Advanced Organic Chemistry III

1. Stereochemistry of Organic Compounds

(1) Structure and size of organic compounds
(a) Bond length

Contents

bond
CH
CC
CN
CO
CF
C=O

1. Stereochemistry of Organic Compounds

2. Stereocontrol in Organic Reactions
3. Stereocontrol in Catalytic Reactions

References

length ()
1.09
1.53
1.47
1.43
1.38
1.22

bond
CF
CCl
CBr
CI

length ()
1.38
1.77
1.94
2.14

bond
CC
CC=
CC
=CC=
=CC
CC

length ()
1.53
1.50
1.46
1.48
1.4
1.38

bond
C=C
C=C=
=C=C=

length ()
1.34
1.31
1.28

CC
1.20
CC (in C6H6) 1.39

Bond length is defined as the distance between two nuclei.

Distortion hardly affects bond length.

General
Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds, Wiley, 1993.
Robinson, M. J. T. Organic Stereochemistry, Oxford University Press, 2000.
( , , 2002.)
Kagan, H. B. La Stereochimie Organique, Press Universitaires de France, 1975.
( , , 1981.)
, , NMR , , 2012.

(b) Bond angle

Bond angle is defined with the positions of three nuclei.
2
3
Typically, the bond angles involved with sp-, sp -, and sp -hybridized carbons are 180, 120, and
109.5, respectively.
Distortion hardly restricts the bond angles. Therefore, the CCC bond angle in cyclopropane is
3
allowed to be 60. However, the strain does not highly distort the angle of two sp orbitals. The
CC bond in cyclopropane is constituted with a banana shaped orbital.

Abbreviations of substituents
http://pubs.acs.org/paragonplus/submission/joceah/joceah_abbreviations.pdf

(c) Dihedral angle

e

dihedral angle

Bond angle is defined with the positions of four nuclei.

Shape of molecule can be defined with bond lengths, bond angles, and dihedral angles.
In stable conformation, each dihedral angle should be 60, 180, or 120 (if the molecule have
2
sp -hybridized atom). (see Conformation of organic molecules)

(d) Van der Waals radius

atom
radii ()
CH3

2.0

Bondi, A. J. Phys. Chem. 1964, 68, 441.

Cl

Br

1.20

1.70

1.55

1.52

1.47

1.80

1.80

1.75

1.85

C6H6 (thickness)

1.7

Generally, van der Waals radius is useful for considering the

bulkiness of substituent.
However, van der Waals volume, which is calculated from the radii,
does not contains the effect of bond rotation.
Solvent accessible surface area is sometimes used for evaluating
the accessibility of a reagent to a substrate.

I
1.98

(e) A-value

(2) Chiral Compounds and Enantiomers

R

Chiral molecule can not overlap with its mirror image. Therefore, chiral compounds have no
symmetry plane () or rotation-reflection axis (Sn).
Achiral compounds are the compounds that are not chiral.
"Chiral molecule" means the molecule possessing any chirality.
"Chiral compound" means the mass of chiral molecules.
"Racemic compound (racemate)" means the 1:1 mixture of both enantiomers (R and S). Each
molecule constituting a racemic compound should be "chiral molecule".
"Optically active compound" means the chiral compound other than racemate. A mixture of
enantiomers is often categorized as optically active compounds, even if R:S is 51:49. However,
the term often indicates pure enantiomer (enantiopure compound or optically pure compound).
"Enantiomer" originally means the mirror image of a chiral molecule (e.g. (S)-2-octanol is the
enantiomer of (R)-2-octanol.). The term often indicates the enantiopure compound, whose
absolute configuration has been known.
"Diastereomer" means any stereoisomers other than enantiomer.
"Epimer" means stereoisomers bearing only one chiral center with the opposite absolute
configuration. The configuration of other chiral centers in the epimer must be identical to the
original compound.

