651.06
Stereochemistry – The Chemistry of Shape
a) Constitutional isomers: order of bond attachment is different
Br
Br
vs.
b) Stereoisomers:
Br
vs.
non-identical compound of identical connectivity
1) Configurational isomers: stereoisomers which are interconvertible by
interchanging groups attached to the same (carbon) atom
vs.
2) Conformational isomers: isomers which are interconvertible by
rotation about single bonds
vs.
when such a rotation requires high energy (> 20 kcal/mol) the
isomers are known as atropisomers
ex.
HO OH
3) Enantiomers:
configurational or conformational isomers which
have a non-superimposable mirror-image relationship
CH3
H
F
Cl
CH3
vs.
F
Cl
H
38
vs.
or
651.06
4) Diastereomers:
any set of configurational or conformational
isomers which do not have a non-superimposable mirror-image
relationship
5) Epimers: diastereomers that differ at one center
Diastereomers behave as different chemical entities (different solubility, reactivity,
spectra, etc.); Enantiomers behave identically except when exposed to a chiral reagent or
polarized light.
o
Optical activity (reported as [! ]20
c = y.yy)
D = x.xxx
20
[! ]D = specific rotation of Na D line (589.3nm)
= [observed rotation (degrees)] / [Length (dm) * g/cc]
c = concentration in g / 100mL
ORD: optical rotatory dispersion
measurement of rotation as a function of wavelength
enantiomers give mirror image curves
Chiral: a stereoisomer non-superimposable on its mirror image
O
S
O
P F
O
R
H
D
Achiral: a stereoisomer superimposable on its mirror image due to a plane of
symmetry
S
H
R
39
H
H
651.06
Reevaluation of Stereochemistry: The Mislow Approach
(JACS 1984, 3319)
-Stereochemistry and chirality have nothing to do with one another. “Chirality and
achirality are purely geometric attributes that are in no way dependent on models of
bonding.” (Mislow & Siegel)
stereogenicity: a property of tetrahedral atoms, in which all four ligands are different;
exchange of any two ligands results in a different isomer. Such (stereogenic) atoms can
be assigned an R or S designation using the Cahn-Ingold-Prelog system.
chirotopicity: a term applied to any atom that exists in a chiral environment; in general,
non-chirotopic atoms lie on a plane or point of symmetry
Note: The term "stereogenic center" is now preferred to "chiral center" or
"asymmetric center".
Ex:
OH OH
OH OH
OH OH
OH OH
Mislow also points out that the term "stereoisomer" is impossible to define in purely
geometric terms and can be abandoned if one attaches no stereochemical significance to
bonding. In addition, if we discard the term "stereoisomer," then "diastereomer" becomes
a meaningless term.
molecules
YES
symmetry
equivalent?
Symmetry equivalent
YES
equivalent?
homoisomers
(the same thing)
NO
enantiomers
sets of atoms
NO
YES
Symmetry equivalent
Symmetry nonequivalent
YES
same
bonding
connectivity?
symmetry
equivalent?
NO
diastereomers
YES
constitutional
isomers
homotopic
equivalent?
NO
enantiotopic
NO
Symmetry nonequivalent
YES
same
bonding
connectivity?
diastereotopic
NO
constitutionally
heterotopic
Flow charts for the classification of symmetry relationships among molecules and topic
relationships among sets of atoms
40
651.06
Topicity
Stereochemical relationships between individual atoms or groups within a single
molecule can be defined in terms of topicity. Thus, two atoms equated by a mirror
reflection of the molecule are enantiotopic and two atoms in equivalent environments
(i.e., the methylene protons in n-propane) are homotopic. Two protons placed in
diasteromeric positions by a mirror reflection are in diastereotopic environments.
! 2,1 (d)
H H
HO
! 3.57 (dd)
! 3.59 (dd)
H H
HO
OH
41
651.06
Cahn-Ingold-Prelog Rules for Assignment of Stereogenicity
1) Assign each subsituent on the stereogenic atom a priority based on the following
considerations:
a) Atomic number (higher atomic numbers get higher priority)
b) In the event of a tie, look at the substitutents attached to each substituent:
c) The higher priority goes to the atom with the highest priority substituent
d) In the event of a tie, give a higher priority to the atom with the greater number
of
higher priority substituents (count multiple bonds as multiple substitutents)
e) In the event of a tie, repeat step b) until a difference is encountered
2) Once prioritites have been assigned, view the molecule from the perspective in which
the lowest priority substitutent is directly behind the stereogenic atom. If the remaining
three substituents are arranged such that traveling from highest to lowest priority occurs
in a clockwise direction, the stereogenic atom is assigned the (R) designation; if traveling
from highest to lowest occurs in a counterclockwise direction, the stereogenic atom is
assigned the (S) designation.
