3 Hb

Ha and
Ha Hb:diastereotópicos,
y Hb: diastereotopic, distinguishable
distinguibles

3.90
3.50 O H

H
1.71 3.82

Ha Hb

3 2 1 0
PPM

52
TOPICITY AND NMR: enantiotopic groups in achiral solvent (CDCl3)

O Ha Hb
Cl
H Ha and Hb are enantiotopic, not
O Cl
H distinguishable by NMR
H Cl

4.84 4.84
O H H
Ha y Hb 2.01 Cl
H Cl
O
2.01
H
H Cl
2.01

4 3 2 1 0
PPM

53
TOPICITY AND NMR: enantiotopic groups in chiral solvent

Appearance of the Appearance of the

spectrum 1H NMR spectrum 1H NMR
Achiral solvent Chiral solvent

54
 TOPICITY AND REACTIVITY

Let us suppose an achiral reagent R, capable to react with two homomorphic groups of
the same molecule according to the following scheme.

1
A R B

A A A
R
+
A A 2 A

A R B

1. If A and A are homotopic, a single reaction product is obtained through a single transition
state (the two transition states are identical).
2. If A and A are enantiotopic, both transition states are enantiomers and therefore of equal
energy. Two enantiomers are obtained in equal proportions (racemic mixture).
3. If A and A are diastereotopic, both the transition states and the products are
diatereoisomers. The final products can be obtained in different proportions.

(see potential E diagrams)

55
 TOPICITY AND REACTIVITY

If reagent R is chiral , the situation is different for enantiotopic groups

1
A R* B
* *
A A A enantiomers in
enantiómeros
R* + different
en distintas
proportions
proporciones
A A 2 A
* *
A R* B
mezcla enantioenriquecida
enantioenriched mixture

1. If A and A are homotopic , a single reaction product is obtained through a single transition
state.
2. If A and A are diastereotopic, both the final products and the transition states are
diastereoisomers and different proportions of products are produced.
3. If A and A are enantiotopic reactions proceed through transition states that are
diastereoisomeric (different energy). If the chiral part of the reagent is not incorporated in
the final product, the final products obtained are enantiomers but can be formed in different
proportions (enantioenriched mixture)

(see potential E diagrams)

56
TOPICITY AND REACTIVITY

Example: Oxidation of ethanol to acetaldehyde catalyzed by the enzyme alcohol

dehydrogenase (ADH)

OH O
ADH
H CH3 D
CH3
OH D
(S)

HR
CH3 OH
HS O
ADH
HR and HS are CH3
D
CH3 H
enantiotopic H
(R)

Ethanol has two potentially reactive enantiotopic hydrogens. The active center of the
ADH enzyme is of chiral nature. By means of deuteration experiments it can be proved
that the oxidation of ethanol to acetaldehyde implies the transfer of only the
hydrogen R to the enzyme.

57
 CONFORMATIONAL ANALYSIS. STEREOELECTRONIC EFFECTS

H H H

H H H
OH OH
H CH2CH3 H CH2CH3

OH H OH
H H
H
H CH2CH3 H CH2CH3
H H

Molecular conformations are the different relative spatial dispositions that the atoms of
a molecule can adopt, as a consequence of rotations through simple bonds, at room
temperature.
The conformations that correspond to energy minimums are called conformers . Normally
the conformers are rapidly converted to each other, so that at the equilibrium the lowest
energy is the most abundant . This distribution of the conformers can have important
repercussions on the reactivity of the molecule.

58
 CONFORMATIONAL ANALYSIS. STEREOELECTRONIC EFFECTS

Hydrocarbons . Review the concepts of Organic Chemistry (2nd year)

Alternating Eclipsed
Representations

Lines and wedges

round round
60o 60o

Easel

Newman

Conformational interconversion in most single molecules occurs rapidly to room T. The isolation
of pure conformers is not normally possible.