R
G eq

A value = G 0 = G ax G eq (in kcal/mol)

G ax

A-value

H
Me
Et
i-Pr
Cy
t-Bu

0.00
1.74
1.79
2.21
2.2
4.7

R
CCH
CH=CH2
Ph
SiH3
SiMe3
SnMe3
Sn(i-Pr)3

A-value
0.41
1.49
2.8
1.45
2.5
1.0
1.10

R
F
Cl
Br
I
OH
NH2
+
NH3

A-value

0.25
0.53
0.48
0.47
0.60
1.23
1.7

OMe
O(t-Bu)
OSiMe3
NHMe
NMe2
PMe2
PPh2

A-value
0.55
0.75
0.74
1.29
1.53
1.5
1.8

R
CHO
COMe
CO2H
CO2Me
CN
CF3

A-value
0.56
1.02
1.4
1.2
0.2
2.4

A-value is widely used for discussing the steric effect of substituent.

In general, A-value correlates with the size of substituent. Furthermore, the value includes the
effect of bond rotation. Therefore, the value reflects the steric environment around the atom
bearing the substituent.
A-value is affected by bond length (CR) as well as by van der Waals radius.

(f) Tips to consider steric effect of a substituent

(a) Central chirality

i) Where is the most important for the related steric repulsion (near or far)?
Me
Me
Me
Me vs
Me
vs
Me
Me
Me
If you will consider the steric effect around the atom
, t-Bu or 2,6-xylyl must be larger than
-CC(t-Bu) group.
If you would like to create a steric hindrance far from
, -CC(t-Bu) should be larger than t-Bu
and 2,6-xylyl.

180
a

ii) Snapshot or motion blur? (in the case of aryl group)

Me

The chirality caused by asymmetric atom is called "central chirality".

Asymmetric atom is not limited to carbon (e.g. N, S, P, etc.). Lone pair can function as a
substituent and is regarded as atomic number 0 in CIP rule (see 35).
OMe
N
NH 2
+
P
Ph
N
Me
Ph S O
Me
N
CO2H
Ph
Me
Ph
Me
H
5
4
1
2
3
Spiro compound 6 is chiral, although they seem to have no asymmetric atom.
compound 7 is achiral because its tetrahydrofuran ring is symmetry plane.

Cl

However,

180

O
=
O O
O
O
O
O
6
7
The molecules possessing symmetry plane (see 8, 9) or rotation-reflection axis (see 10) must be
achiral, even if they have asymmetric atoms (e.g. meso compound).
OH
O
O
Me
HO
OH
OH OH
Me =
Me
Me
Me
Me
O
O
Me
Me
OH
10
8
9

Me
(top view)

(side view)

(snapshot)

(motion blur)

Snapshot may be preferable when you consider the steric hindrance in dynamic phenomena.
Motion blur may be suitable for thermodynamic phenomena.
In snapshot steric effect, phenyl group can be regarded as a smaller substituent than methyl one.
In motion blur steric effect, phenyl group can be regarded as a larger substituent than secondary
alkyl ones.

Metal complexes are possible to be chiral when they are tetrahedral, trigonal bipyramidal, or
octahedral.

(b) Axial chirality

(d) Notations of absolute configuration

Axial chirality takes two forms: atropisomerism and isomerism in allenes.

1) R/S notation
According to CIP rule, determine the priority of each substituent involved with the chirality.

Atropisomerism
Atropisomerism is caused by inhibition of free rotation of a single bond. The inhibition of free
rotation is often observed in the biaryl compounds bearing four ortho-substituents or some
sterically hindered carboxamides.
a

a
a

Central chirality
a
b

1a

a
b

ab
3

A racemate of axially chiral compound can be resolved into each enantiomer when the rotation
barrier is over 20 kcal/mol.
Axial chirality will be stable at room temperature when the rotation barrier is over 30 kcal/mol.
Herical chirality is originated from the accumulation of axial chirality.

Ph

b'

Isomerism in allenes
2
Each terminal carbon in C=C=C is plane because it is sp -hybridized. One of the planes is
perpendicular to another because the internal carbon in C=C=C is linear and hybridized in sp
manner to form two CC double bonds. Therefore, substituted allenes are possible to be chiral
as with biaryls.
The chirality is seen in some spiro bicyclic compounds and alkylidene cycloalkanes.
a
CO2H
HO 2C
a
H
H

b
HO
C
Me
2
b
H
H
a b

d
b

b'

a a' b
clockwise R
anticlockwise S

a'

a
b

d
a

abc
clockwise R
anticlockwise S

a > b, c > d

iv) To distinguish the axial chirality from others, prefix 'a' (or sufix 'a') is sometimes attached to the
chiral descriptor R or S (e.g. (aS)-2,3-pentadiene or (Sa)-2,3-pentadiene)
Planar chirality (cyclophanes, trans-cycloalkenes etc.)
i) Determine 'pilot atom' from the bridging tether. The pilot atom is out of the plane and closest
to the plane. There are two candidates in general. The pilot atom is the candidate binding to
the in-plane atom with higher priority in CIP rule.
ii) Among the atoms in the chiral plane, the atom binding the pilot atom is assigned to 'a'. The
next atom is 'b', and the third atom is 'c'. If there are two candidates, the atom with higher
priority is assigned to 'c' (or 'b').
iii) View the molecule from the pilot atom.