OH
O > C(H)(CH[CCC])2 > C(H)(CH3)2 > C(H)2(C)
Note: If two substituents differ only in their stereogenicity, we give a higher priority to
the (R) configuration and assign r and s designations to the stereogenic center.
Prochirality (Stereotopicity) of sp2 Atoms
Any sp2 atom attached to three different ligands is considered prochiral and the faces of
the multiple bond are either enantiotopic or diastereotopic. The two faces can be
designated as si or re using a variation of the Cahn-Ingold-Prelog convention: the face in
which the travel is clockwise is designated re; the face in which the travel is
counterclockwise is given the si designation.
O
R
O
H
vs.
H
si
R
si
OH
O
pyruvate
reductase
H3C
CO2H
(si facial selectivity)
42
H3C
(S)
CO2H
651.06
Symmetry Operations: operations which convert an object into itself
o
a) Rotation (Cn)
rotation of 360 /n about an axis gives the original species
b) Reflection (σ)
reflection in a plane gives the original species
o
c) Rotation-reflection (Sn) rotation of 360 /n about an axis followed by
reflection in a plane perpendicular to the axis of rotation gives the original species
Relationship Between Chirality and Symmetry Groups
Chiral without stereogenic carbons
Chiral with stereogenic carbons
I II
III IV
Achiral without stereogenic carbons
Achiral with stereogenic carbons
Class I
Cl
H
C
H
H
Cl
Cl
C
OO
optically active
no stereogenic carbons but chiral
43
Cl
H
OO
651.06
Class II
ClH 2C CH3
HO
H 2N
OH
HO
CO2H
HO2C
H 3C CH2 Cl
OH
NH2
non-superimposable mirror images, no plane of symmetry
(lots of molecules in this class)
Class III
H 3C CH3
H 3C
H 3C 2
OH
3 4
1
HO
CH3
CH
4 3 2 1 3
superimposable mirror images
plane of symmetry - C1, C2, C3, C4, OH plane
(lots of molecules in this class)
Class IV
O
OH
OH
HO
OH O
meso compound, 2 stereogenic centers but a plane of symmetry running through
the molecule
44
651.06
Cycloalkanes:
Draw the possible stereoisomers of 1,2-dimethylcyclobutane
CH3
CH3
CH3
H
H
CH3
H
H
H
CH3
CH3
H
meso
enantiomers
Draw the possible stereoisomers of 1,3-dimethylcyclobutane
CH3 H
CH3 CH3
CH3
H
H
achiral
H
achiral
one plane of symmetry
two planes of symmetry
Diastereomers:
OH O
HO
O
H
OH
OH
H
OH
D-erythrose
enantiomers
OH
L-erythrose
Diastereomers
Diastereomers
Diastereomers
enantiomers
D-threose
L-threose
O
OH
OH O
HO
H
OH
H
OH
OH
45
651.06
Stereochemistry of Transition States
Like ground state molecules, transition states also have stereochemical properties:
‡
H
Ph
H
Li
O
‡
Ph
vs.
Li
O
O
O
enantiomers
-same energies, so equally populated
‡
H
‡
H
Ph
O
Ph
Li
vs.
O
O
Li
O
diastereomers
-different energies, so differentially populated
46
651.06
Conformation
a) Ethane
Staggered Ethane Conformation
H
H
H
H
H
HCCH
dihedral
H
H
angle = 60 o
HH
Newman
projection
H
H
H
staggered form = (S)
(rear H's bisect front H's)
Eclipsed Ethane Conformation
H
H
H
HCCH
dihedral
angle = 0 o
H
HH
HH
H
H
Newman
projection
HH
eclipsed form = (E)
(rear H's behind front H's)
E
E
E
E
ENERGY
3 Kcal/mol
S
S
0o
60o
180o
120o
S
240o
Angle of rotation, degrees
47
300o
360 = 0 o
651.06
b) Butane
H3C
H
CH3
H
H
1
H3C CH3
H
H
H
H
fully
eclipsed
(one eclipsed CH3-CH3;
and two eclipsed H-H )
H
2
CH3
H
H CH3 CH3
H
H
H
CH3
gauche
(offset CH3-CH3 and
offset H-H)
H
H
H
H
CH3
H
H3C
H
3
H CH3
partly
eclipsed
H
H
H
H
(two eclipsed CH3-H;
and one eclipsed H-H)
CH3
4
CH3
H
H
H3C
H
CH3
HH
anti
H
(CH3 's 180o apart
and H-H offset)
H
H
CH3
1
1
3
ENERGY
6 Kcal
/mole
2
3
4 Kcal
/mole
4 Kcal
/mole
0.9
Kcal
/mole
0o
60o
2
0.9
Kcal
/mole
4
180o
120o
Angle of rotation, degrees.