59
 CONFORMATIONAL ANALYSIS. STEREOELECTRONIC EFFECTS

The different conformations around a simple bond can be named according to the dihedral
angle θ (theta).
= 60
Convention to assign the dihedral angles: θ
O
H3C Cl
- If the substituents of one end of the single bond are all different from
those of the other end, θ is the angle formed by the substituents of
H
higher priority of each end of the bond. NH2

OH
- If there is only one substituent common to both ends of the bond, θ is Cl H
the angle between both substituents, although their priority was lower
CH3
than that of the rest of the groups. H
= 180º
Et θ

- If there are two or three common substituents, θ is defined by the = 60

θ
common substituents of higher priority Cl
Br Cl

F H
H

60
 CONFORMATIONAL ANALYSIS. STEREOELECTRONIC EFFECTS

Conformations of ethane

Alternating conformations are more stable than eclipsed ones

Rotation barrier: 3 kcal/mol torsional tension (1 kcal/mol per interaction)

61
 CONFORMATIONAL ANALYSIS. STEREOELECTRONIC EFFECTS

Conformations of butane: anti, gauche and eclipsed

antiperiplanar

eclipsed

conformers alternating

180 240 300 0 60 120 Dihedral angle

antiperiplanar syncline
(gauche)
62
 CONFORMATIONAL ANALYSIS. STEREOELECTRONIC EFFECTS

Conformations of cyclohexane: chair, boat and twist-boat

H H
H
H
H
H
half-chair
H H
H
H
H H

boat

twist-boat

twist-boat
10.8 kcal/mol 6.8 kcal/mol

chair chair

reaction coordinate

At room temperature, interconversion between conformers

occurs about 100,000 times per second!

63
 CONFORMATIONAL ANALYSIS. STEREOELECTRONIC EFFECTS

Unfavorable 1,3-diaxial interactions shift equilibrium toward equatorial conformers.

CH3
H
H
95 : 5
H CH3
∆Gº = 1.7 Kcal/mol

Free energy variation for the interconversion between conformers

of cyclohexane with an equatorial or axial substitution
sustituent ∆Gº(kcal/mol) sustituent ∆Gº(kcal/mol)

H 0 F 0.25

CH3 1.70 Cl 0.52

CH3CH2 1.75 Br 0.55

(CH3)2CH 2.20 I 0.46

(CH3)3C ca. 5 OH 0.94

Note: In all the examples the equatorial conformer is the most stable.

64
 CONFORMATIONAL ANALYSIS. STEREOELECTRONIC EFFECTS
Systems containing heteroatoms. Anomeric effect

Stereoelectronic effects are all those effects on the reactivity of a molecule produced by the
particular spatial arrangement of certain pairs of electrons , both bonding and non-
bonding. (Deslongchamps)

The anomeric effect is a type of stereoelectronic effect that is observed in 6-membered

heterocyclic rings containing polar substituents on the carbon next to the heteroatom, and
manifests itself in the preference of the polar group to adopt an axial arrangement, as
opposed to what is normally observed for substituted cyclohexanes. The term “anomeric
effect” is because this effect was observed initially in the anomeric carbon of the hemiacetal
form of sugars.
OH OH
O
∆G < 0
O CH3
O H O
HO HO H
HO HO
OMe
MeOH H CH3 predominant
Mayoritario
OH OH
2-metiltetrahidropirano
OMe 2-methyltetrahydropyran
anomeric
C anomérico predominant
Mayoritario
∆G > 0
OAc OAc O
O X

O H O
AcO AcO X
AcO AcO
OAc
AcOH predominant
Mayoritario X = OR, NR2, F, Cl, Br
OAc OAc
K=5 OAc
predominant
Mayoritario 65
 STEREOELECTRONIC EFFECTS

Anomeric effect
Lemieux (1950) considers that it is a destabilizing
effect of electrostatic origin. In favor of this
O
interpretation is the fact that the equatorial form
O is predominant in polar solvents.
X
X
Deslongchamps (1980) maintains the electrostatic
n n component, but gives greater importance to the
orbitals. The origin of the effect would be in a
O binding (stabilizing) interaction between a n orbital
O
of the heteroatom and the orbital σ * of the C-X
bond, which occurs only if X is axial (coplanar
σ*
C-X σ* orbitals). With non-polar groups (alkyl) this
C-X
interaction is not very effective due to the
(hyperconjugation) difference of E between the orbitals involved.