(c) Planar chirality

Planar chirality appears when a planar molecule loses its symmetry plane by bridging with short
tether or forming -complex.
The chirality is seen in some cyclophanes, metallocenes, and trans-cycloalkenes.

CO2Me
Br

N
Me

a' 2

Axial chirality
i) Determine the priority of the two substituents on each atom involved with the chiral axis.
ii) The sequence of substituents becomes a > b > c > d or c > d > a > b. Both sequences result
in the same configuration.
iii) Put the substituent with the lowest priority (d or b) on the location far from you. Confirm the
direction of a b c (or c d a).

t-Bu

Fe

abc
clockwise R
anticlockwise S

a >b

Me

O
OH
OH

(in the case of spiro compounds)

a >b >c >d

=
b

a
180

Br
: pilot atom

CO2H

Br

abc
clockwise R
anticlockwise S

iv) To distinguish the planar chirality from others, prefix 'p' (or sufix 'p') is sometimes attached to
the chiral descriptor R or S (e.g. (pS)-(E)-cyclooctene or (Sp)-(E)-cyclooctene)
Planar chirality (metallocenes)
Three rules have been proposed to assign the stereochemical descriptor, R or S, for the planar
chiral metallocenes. One is based on central chirality and proposed by Prelog, Cahn, and
Schloegl (Rule 3). Others are based on planar chirality and proposed by Ugi and Schloegl,

independently (Rule 1 and 2).

Unfortunately, the rules 1 and 2 resulted in configuration different from each other.
rules 2 and 3 reach the same result in most cases.
Rule 1
(i) View the substituted Cp ligand from the side opposite to the metal atom.
(ii) Confirm the direction of a b.
b

Fe

90

Fe

a >b

The notation can be applied to axial and planar chiralities.

In the case of planar chirality, pR and pS configurations correspond to P and M, respectively.
For axial chirality

However,

a
c

Br

a
d

Rule 3
(i) Treat chirality of metallocene as central chirality of the cyclopentadienyl carbon with the
highest priority.
(ii) Consider the metal atom to bond to the carbons in Cp ring.
(iii) The absolute configuration can be similarly assigned to R or S with the rule for central
chirality.

Me

Br

Me

3C
Me

Br

123
clockwise R
anticlockwise S

CHO
OH
CH2OH

HO

CHO
CHO
H
CH2OH

H
CHO
HO
O
HO
HO
H 2N
H
OH =
HO
H
CH2OH
OH
HO
D -glucose
L -serine

CHO
OH
H
OH
H
OH

(+) and () are used for

(e) Characteristic properties of chiral compounds

Most properties of an enantiopure compounds are identical to those of its enantiomer.
Exceptionally, the direction of optical rotation is different.
However, an enantiopure compound is different in most properties from its racemate.

K. Schloegl, Forschr. Chem. Forsch. 6, 479 (1966).

2) P/M notation
P/M notation is based on the chirality of helix (helicity).
The descriptor P is used for right-handed helicity, and M is used for left-handed helicity (from
before backward).

1) Crystals of racemate
Three types of crystalline racemate are known, as follows: racemic conglomerate, racemic
compound, and psudoracemate. Most racemates preferentially to form racemic compounds.
Racemic conglomerate
Racemic conglomerate is a mechanical 1:1 mixture of R crystals and S crystals. Each crystal in
the mixture is homochiral (constits of a sole enantiomer).
Preferential formation of racemic conglomerate requires that the interaction between R and R (or
S and S) is stronger than that between R and S.
Racemic conglomate is much rarer than racemic compound.

from before backward

clockwise P
anticlockwise M

(P)-[6]helicene

CHO

OH
HO

4) Notations based on the direction of optical rotation

Descriptor (+) or () corresponds to the direction of optical rotation.
dextrorotatory and levorotatory compounds, respectively.
Descriptors d and l are equivalent to (+) and (), respectively.
dl notation is not related to D/L notation.