48
6 Kcal
/mole
240o
300o
360 = 0o
651.06
Alkane Steric Interactions
Gauche butane
=
0.9 Kcal/mol
Eclipsed H...H
=
1 Kcal/mol
Eclipsed H...CH 3 =
1.5 Kcal/mol
Eclipsed CH 3...CH3 =
4 Kcal/mol
Substituted Butane
X
Y
X,Y = OR, Cl, F (electronegative groups)
Egauche < Eanti
“gauche effect” ascribed to a dipole / dipole interaction
c) Pentane
H
HH
H H
H
1,7 interaction
very bad steric interaction ( > 5 kcal/mol )
d) Butadiene
H
s-trans
H
s-cis
e) acrolein
O
H
H
O
H
H
s-trans
H
H
H
H
s-cis (less stable ≈ 0.5 - 1.0 kcal/mol)
49
651.06
f) alkenes
R1
R2
Y
R3
lobes of !*
R1 eclipses C=Y to allow R2 & R3 to hyperconjugate
(allows overlap with π*)
-contributes electron density to electron deficient π*
(esp. when Y = N, O and R2 & 3 = H > C > N > O > X)
- C-H hyperconjugates better than C-C > C-O (C-N)
Y
R1
R2
R1
R3
Y
R2
R3
∴ the more electropositive R2 & R3 the better
Topics in Stereochem, 1971, 5, 167
ex
H 3C
H
H
O
>
H
H
O
H
H 3C
H
by ≈ 1 kcal/mol
Exception!
F
O
O
F
H
dipole / dipole
repulsion
H
-true for carbonyls
-not true for olefins (due to sterics)
H
H
H
H
H
H
H
H H
1,6 interaction
approx. 1 kcal/mol
H
H
H
H 3C
bisected
approx. 2 kcal/mol
2 kcal/mol energy difference is typical for not eclipsing a bond
(Ebisected - Eeclipsed ≅ 2 kcal/mol)
50
H
H
H CH3
lowest E
0 kcal/mol
651.06
perpendicular
+0 kcal/mol
H 3C
H
H
H 3C
H
H
bisected
+0.5 kcal/mol
H
H
H 3C
H
eclipsed
+0.6 kcal/mol
H 3C
H
H
H CH
3
H 3C
H 3C
H 3C
H
H H 3C
H
H
H H
H
H
eclipsed
+4 kcal/mol
bisected
+5 kcal/mol
substituted sp2 - sp2
O
H 3C
H
O
H
CH3
CH3
CH3
H
H
≈4
:
1
O
H
H 3C
ΔG ≈ 0.5 kcal/mol
O
H 3C
CH3
CH3
H 3C
CH3
≈1
α - CH3 destabilized s-cis
:
H
2
51
β - CH3 destabilized s-trans
651.06
O
O
R1
O
R2
R1
O
R2
ΔG ≈ 10 kcal/mol
NH
R2
ΔG ≈ 15 kcal/mol
s-trans (favored by 3-4 kcal/mol)
O
O
R1
N
H
R2
R1
s-trans
s-cis
O
R1
O
R
N 2
R3
R1
N
R2
R3
ΔG ≈ 12 kcal/mol
for R2 larger than R3
Dale, Stereochemistry & Conformational Analysis (Verlag Chemie)
O
CH3
H
N
CH3
52
651.06
g) Cyclohexane
3 representations
Hax
Hax
H eq
H eq
3
Hax
Heq
4
2
5
Heq
1
Heq H 6 Heq
ax
Hax
Hax
a dot denotates a non-visible
bond (H eq on C-1) toward the observer.
Hax Hax
H eq
2
H eq
Hax
Heq
6
1
Hax H 4 Hax
ax
Heq
an open circle denotates an invisible
bond (H eq on C-4) away from the observer.
H
H
H
3
5
4
H
H
H
H
H
1
2
6
H
H
H
53
H
651.06
interconversion of cyclohexane conformers
Chair 1
H eq
H eq
Chair 2
Hax
Hax
Hax H
eq
3
5Heq
4
2
Hax
1
H "ax"
6
Heq Hax Heq
Hax
H"eq"
H"eq"
H "ax" H"eq"
H"ax"
4
2
3
6
1
H "ax"
5
H"ax"
H "eq"H"ax"
H"eq"
H"eq"
Note that the ring flip
interchanges axial and
equatorial protons
Bring C2,1,6,5 all into same plane
while keeping C 3,4 unchanged
H
H
H
3
H
4
H
2
C1 C6 5
H
4
H
H
Half-Chair 1
2
C1
3
C6
5
Half-Chair 2
The eight hydrogens
shown are all eclipised
HH
H
H
In the twist-boat form, the two flagpole
hydrogens are "offset" so they do not
directly run into each other as in the
boat form.