Cl
O In the trans-2,3-dichloro-1,4-dioxane,
O
O Cl conformation with the axial Cl also
O
Cl predominates. Measurements indicate that the C-
Cl Cl bond is longer and the CO bond is shorter than
in other molecules.
trans – 2,3 – dichloro- 1,4 - dioxane
trans-2,3-dicloro-1,4-dioxano
66
 STEREOELECTRONIC EFFECTS

Exo-anomeric effect

The exo-anomeric effect refers to the conformation of the O-glycosidic bond (gauche
effect)

H H H
H H O H H O H H O
H H H
H H H H H H
H H σ* H H H H
H O H O H O
CH3 H3C
n CH3

most stable
conformation
O O
H3C

H H
gauche
O Exo-anomeric effect = CH3
CH3
gauche effect
H

Allows hyperconjugation
n→σ*
67
 STEREOELECTRONIC EFFECTS

Anomeric effect in acyclic systems

CH3-CH2-CH2-CH3 CH3-O-CH2Cl

H H CH3
O O
CH3 Cl Cl
CH3
CH3 Another way to see it:
resonance limits
H H H H H H
σ*

CH3 Cl Cl
H H CH3 n CH3

O CH3 O
H H H H H H
CH3 σ*
CH3 H
H H

most stable conformation most stable conformation Cl H Cl

pair of lonely electrons

antiperiplanar with respect
to the polar link.
68
 INFLUENCE OF CONFORMATION ON REACTIVITY

E2 Reaction
Cl
-
B
fast reaction
reacción rápida
+
H
H

-
B

Cl
H + slow reaction
reacción más lenta

Diels-Alder reaction

slow
lenta

s-trans s-cis

fastrápida
más

cyclopentadiene has
el ciclopentadieno tiene
la conformación cis fijada
fixed cis-conformation 69
 STEREOSELECTIVITY AND STEREOSPECIFICITY IN ORGANIC
REACTIONS

Stereospecific reaction: the reaction in which different stereoisomerically starting compounds

lead to stereoisomerically different products under the same reaction conditions.
More precisely: A reaction is stereospecific when the configuration of the product is
determined by that of the reactant, and when such configuration is a consequence of a
particular reaction mechanism with a very precise stereochemistry (eg. SN2 reaction,
hydroboration or epoxidation of alkenes).

Stereoselective reaction: Those reactions that mechanistically could lead to two or more
stereoisomers but one of them predominates (or is exclusively formed) over the others.

70
 Examples of STEREOSPECIFIC reactions

Hydroxylation with OsO4: Stereospecific syn, two OH groups are introduced by the same
side of the double bond.
OH
H CH3
CH3 CH3 CH3 OH
1. OsO4 H
OH OH
H CH3
H H 2. NaHSO3
H CH3 OH
(Z) OH eritro
erythro
OH
H CH3
CH3 H OH
1. OsO4 H CH3 +
OH H3C OH
H CH3 2. NaHSO3 H
H3C H OH
(E) OH treo

Epoxidation with peracids: Stereospecific syn. The stereochemistry of the double bond is
maintained in the epoxide.
CH3 CH3 O H H
MCPBA CH3 CH3
CH3 CH3
H H H H O
(Z)
CH3 H O H3C H O
MCPBA + CH3
H3C H H H CH3
H CH3 H CH3 O H3C H
(E)
71
 Examples of STEREOSPECIFIC reactions

Substitution reactions SN2: Occur stereospecifically with inversion of configuration.

But OSO2Ar NaSPh But H

trans
H H H SPh

But H NaSPh But SPh

cis

H OSO2Ar H H

Pyrolysis of amine oxides : Require a syn-coplanar arrangement of the proton and the N-
oxide group.

CH3 CH3
CH3 H3C H3C
N O N O CH3 Ph
H N(O)Me2 heat
calor
H Ph H CH3 H CH3
H H CH3
CH3 Ph
Z
erythro
eritro
CH3 Ph
H CH3
heat
calor
treo E
72
 Examples of DIASTEREOSELECTIVE reactions

Dehydrohalogenation : the most stable olefin is formed mostly.

t-BuOK CH3 H CH3 CH3

+
I DMSO H CH3 H H
60% 20%
I I
H CH3 H CH3
CH3 H CH3 CH3
CH3 Hb Ha CH3
Ha H CH3 H H
Hb
conformació
most stable més
estable
conformation

Addition to alkenes : the addition of formic acid to norbornene produces a single

stereoisomer (exo)

HCO2H
exclusive
OCOH

73
 Examples of DIASTEREOSELECTIVE reactions

Addition to carbonyl (alkylation) : The addition of methylmagnesium iodide to 2-

phenylpropanal produces twice as much erythro as treo.