Fe 2
4

Br

L -glyceraldehyde

OH

K. Schloegl, J. Organomet. Chem. 300, 219 (1986).

Fe

The abcd unit can be regarded as a helix.

View the helix from a.
Confirm the direction of the helix.

D -glyceraldehyde

HO

3) D/L notation
D/L notation is sometimes used for the stereochemistries of carbohydrates and -amino acids.
Descriptors D and L strongly relate to the stereochemistries of (R)-(+)- and (S)-()-glyceraldehyde,
respectively. D and L, must be smaller in size than other characters.

abc
clockwise R
anticlockwise S

Fe 2

c
b

Br

Me

Me

For planar chirality

a
c

or

Rule 2
(i) Assign the metal atom to the pilot atom.
(ii) Regard the centroid of the substituted Cp ligand as atom 'a'.
(iii) The cyclopentadienyl atom bearing the substituent with the highest priority is 'b'.
(iv) The ortho-atom with higher priority is assigned to 'c'.
(v) View the Cp ring from the pilot atom, and then confirm the direction of a b c.

Br

a
d

a > b, c > d

I. Ugi et al., J. Am. Chem. Soc. 92, 5389 (1970).

Fe

a
c
b

ab
clockwise R
anticlockwise S

90

(M)-[6]helicene

 Chiral compounds, which preferentially form racemic conglomerate, can be resolved into each
enantiomer through preferential crystallization without any other chiral source.

ammonium salt 3RR and 3SR. If 3RR is less soluble than 3SR, 3RR can selectively be obtained
through crystallization.
Purity of the crystals can be enhanced by recrystallization.
Enantiopure (R)-1 will be obtained by decomposing the pure 3RR in hand with acid.

Racemic compound
In racemic compound (true racemate), each crystal contains R and S molecules in 1:1 ratio.
The both enantiomers form a racemic pair in a unit cell.
Most chiral compounds prefer the formation of racemic compound to that of racemic
conglomerate. In many cases, a chiral molecule has stronger affinity for its enantiomer than for
itself.
Nevertheless, homochiral crystals are preferentially obtained from the compound with relatively
high enantiomeric excess

MeO
H

(true racemate)

psudoracemate

RRRRRR

RSRSRS

RRSRSS

SSSSSS

SRSRSR

SRRSSR

racemic conglomerate

+ H 2N

Me

H
2

CO2H

(S)-1

Ph

+R

H
+R

Ph 3RR
(crystallize)

CO2H
Ph (R)-1

Me

CO2 H 2N

H 3O+ MeO

Me

CO2 H 2N

Ph

MeO
Ph

Ph 3SR
(in solution)

Equimolar resolving agent (to racemate) is requires for the resolution controlled by type 1
thermodynamics. Halfmolar resolving agent may be enough for an efficient resolution, if it is
controlled by type 2 or 3 thermodynamics.

Psudoracemate
In crystals of psudoracemate, both enantiomers coexist in an unordered manner.
This type of chiral compound is very rare.

racemic compound

MeO
CO2H

Ph (R)-1

MeO
Ph

Type 1

Type 2

Type 3

R + S

RS

(less soluble)

R + S

RS

(less soluble)

R + S

RS

S + S

SS

(more soluble)

S + S

SS

(soluble)

S + S

SS

Representative resolving agents

for acids
N

2) Melting point
Melting point of chiral compound is affected by its enantiomeric excess. Each type of crystalline
racemate exhibits characteristic behavior in solid-liquid phase transition.
In racemic compound, racemate is generally higher in melting point than its enantiopure form.

OMe

H
N H

OH

Me

N
NH 2

O
brucine (R = OMe)
strychnine (R = H)

NH 2

OH

OMe
quinidine

quinine

Me

for bases
OH
HO 2C

Binary phase diagrams describing the melting behavior of a) 3-fluoromandelic acid (racemic compound); b) 2,3-diacetoxybutane
(psudoracemate); c) 1.2-diphenylethane-1,2-diol (racemic conglomerate).