HH
H H
H
H
H
H
Twist-boat (two views)
H
H
HH H
H
H
4
H
H
H 1 HH
HH
H
H
HH
HH
H
H
1
4
H
"Flagpole Hydrogens"
Boat (three views)
54
H
651.06
energetics of the cyclohexane interconversion process
Half-chair 1
E
n
e
r
g
y
Half-chair 2
boat
10.1
Kcal/mol
1.5 kcal/mol
Twist boat 2
Twist boat 1
10.1
Kcal/mol
3.8
Kcal/mol
Chair 1
Chair 2
Reaction co-ordinate
Substituted Cyclohexanes
a) Methylcyclohexane
Hax
Hax
3
H eq
H eq
2
Hax
1
Hax
Heq
4
5
Heq H 6Heq
ax
Hax
CH3
H
H
H
5
3
H
H
4
H
H H
H
H
1
2
H
H eq
6
H H
55
H eq
H
Hax Hax
Hax
2
6
1
4
Hax H
Hax
ax
Heq
CH3
651.06
interconversion of equatorial and axial methylcyclohexane
Hax
Hax
Hax Heq
3
5 CH3
4
H eq
H eq
2
H
H
1
6
Heq Hax Heq
Hax
Hax
HH
2
H
H
4
3
6
H
H
H
1
H
Chair 1
H
5
CH3
H
Chair 2
H
CH2
H
H
H CH3
Hax Hax Hax
H eq
H eq
2
6
1
4
Hax H
ax
Hax
H
Heq
H
CH3
The equatorial methyl group is in
an anti-butane conformation;
no destabilizing interactions.
H
H
H
2
1
6
H
H
CH3
H
H
Newman
projection of
gauche butane;
(0.9 Kcal/mol)
destabilization.
The axial methyl group is in a gauche
butane conformation with the two axial
protons on C-1 and C-3; a total of
(1.8 Kcal/mol) destabilization.
The amount of energy necessary to convert from an equatorial form to an axial form is
called the A-value for a given substituent.
review:
Topics in Stereochem., 1, 199?
Typical “A” Values For Monosubstituted Cyclohexanes
(Kcal / mol)
F
0.25
Cl, Br, I 0.50
CH3
C2H 5
OH
OCH3
0.70
0.70
n-C3H 7
i-C3H7
2.10
2.10
NH2
NR2
1.80
2.10
t-C4 H9
5.60
1.20
0.20
C6H 5
3.10
CO2H
CN
56
(Kcal / mol)
1.80
1.90
651.06
b) trans-1,2-dimethylcyclohexane
H
H
H
H
H
H
3
2
H
4
1
H
6
H
5
H
HCH43 H
H
CH3
H
CH3
2
H
H
3
H
H
H
2
H
H
6
4
H
H
CH3
Chair 2 <1%
H
1
5
H
Chair 1 >99%
H
H
6
1
CH3
H
CH3
H
H
2
H
The diequatorial dimethyl cyclohexane
has one gauche butane type interaction...
this results in a destabilization of the
diequatorial isomer by 0.9 Kcal/mol.
The difference in energy between
the two forms favors the diequatorial
conformer by 2.7 Kcal/mol, this means
that this form will represent 99% of
the equlibrium mixture.
57
H
CH3
1
6
H
CH3
H
H
The two axial methyl groups
(on C5,6) are each in a gauche
butane conformation
with two axial protons
on C-1 and C-3, and C-2 and
C-4
respectively; this results in
a total of four destabilizations,
each worth 0.9 Kcal/mol...
Total = 3.6 Kcal/mol.
651.06
c) cis-1,2-dimethylcyclohexane
H
H
H
H
H
H
3
2
H
H
5
4
1
6
H
H
CH3
H
HH
2
H
H
CH3
3
H
1
H
H
H CH3
H
5
CH3
Chair 2
H
H
H
2
1
6
H
4
6
Chair 1
H
H
4
H
H
H
CH
CH3 3
H
H
2
H
The monoaxial, monoequatorial
dimethylcyclohexane has three
gauche butane type interactions;
this results in a destabilization of
this isomer by a total of 2.7 Kcal/mole.
H
H
H
1
6
H
CH3
CH3
Same for this form.
Each of these isomers will be present in equlibrium in equal
amounts, (50% : 50%) since they are of equal energy.
d) cis-1,3-dimethylcyclohexane
Chair 2
Chair 1
H
H
H
H
H
H
H
CH3 H
H
CH3
H
H
HH
H
H
H
H
H
H
CH3
CH3
H
H
H
H
H
2
1
H
CH3 CH3
6
1,3-diaxial CH3-CH3 interaction
(3.7 Kcal/mol destabilization)
Chair 1 has no destabilizing
steric interactions; the two
equatorial methyl groups are
both anti-butane type.
Chair 2 has two gauche butane interactions
(0.9 kcal/mole each; dotted arrows), in
addition to the 3.7 Kcal/mol (solid arrows)
for a total of 5.5 Kcal/mole!