H3C H3C OH H3C OH

CH3MgI H H
H +
CHO
H CH3
Ph Ph CH3 Ph H

erythro
eritro (67%) treo (33%)

The selective formation of a particular configuration by generating a new chiral center in

an already chiral molecule is an example of asymmetric induction. The corresponding
transition states are diastereomeric.

Addition to carbonyl (reduction)

OTMS OTMS OTMS

NaBH4
+
O HO H
H HO
O O O
O 66% O 30% O
74
 Examples of DIASTEREOSELECTIVE reactions

DIASTEREOSELECTIVITY IN THE ADDITIONS TO CARBONYL GROUP

The carbonyl group reacts with a large number of Nu (sp3)

n
nucleophiles giving addition reactions in which
the trigonal carbon sp2 is transformed into a π* (C=O)
tetrahedral sp3 carbon. The process involves the
interaction between the HOMO of the nucleophile R
and the LUMO of the carbonyl group.
Repulsion between π
Maximum overlap (C=O) and
This interaction requires a very specific approach between n and π*(C=O) nucleophile
angle of approx. 107º, which is known as the
Bürgi-Dunitz angle.
Bürgi-Dunitz angle
This angle is a compromise between the Nu:
orthogonal approach to maximize the HOMO and
LUMO interaction, and the angular approach to 107º
minimize the repulsion exerted by the electrons of C O
the carbonyl p-system (carbonyl HOMO)
R

75
 Examples of DIASTEREOSELECTIVE reactions

DIASTEREOSELECTIVITY IN THE ADDITIONS TO CARBONYL GROUP

If the two faces of the carbonyl group are not homotopic, the addition of the nucleophile
results in a new center of chirality. The configuration of this new center will depend on the face
of the carbonyl group by which the nucleophile approaches. More specifically, if the two faces
are diastereotopic (differentiable) the attack by one of them may be favored with respect to
the other, giving rise to diastereoselectivity.
There are different factors that control the organic reactions (electrostatic, orbital and steric),
and the steric factors are usually control the stereoselectivity of the carbonyl additions.

OH H
NaBH4
enantiotopic Me
O
Me + Me
faces
H OH
1 : 1
sterically hindered Me Me Me
Aproximación
approach
impedida estéricamente

Me Me Me
NaBH4 Me OH Me H
Me +
O
DIASTEREOSELECTIVE
REACTION H OH

caras diastereotópicas Majority

Majoritario minoritario
Minority
diastereotopic faces
(diastereomers) 76
 Examples of DIASTEREOSELECTIVE reactions

DIASTEREOSELECTIVITY IN THE ADDITIONS TO CARBONYL GROUP

In conformationally flexible molecules (acyclic ketones and aldehydes), diastereoselectivity

can also be observed in the nucleophilic addition, especially when a stereogenic center
exists close to the carbonyl group.
Most studies have focused on the case in which there is a stereogenic center in position α
to the carbonyl group . In these cases it is not so obvious to predict which face of the
carbonyl is less sterically hindered. Two models have been proposed that explain the
diastereoselectivity of the reaction:

Felkin-Anh model
Cram chelate model

77
 DIASTEREOSELECTIVITY IN THE ADDITIONS TO CARBONYL GROUP

Felkin-Anh model

The main key of this model is to avoid the eclipsed conformation between the R substituent
of the carbonyl and the larger (L) substituent in the α carbon in the ET:
Felkin rules:

• ET similar to the reactants.

• Alternating conformations, not eclipsed, to minimize steric interactions.
• The main steric interactions involve the nucleophile, the R group and the large (L) and
medium (M) groups, but not the carbonyl oxygen.

Nu:

H3C (S) H CH3 (M)

O
H
R O
Ph R

(L)

78
 DIASTEREOSELECTIVITY IN THE ADDITIONS TO CARBONYL GROUP

Felkin-Anh model

1. Draw the Newman projection with the most voluminous group ( L ) perpendicular to the
carbonyl group (two possible conformations A and B).
2. Nu- is approached following the Bürgi-Dunitz angle in anti to the L group, and close to the
smaller substituent ( S ) to minimize steric interactions.