CO2H
OH
tartaric acid

(f) Resolution of chiral compounds

1) Use of resolving agent
Although an enantiomer is impossible to be separated from its racemate, an epimer is physically
separable from the mixture of diastereomers.
Therefore, formation of diastereomers with an optically active resolving agent is very useful for
the optical resolution of racemates.

OBz
HO 2C

OH
HO 2C

Me

OH
CO2H

CO2H
OBz

Me

CO2H
malic acid
HO 3S

O
camphorsulfonic acid

O
O
P
OH
O

mandelic acid

Crystallization or chromatographic separation after derivatization

This method is useful for the resolution of chiral alcohols and ketones. It is applicable for the
resolution of chiral (secondary or primary) amines and acids.
In the resolution of a racemic alcohol 4 (e.q. R and S), the racemate is esterified with an
enantiopure acid anhydride 5 (e.g. R), which is the resolving agent. The esterification will give a
mixture of diastereomeric esters 6RR and 6SR (RR and SR). Both diastereomers can be
separated by column chromatography or crystallization. Each pure diastereomer in hand can
be transformed to (R)- or (S)-alcohol through hydrolysis.

Crystallization of diastereomeric salts

This method is useful for resolution of chiral carboxylic (phosphonic or sulfonic) acids, amines,
and phosphine oxides.
Acidic functional group (e.g. -CO2H, -SO3H) can readily form salts with basic functional groups
(e.g. -NH2). The acidbase pair is easier to crystallize from organic solvent than each
compound, because the salt is generally less soluble.
Treating racemic carboxylic acid 1 with stoichiometric enantiopure amine 2 gives the mixture of

Me
H

OH

Ph (R)-4

Me
Ph

+ O

OH
H (S)-4

H Me O

R
R

Ph

H
5

Ph

HO 2C
6RR

will be S-enriched.
of S-compound.

Me H

4) Kinetic resolution
In general, chiral reagents and catalysts exhibit different reaction rate for each enantiomer of
substrates. If the reaction of the R-enantiomer is faster than that of S-isomer, the recovered
substrate should be S-enriched. Therefore, the reaction of a racemate with a chiral reagent (or
through asymmetric catalysis) is usable for the resolution.

HO 2C
6SR

(separable with
chromatography
or crystallization)

hydrolysis
(R)-4

(S)-4

Me

O
H

Me
O

Me
CO2H
O

Me

Me

Me

Me

Me

Me

(for ester derivatization)

O
O
O
H
H
Noe reagent

Me

S a

(slow)

NCO
Me

OH
(for urea derivatization)

OH

MeHN

Ph
NHMe

TMS

N
NH 2 OMe
SAMP

R a
&
S (almost enantiopure)

R
& + a
S

OH

OAc ,

pentane

OAc

Me

Me
49%

TMS

TMS

47%

Marshall, J. A. Org. Synth. 2005, 82, 43.

OH

2) Chiral HPLC
A racemate is resolved to each enantiomer through
the column chromatography with a chiral stationary
phase, which is typically composed of a chiral
compound and silica gel.
Information of each chiral column can be obtained
from the following web sites.
Daicel: http://www.daicelchiral.com
Sumichiral: http://www.scas.co.jp/service/apparatus/
hplc/sumichiral_introduction.html
Astec: http://www.sigmaaldrich.com/japan/
analytical-chromatography/hplc/chiral-astec.html
3) Preferential crystallization
Racemic conglomerate can be resolved through
recrystallization without resolving agent, if you have
its homochiral single crystal.
To a saturated hot solution of the racemate, its
homochiral crystal (e.g. R) is installed. The same
enantiomer (R) will be crystallized in preference to the antipode (S).

if kR >> k S

Amano Lipase AK

Me
Ph

CO2Et

OH
diethyl tartarate

(fast)

(50:50)

(for lactor derivatization)

EtO 2C

R a

The efficiency of kinetic resolution (s) is expressed by the ratio of the reaction rate of each
enantiomer (kR/kS).
s = kR/kS = ln[(1C)(1-ee)]/ln[(1C)(1+ee)] = ln[1C(1+ee')]/ ln[1C(1ee')]
C: conversion
ee = enatiomeric excess of unreacted substrate
ee' = enatiomeric excess of product
Examples

for ketones and aldehydes

OH

kS

S + a

O
O

Me

kR

R + a

A racemic chiral ketone or aldehyde can be resolved through the reaction with an enantiopure
primary amine, which gives a mixture of diasteromeric imines.
Representative resolving agents

for alcohols
H O

The recrystallization of the mother liquor will preferentially form the crystals

Ti(O-i-Pr)4 & (+)-DIPT

t-BuOOH

C6H13

OH

OH
C6H13

C6H13

s = 83

Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.