58
H
H
651.06
e) Various mono-substituted cyclohexanes
= H coming out of page
= H going into page
dot ! Hd
H
H
H
CR1 R2R3
Hb
R2
Ha
H
H
R1
H
Hb Hc
He
Hd
H
H
CR1 R2R3
H
H
R1
Ha(eq)
Hc
Ha
dot ! He
H
R3
R2
equatorial
H
R3
Ha(eq)
axial
Destabilizing Interactions
R1
R2
R3
Equatorial
Axial
H
H
H
none
(2) g.b.
Energy Diff.
(kcal/mol)
1.8
Me
H
H
(2) g.b.
(2) 1,3-diax.
5.6
H
Me
H
(1) g.b.
(3) g.b.
1.8
H
H
Me
(1) g.b.
(3) g.b.
1.8
Me
Me
H
(3) g.b.
5.6
H
Me
Me
(2) g.b.
(1) g.b. plus
(2) 1,3-diax.
(4) g.b.
Me
H
Me
(3) g.b.
5.6
Me
Me
Me
(4) g.b.
(1) g.b. plus
(2) 1,3-diax.
(2) g.b. plus
(2) 1,3-diax.
1.8
5.6
f) 6-member ring heterocycles
H
H
O
O
H
CH3 H
CH3
CH3
CH3
H 3C
O
O
H 3C
CH3
CH3
favored ΔGo ≈ -2 kcal/mol
Why?
59
651.06
g) Other rings
5:
HH
H
H
H
H
H
H
H
H HH
“envelope”
“half-chair” (2 of them)
8:
H
HH
H
“boat-chair”
“chair-chair” or “crown”
10:
HH
HH
“boat-chair-boat”
cyclohexene:
H
H
H
H H
H H
H
H
60
H
H H
H H
H
H
651.06
h) Bicyclics
decalin:
H
trans
H
H
H
Ha
H
Hb
ring-flip
Ha
Hb
H
cis
H
H H
H
(3) 1,6-interactions = 3 ( 0.87 kcal/mol ) = 2.61 kcal/mol
methyldecalin:
CH3
CH3
vs
H
H
H
H
H
CH3 H
H
CH3
H
VS
H
4 gauche
5 gauche
ΔE = 0.9 kcal/mol
61
651.06
Stereochemistry and Chemical Reactions
Increasingly important topic: the FDA has mandated that all new drugs be sold as single
enantiomers! Much effort is now put in to the development of enantioselective reactions
and asymmetric catalysis.
A) Achiral compounds.
Achiral compounds react with achiral reagents to produce achiral products.
1) Addition of an achiral reagent to an achiral substrate
a) bromination of an achiral olefin
Formation of bromonium ion intermediate from either face of the
olefin generates the same symmetrical (achiral) species
Br+
C CH2
CH3
CH3
CH3
C
Br2
CH2
CH3
achiral
Br-
BrC
CH3
CH3 Br
C
CH3 CH2 Br
Achiral and identical
Identical
achiral
CH3
Br-
CH2
Br-
Br+
CH3 CH2 Br
C
CH3 Br
b) osmylation of an achiral olefin
Syn addn OsO 4
below olefin.
CH3
CH3
CH3
CH3
achiral
achiral
1) OsO4
2) NaHSO3
CH3
CH3
C CH
CH3
3
C
OH
OH
Achiral and identical
Syn addn OsO 4
above olefin.
62
OH
HO C
CH3
CH3
C
CH3
CH3
651.06
B) Prochiral compounds.
Prochiral compounds are an important subclass of achiral compounds (those
containing no preexisting chiral centers). Prochiral materials bear at least one sp2
atom which becomes a stereogenic center in the course of a chemical reaction.
Prochiral compounds react with achiral reagents to produce racemic products
(enantiomers have exactly equal free energy and therefore will be formed in equal
amounts when produced from achiral reagents). Optical activity never arises
spontaneously in the reactions of prochiral compounds.
Prochiral center
(becomes a chiral center
in the product)
H
CH3
H
C
CH2
Br-
Br+
C
CH2
CH3
Br -
Br 2
H
prochiral
CH3
Br -
C
50% R
C
CH2Br
The two enantiomers are produced in
exactly a 50:50 ratio
or
CH3
Br
H
CH2
Br-
CH3
Br+
CH2Br
H
50% S
C
Br
Formation of bromonium ion intermediate is equally likely from either face of the olefin.
c) bromination of a prochiral olefin
d) osmylation of a symmetrical trans-olefin
Syn addn OsO 4
below olefin.
OH
Anti addn
CH3
H
CH3
CH3
H
CH3
OH
H
meso
H
1) OsO4
2) NaHSO3
Syn addn OsO 4
above olefin.
H
CH3
CH3
CH
C
OH
OH
50% R,R
OH
HO
C
H
C CH3
CH3
H
50% S,S
These enantiomers will be produced in equal amounts since OsO 4 is an
achiral reagent and access to either face of the olefin is equally likely.