R
S R S
Nu S M
L L Nu
L
R majority
HO Nu
O M HO M

M Conformation
Conformación A A Mayoritario
majority
S
diastereoisómeros
R diastereoisomers
L
O O HO
S S M
S
R minority
L L Nu L
Nu Nu OH
M R M
R

Conformation
Conformación B B minority
Minoritario

79
 DIASTEREOSELECTIVITY IN THE ADDITIONS TO CARBONYL GROUP

Cram chelate model E

Br Br Me
Me
Requirements: Mg Mg
O O

•Carbon α asymmetric Me O
R
Me O
R
•Coordinating L S S L
substituent (O, N)
•Presence of metals in
the reaction medium
capable of being
coordinated.
Me OH HO Me

Me O Me O
R R
L S S L

E
If the carbon α has coordinating substituents and there are metals in the reaction
medium, a chelate is formed between the metal, the coordinating atom and the carbonyl
oxygen so that the attack of the nucleophile is produced by the less sterically hindered
face (cyclic model) .
80
 DIASTEREOSELECTIVITY IN THE ADDITIONS TO CARBONYL GROUP

Model of Felkin-Anh

Nu:
L L L
−
δ
R O R OH
R C O C C
S S − M S M
M δ
Nu Nu
Nu:

(L= large; M= medium; S= small)

Cram chelate model
L L

R OH
R C O C
M
X
: S X:
S Nu
Nu:

81
 DIASTEREOSELECTIVITY IN THE ADDITIONS TO CARBONYL GROUP

Cornforth model / Felkin-Anh polar model: Halogens in carbon α

O HO Me Me OH
Me Me Me
MeMgCl
H H + H
H
H H

Cl Cl 88 : 12 Cl

If the carbon α has a halogen, it behaves as if it were the most voluminous group in
the polar Felkin-Anh model , standing perpendicular to the carbonyl (stabilization of the
transition state by hyperconjugation), or it is located in anti carbonyl in the model of
Conforth , to minimize dipolar repulsions between C-X and C = O. In both cases the result is
the same (debate)

σ* C-Z
Z
Z
π* C=O
M
R O
S O
S M
R
Nu
polar Felkin-Anh model

82
 EXAMPLE OF ENANTIOMERICALLY PURE COMPOUNDS
Cl
Me
O O
NHMe Pr H
N Me N
∗ ∗

NMe2
H O N O O
Cl H
N
OH
C etamine
Cetamina thalidomide
Talidomida
feniramine dexchloro
Dexclorofeniramina Picenadol
R - (+) Analgesic and
S is 200 times more Hypnotic and analgesic Analgesic antiemetic.
powerful than R d is active d is opiate S- (-) teratogenic
l is toxic agonist
l is antagonistic
NMe
∗ 2 Ph Ph Me2N
∗
∗ O O O O ∗ At the biological level, bioactive substances
Me Me
exert their action by interacting with
receptors present in cells. These receptors
(proteins, sugars or nucleic acids) are CHIRAL
NOVRAD
DARVON so the activity of the two enantiomers of a
(2S, 3R)-(+)-dextropropoxifeno (2R, 3S)-(-)-dextropropoxifeno
drug can be different.
DARVON analgesic
NOVRAD antitussive

83
 OBTAINING ENANTIOMICALLY PURE COMPOUNDS (OR
ENANTIOMERICALLY ENRICHED)

SYNTHESIS OF ENANTIOMERICALLY PURE COMPOUNDS

Natural products

ENANTIOSELECTIVE REACTIONS

Chiral auxiliaries
Chiral reagents
Chiral catalysts

RESOLUTION OF RACEMATES

Formation of derivatives
Kinetic resolution
Chiral chromatography

84
 ENANTIOSELECTIVE REACTIONS
Chiral auxiliary : An enantiomerically pure substance that covalently bonds to the substrate
and separates from the product after the reaction. By joining the auxiliary to the substrate, the
enantiotopic groups are transformed into diastereotopic and can be differentiated by
conventional achiral reagents.
O O Li O
Ha
Hb LDA MeI

d,l
N -H
2O
NH2 OMe
S-AMP

N O
N N
N OMe LDA OMe MeI OMe O3
N N
Ha Li 99% ee
Hb
+ S-AMP

Some chiral auxiliaries used for the alkylation of ketones

85
 ENANTIOSELECTIVE REACTIONS

Chiral reagent. A conventional reagent can be reacted with an enantiomerically pure

substance to give a chiral reagent. This chiral reagent is able to differentiate groups or
enantiotopic faces.