(g) How to determine absolute configuration

1) Chemical transformation
a) The target molecule is reacted with a known optically active compound. If the product, which
must have two chiral centers, is crystalline solid, it is subjected to X-ray crystal structure analysis.
The absolute configuration of the target is found through the resulting structure, because the
absolute configuration of one of its chiral centers is known.
Ph S COCl

OH
R1

R2

(target)

OMe

O
Ph

S
b

MeO

X-ray crystal structure

O

R1 a R1

Compare the stereochemistry of chiral

center a with that of chiral center b.

b) The target molecule is transformed to a known optically active compound. Possibility for
racemization must be considered during the transformation. The specific rotation of the
resulting product is compared with the reported []D. Comparison of the retention times in the
chiral HPLC analyses is also useful for the assignment of absolute configuration.

The resulting mother liquor

target

Prepare two samples of the secondary alcohol. Each Sample is esterified with (R)- or (S)-MTPA
to prepare (R)- and (S)-MTPA esters (MTPA is 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid).
1
For each proton in the secondary alcohol moiety, calculate the difference between the H NMR
chemical shifts of (S)- and (R)-MTPA esters ( = S R) as shown in above figure.
In MTPA esters, their CF3 groups are located at the pseudo eclipse of the proton attaching to the
chiral carbon of the secondary alcohol. The aromatic ring in MTPA induces upfield shift of the
resonances of the protons in the secondary alcohol moiety. Therefore, if is negative, the
proton should be located over the aromatic ring of (S)-MTPA.

Measure its optical rotation and caluculate []D.

other compound
(Its []D has been reported.)

Compare it with the []D reported in the literature.

c) The authentic sample of the target molecule is synthesized from a known optically active
compound. The specific rotation or the chiral HPLC retention time of the authentic sample allow
us to assign the absolute configuration.

other compound
(Its []D has been reported.)

authentic
sample

optical rotation.
Measure its retention time in chiral HPLC.

Trost method
Trost method uses O-methylmandelic acid instead of MTPA. The procedure is very similar to
advanced Mosher method.
O-Methylmandelic acid is easier to react with secondary alcohols than MTPA, but may be
racemized during the esterification.
In the O-methylmandelates, their OMe groups are located at the pseudo eclipse of the proton
attaching to the chiral carbon of the secondary alcohol.

Compare the value with that of the target.

2) Crystallography (Bijvoet method)
Commonly, X-ray single crystal analysis gives no information about the absolute configuration of
the chiral compound. However, the configuration can be determined with the crystallography,
when the compound has one heavy-weight atom.
The heavy-weight atom induces anomalous X-ray scattering, which caused that intensity F(h k l)
is not equal to that of F(h k l) in a chiral crystal.
Flack parameter (x) is widely used for estimating the absolute configuration of crystal structure.
2
2
I(h k l) = (1x)|F(h k l)| + x|F(h k l)|
x: Flack parameter
I: the square of the scaled observed structure factor
F: the calculated structure factor
If x is near 0, the crystal structure has the correct absolute configuration. If the crystal structure
has the inverted configuration, x is near 1.
Bijvoet method is applicable for chiral compounds bearing no heavy-weight atom. In this case,
a protective group containing a heavy-weight atom (e.g. p-bromobenzoyl) is installed to the
target molecule.

upfield shift

R2
O
R1
S CF 3
H
O
(S)-MTPA ester

MeO
O

R2
R1
R CF 3
H
O
(R)-MTPA ester

= S R
If > 0, the proton belongs to R1.
If < 0, the proton belongs to R 2.

(S)-O-methylmandelate
Trost, B. M. J. Org. Chem. 1986, 51, 2370.