Anti addition (to give the meso compound from a symmetrical trans-olefin)
is not observed since OsO4 adds via a concerted syn addition mechanism!
63
651.06
C) Chiral compounds.
1) Pure enantiomers
a) bromination of a single enantiomer of a prochiral olefin
Formation of bromonium ion
intermediate is preferred from
the top face (steric effect).
Symchiral
single enantiomer
(optically active)
prochiral center
H
C CH2
CH 3
H
(S)
Cl
Br
H
Br-
Br+
H
C
CH2
H
C CH 3 Br Cl
Br 2
This stereogenic center
remains the same in
starting material and
product.
(S)C
3
optically active
(S,R) diastereomer
Major product
Cl
Br -
C
CH 2
C CH 3 Br+
Cl
CH CH2Br
Major
H
H
H
(R) C
Minor
CH2Br
H
Br-
(S) C
H
(S) C
Br
CH3
optically active
(S,S) diastereomer
Minor product
Cl
The two transition states have different energies; therefore the two
diastereomeric products will be formed in unequal amounts.
When reactions can produce a mixture of diastereomers, the products will always be
formed at different rates; thereby producing unequal amounts of the diastereomers. The
ratio of the diastereomers can be either almost 50/50 or may range up to >99.9999 to
.0001 but, in principle, one expects that diastereomers should be formed in differing
amounts since they have different free energies.
64
651.06
Stereospecificity:
The product (or mixture of products) from the reaction of two (or
more) isomeric starting materials under the same reaction conditions are different.
Br
+
Br
+
Br2
Br-
Br
+
Br
erythro
Br
Br
Br
-
+
+
Br2
Br
+
Br
Stereoselectivity:
Br
Br
Br
threo
Br
given a particular starting material and a particular set of reaction
conditions, one of the possible diastereomers / enantiomers is formed in excess.
H
MeMgBr
O
OH
tBuOOH
OH
Ti(OiPr)4
HO
CO2Et
HO
CO2Et
65
OH
O
651.06
2) Racemic mixtures
When the starting material of a chemical reaction is a racemic mixture (a 50:50
mixture of one enantiomer and its mirror image) the creation of a new chiral center again
results in the formation of diastereomers. However in this case, each of the diastereomers
is accompanied by equal amounts of its mirror image so a racemic mixture of
diastereomeric products is formed.
a) bromination of a racemic prochiral olefin
Br+
C
CH2
H
C CH3 BrH
H
H
(S)
Cl
C CH2
CH3
Cl
(S,R) stereisomer
Major product
-
Br
C
Cl
C
CH3
H
Cl CH2Br
(R)C
CH3
(R,R) stereisomer
Minor product
Br-
C
Cl Br+
(S) C
H
(R) C
Major
CH 2Br
H
CH2
Cl
Br
CH3
(R,S) stereisomer
Major product
The (S,R/R,S) racemic stereoisomers are diastereomeric to the (R,R/S,S) racemic stereoisomers.
66
enantio
mers
H
(R) C
Minor
CH 3
H
Br
H
enantiomers
CH3
Br 2
Br
CH3
(S,S) stereisomer
Minor product
Cl
C CH2
Cl
Br
C
(S) C
(S) C
Br+
H
H
H
Minor
H
CH 2Br
H
CH2
C CH3 Br+
50:50 R:S
Enantiomeric mixture
(R)
CH3CH2Br
C
(S)
Major
H
H
H
H
Br 2
Cl
C CH2
Cl
Br
H
(R) C
651.06
3) Resolutions of racemic mixtures.
An analogous situation occurs when we consider the reaction of enantiomers with
a chiral reagent. This also results in the formation of a pair of diastereomers; once again,
since diastereomers have different energies, they should be formed in unequal amounts.
This allows us to perform resolutions (chemical separations of enantiomers).
Classical resolution:
Single
enantiomer
(1.0 equivalent)
slow
R*
R,S
fast
a racemic dl pair
(1:1 mixture
of enantiomers)
R,R*
S,R*
Diastereomers
If this reaction is run until the total amount of the
slow-reacting component has been completely consumed,
it will produce a 50:50 mixture of two diastereomers which
can be separated. If we then perform chemistry on the
diastereomers to regenerate the two component parts, we
would have achieved a classical resolution by forming
(and then cleaving) the diastereomeric derivatives.
Kinetic resolution:
Consider the limiting case where the slow reaction is about 100 times slower than the fast
reaction, and we use only 1/2 the stoichiometric quantity of our optically active reagent R*;
this will provide the following mixture:
Single
enantiomer
(0.5 equivalent)
slow
R,S
R,R* (almost none formed ...ca. 0.5% yield)
R*
a racemic dl pair
(1:1 mixture
of enantiomers)
fast
S,R* (50% formed) + 50% recovered R enantiomer
Easily separated; each in essentially optically
pure form.
67
651.06
D) Asymmetric induction.