+ 3 3H
Li AlH4 LiAl H + 2
OH O

achiral reagent 3 chiral reagent

(-)-mentol

O
OH
NMe2
NMe2

LiAlH4 rac.

LiAl(mentol)3H 77% ee

86
 ENANTIOSELECTIVE REACTIONS
Chiral catalyst : The enantiomerically pure substance is used in a catalytic amount
accompanied by a conventional reagent in a stoichiometric amount.
S
P* + C* C*
R + C* (R-C)*
P* R

R S (R-C)*
S + C* (S-C)* P* + C*
C* = chiral catalyst, R= reagent S =
substrate, P* = chiral product

Example: enantioselective epoxidation of sharpless allylic alcohols

Ti(OiPr)4/ DET system catalyzes the enantioselective epoxidation of allylic alcohols
R2
t-BuOOH / CH2Cl2 O HO OH
R1 R3 ee> 90% (-)-DET
R2 R3 Ti(OiPr)4 / (-)-DET cat. EtO2C CO2Et
OH
OH
R1
R1
t-BuOOH / CH2Cl2 R2 HO OH
ee> 90% (+)-DET
Ti(OiPr)4 / (+)-DET cat. O EtO2C CO2Et
OH R3

(diethyl tartrate)
87
 ENANTIOSELECTIVE REACTIONS

Example: reaction with enzymes

The enzyme fumarase catalyzes the addition of water to the face si, si the fumaric acid
leading exclusively to the L-malic acid.

HO2C H Fumarase H CO2H CO2H

Fumarasa
HO H
HO2C OH
H CO2H H2 O H H H
H CO2H
si si

88
 RESOLUTION OF RACEMATES. REVERSIBLE TRAINING OF DERIVATIVES
The racemic mixture is reacted with an enantiomerically pure substance by transforming into a
diastereomer mixture separable by physical methods. Once separated, the reaction is reversed
to obtain each pure enantiomer.
OH OH
HO HO
+
NHMe NHMe
HO HO
adrenalin
R-(-)-adrenalina adrenalin
S-(+)-adrenalina

HO CO2H
Ac (+) tartárico
tartaric
HO CO2H

(-)adrenalin-(+)tartaric (+)adrenalin-(+)tartaric
(-)adrenalina-(+)tartárico + (+)adrenalina-(+)tartárico

crystalization
cristalización

(-)adrenalin-(+)tartaric
(-)adrenalina-(+)tartarico (+)adrenalina-(+)tartárico
(+)adrenalin-(+)tartaric
OH OH

(-) adrenalin
(-)adrenalina (+) tartaric
(+)tartárico (+) adrenalin
(+)adrenalina
89
 KINETIC RESOLUTION OF RACEMATES

The kinetic resolution is based on the fact that the reaction rate of two enantiomers versus a
chiral agent is different. In the most favorable case one of the enantiomers reacts completely
while the other does not at all.

90
 RESOLUTION OF RACEMATES. QUIRAL CHROMATOGRAPHY

Chiral chromatography uses a chiral stationary phase. Generally, silica gel functionalized
with cellulose or amylose derivatives is used for HPLC or with cyclodextrins for GC. Each
enantiomer is retained with a different force and therefore elutes at different times.

RO O Me
O
R= HN
O
RO OR
n Me

Silica gel

Tris (3,5-dimetilfenilcarbamat) de cel·lulosa CHIRALCEL OD (DAICEL)

91
Este material docente ha sido elaborado en el marco de una convocatoria de ayudas para el
desarrollo de proyectos de innovación educativa y mejora de la calidad docente (convocado
por el Vicerectorat de Polítiques de Formació i Qualitat Educativa de la Universitat de
València, en el curso 2017-2018). Código: UV-SFPIE_RMD17-725369

Estas diapositivas forman una parte del contenido docente de la asignatura “Química
Orgánica Avanzada” del Máster Universitario en Química.

https://creativecommons.org/licenses/by-nc-sa/3.0/es/