PGME method
PGME (phenylglycine methyl ester) method is useful for determining the absolute configuration of
the chiral -carbon of carboxylic acid.
In the PGME amides, their CO2Me groups are located at the pseudo eclipse of the -proton of the
chiral carboxylic acid.

upfield shift

upfield shift

O
H
R2
1
R
N S CO2Me
H
H
(S)-PGME amide

upfield shift
OMe

H
R2
O
1
R
S OMe
H
O

H
R2
O
R1
R OMe
H
O
(R)-O-methylmandelate

3) Advanced Mosher method and its related methods

see: Riguera, R. Chem. Rev. 2004, 104, 17.
Advanced Mosher method
Advanced Mosher method is empirical, but very useful for determining the absolute configuration
of an unknown chiral secondary alcohol. This method is applicable for the chiral secondary
alkyl primary amines.

upfield shift

upfield shift

R2
R1
H

H
N
H

= S R
R

CO2Me If > 0, the proton belongs to R 2.

If < 0, the proton belongs to R1.

(R)-PGME amide
Kusumi, T. Tetrahedron Lett. 1995, 36, 1853; J. Org. Chem. 2000, 65, 397.

= S R

4) Circular dichroism (CD) spectrum

Circular dichroism is active for only optically active compounds.
Positive Cotton effect means that an enantiomer gives a positive peak in its CD spectrum.

If > 0, the proton belongs to R 2.

If < 0, the proton belongs to R1.

Octant rule
This method is empirical and useful for determining the absolute configuration of cyclic ketones.
First, consider the most stable conformation for the target molecule. Geometry optimization with
MO or MM may be useful for the consideration.

(original) Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.

(alcohol) Kusumi, T.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(amine) Kusumi, T.; Kakisawa, H. Tetrahedron Lett. 1991, 32, 2939.

 Space around the carbonyl group is divided into

eight sectors as shown in figure (a).
In octant rule, the atoms in the + sectors induces a
positive Cotton effect. The atoms in the sectors
induces a negative Cotton effect.
The Cotton effect can be predicted as above.
Compare the prediction with the observed CD
spectrum (n* (C=O), ca. 300 nm).

Rf
Me
Me

OH
OH

Ar

Cl

O
O

Ar
O

O OH

O
H

NMe 2

(h) How to analyze enantiomeric excess

Percentage of enantiomeric excess (% ee) is commonly used for representing the ratio of
enantiomers. (% ee (R-enriched) = ([R] [S])/([R] + [S]) 100)
1) Specific rotation
Specific rotation is usable for measuring enantiomeric excess, if specific rotation of enantiopure
compound has been reported.
% ee = [a]D (sample)/[a]D (100% ee) 100
However, the specific rotation is significantly affected by inpurity, solvent, and temperature.
Sometimes, concentration of the sample affects the specific rotation.
2) Chiral HPLC and GC
Chiral HPLC or GC analysis is commonly used for measuring enantiomeric excess.
Chiral HPLC is effective for relatively polar compounds (alcohol, ketone, ester, amide etc.) with a
UV active moiety (-bond).
Chiral GC is usable for less polar compounds (hydrocarbon, ether etc.) as well as above
compounds. UV active moiety is not required, but the sample must be volatile.
3) Chiral shift reagent
1
Prepare NMR sample of the target compound in CDCl3 or C6D6 and measure H NMR. Add a
1
small amount of a shift reagent to the NMR sample, and then measure H NMR again. Repeat
the process several times until a proton signal completely splits. The enantiomeric excess of
the sample is calculated from the ratio of the integrals of each split peak.
Representative chiral shift reagents

O
HN

O
3

R f = CF 3 (tfc) or C 3F 7 (hfc)
M = Yb or Eu

NMe 2

H
Ar

NO 2

M(tfc) 3 or M(hfc) 3
Octant rule for standard ketones. (a) Signs of the
sectors in a left-handed Cartesian coordinate system;
(b) projection of the rear sectors (z < 0).