Reaction of achiral compounds with optically active chiral reagents allows the
stereogenic center of the reagent to take an active part in the creation of a new
stereogenic center on the substrate (a diastereomeric process). To the extent that these
two reaction pathways differ in energy, absolute stereochemistry will be induced in the
product; a process referred to as asymmetric induction. We measure the effectiveness
of such a process in terms of enantiomeric excess (ee).
Pro-R transition state
Cl
R
B
O
H
Me
H
Me
t-Bu
Cl
H
+
Me
prochiral center
t-Bu
C
CH3
Severe
interaction
O
Me
Me
Me
Me
B
Me
(R) Center created
at *'d stereogenic atom
Pro-S transition state
Prochiral ketone
Me
Me
R
B
H OMe
*
t-Bu
Cl
Cl
R
B
O
H
t-Bu
H
Me Me
Moderate
interaction
Cl
H
Me
+
R
B
O
H
t-Bu
*
Me
(S) Center created
at *'d stereogenic atom
The optically active borane is unsymmetrical. There are two different orientations (transition states) from which the
hydrogen from the borane can be delivered to the carbonyl group of the ketone. The (Pro-S) transition state has
smaller through-space interactions between the methyl group on the borane and the methyl group of the ketone and is
therefore preferred.
68
651.06
Stereochemistry of Reactions (cont.'d))
1) Cram’s Rule
To explain the selectivity seen in nucleophilic addition to carbonyls
NaBH 4
+
O
OH
OH
Minor
MAJOR
Cram proposed the following rule (where S, M, L denote the size of the
substituent)
JACS 1952, 74, 5828
JACS 1959, 81, 2748
HO Nu
S
M
R
L
O
S
M
R
Nu OH
R
L
L
M
S
M
O
S
L R
M
Nu
OH
S
Nu
Nu
R
L
M
R
minor
OH
L
S
Nu
major
1
:
1.5 - 4
According to Cram, the nucleophile should attack from the side of the
smallest substituent.
-assumes a reactive conformer when L eclipses R
-problem: when M = Cl the wrong product is predicted
69
651.06
2) Karabatsos model
MO
S R L
Nu
-assumes a reactant-like transition state
-Nucleophile approaches from side of S.
-model breaks down when S ≠ H
JACS 1965, 87, 1367
JACS 1969, 91, 1124, 3572 & 3577
3) Felkin-Ahn model
O S
L
R M
Nuc
vs
M O
L
S R
A
B
TL 1968, 2199
-observation
previous models suffer from torsional strain
-assumptions:
a) reactant-like transition state
b) incoming nucleophile avoids L
c) incoming nucleophile will approach anti to most electroneg. atom
Which to use?
a) as M or R increase in size, B is favored over A
b) if an electronegative atom (-O, -N, -X) is present, make it L and
make the larger of the two remaining substituents M.
c) does not work well for cyclic systems
70
651.06
tBu
OH
OLi
+
tBu
O
OH
A (syn / Cram)
H
tBu
+
O
C (anti / Cram)
86%
0%
O
tBu
OH
tBu
+
O
OH
B (syn / anti-Cram)
O
D (anti / anti-Cram)
14%
0%
syn / anti > 98 : 2
Cram / anti-Cram
6:1
4) Cieplak Hypothesis
O
CH3
MeLi
OH
+
OH
CH3
minor
MAJOR
Cieplak proposed “that the carbonyl group has undergone extensive pyramidalization in
the transition state, and the outcome is primarily a consequence of interactions between
the vicinal occupied σ orbital and σ∗ orbital of the incipient bond between the nucleophile
and the carbonyl group.”
Eliel & Wilen, Stereochemistry of Organic Compounds, Wiley & Sons: NY, 1994.
Nu
Filled
O
Filled
Vacant !"
vs
O
Vacant !"
Nu
axial approach
equatorial approach
71
651.06
O
HO
OH
NaBH 4
+
i-PrOH
X
X
H
X
Z
E
X
E/Z
Cl
59:41
p-Cl-C6H5
60:40
C6H5
58:42
p-HO-C6H5
44:56
p-H2N-C6H5
34:66
H
O
O
RCO3H
+
F
F
66
F
:
see: JACS 1981, 103, 4540
JACS 1989, 111, 8447
JACS 1986, 108, 1598
72
34
651.06
5) Bürgi - Dunitz Angle
Angle of nucleophilic attack to an sp2 hybridized carbon should be ~110o!
~110 o
O
Nuc
This was proved by the following crystallographic data
O
O
O
CH3
O
N(CH3) 2
Ph Ph
N
O
Methadone
O
Cryptopine
O
O
O
O
O
O
O
N
O
O
O
O
O
O
O
O
H
O
O
N
N
Protopine
Retusamine
Clivorine
CH3
N
C O
Compound
C=O Length (Å)
N…C Distance (Å)
N-C-O Angle
methadone
1.214
2.910
105.0
cryptopine
1.209
2.581
102.2
protopine
1.218
2.555
101.6
clivorine
1.258
1.993
110.2
retusamine
1.38
1.64
110.9
N-brosylmitomycin A
1.37
1.49
113.7
JACS 1973, 95, 5065
JACS 1974, 96, 1956
73
651.06
Ph
Ph
O
Ph
Ph
NaBH4
NH
NH
Why?
O
O
6)
OH
Baldwin’s Rules (J. Chem. Soc. Chem. Comm. 1976, 734)
Exo
X
X
Y
Y
Endo
Y
X
X
Y
a) Tetrahedral systems
1) 3 to 7-Exo-Tet are all favored processes with many literature precedents
2) 5 to 6-Endo-Tet are disfavored
!
!
X
X
Y
3-Exo-Tet
!=
Y
X
180"
X
X
Y
Y
4-Exo-Tet
5-Exo-Tet
Y
Y
X
X
Y
Y
X
5-Endo-Tet
6-Endo-Tet
7-Exo-Tet
74
X
Y
6-Exo-Tet
651.06
b) Trigonal systems
1) 3 to 7-Exo-Trig are all favored processes with many literature precedents
2) 3 to 5-Endo-Trig are disfavored, 6 to 7-Endo-Trig are favored
X
!
Y
Y
X
3-Exo-Trig
X
X
5-Exo-Trig
Y
Y
Y
7-Exo-Trig
Y
Y
X
X
3-Endo-Trig
X
Y
X
6-Exo-Trig
Y
4-Exo-Trig
Y
Y
X
Y
X
!
X
! = 109"
4-Endo-Trig
X
6-Endo-Trig
5-Endo-Trig
7-Endo-Trig
c) Digonal Systems
1) 3 to 4-Exo-Dig are disfavored processes, 5 to 7-Exo-Dig are favored
2) 3 to 7-Endo-Dig are favored processes
X
!
! " 120#
!
X
Y
!
Y
75
!
651.06
X
Y
3-Exo-Dig
X
X
X
Y
3-Endo-Dig
Y
4-Exo-Dig
X
Y
6-Exo-Dig
5-Exo-Dig
Y
7-Exo-Dig
Y
Y
Y
X
X
X
X
6-Endo-Dig
5-Endo-Dig
4-Endo-Dig
Y
Y
X
7-Endo-Dig
ex.
O
O
rig
-T
xo
5-E
O
HO
MeO
5-E
nd
o-T
rig
CO2Me
O
7) Anomeric Effect
A polar group on a carbon α to a heteroatom prefers the axial position.
One set of lone pair electrons on the polar atom connected to the carbon
atom can be stabilized by overlapping with an antibonding orbital of the
bond between the carbon and the other polar atom.
Y
X
Y
vs
X
!"
!"
76
X= electronegative atom
651.06
OH
HO
HO
OH
OH
O
HO
HO
OH
OH
O
OH
• Kinetic anomeric effect:
O
Cl
Ag+
O
O
MeOH
OMe
O
OMe
8) Stereoelectronic Control
O
OLi
O
LDA
E
E
O
+
E
cis
45
trans
:
55
look at the transition state:
E
cis
E
cis
(cis)
O
boat-like
OLi
O
trans
E
trans
(trans)
E
77
chair-like
651.06
O
O
O
R
CH3 I
base
O
CH3
R
R
CH3
R
+
trans
cis
R
H
2
1
CD3
2
1
CO2R
4
1
E
axial
CO2R
E (ax.)
OR
CO2R
base
H
H
minor
OM
(5-7:1)
CO2R
equatorial
E (eq.)
E
MAJOR
see:
JACS 1956, 78, 6629
9) Macrocyclic Stereocontrol
1) LDA
O
O
O
2) MeI
+
O
50
O
:
Tetrahedron 1981, 37, 3981
works for rings ≥ 9 members
78
O
1
651.06
O
H
O
E
approaches from exterior of the ring
See, for ex. JACS 1984, 106, 1148
10) Acyclic Stereocontrol
The stereochemistry of the molecule near the reaction site determines /
influences the stereochemistry of the reaction product.
OH
R1
LDA
CO2R2
O
O
OR2
H
Li O
Li
O
R1
R1 H
OR2
E
N
OH
CO2R2
R1
E
t
BuOOH, VO(acac)2
OH
CH2 Cl2, 0o C
O
+
OH
95
for a general review: Tetrahedron 1980, 36, 3
79
:
Li
O
5
OH
651.06
Example – Diastereoselective reduction of β-hydroxyketones:
OH
O
OH
O
NaBH4
Zn(BH4)2
OH
OH
OH
OH
O
O Zn
H-BH4
OH
O
NH4+ -BH(OAc)3
OH
OH
OH
H
OH
O
H B OAc
O
OAc
80
OH
H
OH