O
Me

Exciton chirality method

This method is theoretical and useful for determining the absolute configuration of
cycloalkanediol or diamine. Two equivalent chromophores (e.g. p-Me2NC6H4CO2-) in a
molecule are required for the assignment.
The two chromophores cause the split of their CD peak. One is negative and the other is
positive.
When the longer wavelength band of the split peak describes a positive Cotton effect and the
shorter one describes a negative Cotton effect, the two chromophores arranged in a
right-handed helix.
O

HN

HN
N

O
HN

(3) Diastereomers
(a) Notations of diastereomeric stereochemistry

5) R*/S* (or RS/SR) notation for relative configuration

R/S notation is applicable in relative configuration. This notation is unambiguous.
Assign the absolute configurations of all chiral center in an enantiomer. Attach an asterisk to
each R or S descriptor.
(2R*, 3S*) is equivalent to (2S*, 3R*).
OH OH
(2R*,3S*,5R*)-1,2,3,5-hexanetetraol
Me
OH
= (2S*,3R*,5S*)-1,2,3,5-hexanetetraol
OH

1) E/Z notation for alkenes

As with R/S notation, E/Z notation unambiguously defines the geometrical configuration of
alkenes. The notation is based on CIP rule.
i) Determine the priority of the two substituents on each atom involved with the CC double bond.
ii) Confirm the positional relationship of each substituent with higher priority.
a

positional relationship between a and c

the same side Z
opposite side E

6) l/u notation for relative configuration

Determine the absolute configurations (R/S or P/M) of all chiral centers, and then arrange them
according to the numbering rule in IUPAC nomenculture.
If the absolute configurations of two neighboring chiral centers are identical or similar each other,
the relative configuration is l (like). Otherwise, u (unlike) must be used as the stereochemical
descriptor.
For
example,
uu-1,2,3,5-hexanetetraol
is
equivalent
to
(2R*,3S*,5R*)-1,2,3,5-hexanetetraol.
OH OH
HO
O
R
S
HO
OH
R
R CHO
HO
HO
OH
OH OH uul-2,3,4,5,6-pentahydroxyhexanal
D -glucose

a > b, c > d
2) cis/trans notation
Cis/Trans notation is ambiguous, but often used for indicating the geometrical configuration of
alkenes or the relative configuration of cyclic skeletons including two chiral centers.
Priority of each substituent is determined with common sense, which causes the ambiguity (CIP
priority or main chain in IUPAC nomenclature?).
In the case of alkene geometry, cis and trans configurations correspond to Z and E, respectively.
a

a
b
c
d

a > b, c > d

a
b
c
d

positional relationship between a and c

the same side cis
opposite side trans

(b) Treatment of stereochemistry in CIP rule

In CIP rule
Atomic number
larger higher priority
Isotope
atomic mass: larger higher priority
Alkene stereochemistry
priority: Z > E (cis > trans)
In most cases, the priority of two geometrically isomeric groups can be determined by Z/E
system. However, the system is useless to 4-substituted alkylidenecyclohexanes, although
they can be regarded as axially chiral molecules. In this case, the alkene configuration is
determined from the substituent bearing the chiral center.
CO2H

3) erythro/threo notation for relative configuration

Erythro/threo notation is ambiguous, but often used for indicating the relative configuration of
acyclic vicinal chiral centers.
Erythro and threo forms are strongly related to the
stereochemistry of erythrose and threose.
If the substituents on each chiral carbon are arranged in a similar manner, the configuration is
threo. Otherwise, the configuration is erythro.
OHCCH2OH
b b'
1 OH
2

D -erythrose

HO

1 OH
2

D -threose

HO

=
CHO =

1 OH
3

1 OH

=
CHO =
2

OH

OH

OHCCH2OH
H

HO

OH

c'

a'

b b'
c'

a b c vs a' b' c'

the same direction erythro
opposite direction threo

HO 2C

H Me
Diastereomeric groups
( Enantiomeric groups

a'

4) syn/anti notation for relative configuration

Syn/anti notation is less ambiguous than erythro/threo notation and applicable to various acyclic
compounds.
Draw the structure of the target compound with zig-zag projection. If two substituents are
arranged on the same face, the configuration is syn. Otherwise, the configuration is anti.
OH OH

Me

Me

4H

Me 3

trans

cis

CO2H

priority: l > u
R > S or M > P?)

(c) How to determine stereochemistry of diastereomer

1) Crystallography
If the sample is crystalline solid, its X-ray crystal structure analysis is the most reliable.
2) NMR
i) 1,2-Disubstituted alkene
nOe (nuclear Overhauser effect) difference spectrum
Positive nOe will be observed between two substituents, which are located in the cis position

2,4-syn, 2.5-anti

OH

each other.
NOESY should be avoid to use for the purpose.

CHR2

OCH3
H

R 2HC

?
O

CHR2

iv) Acyclic compound

see: Bifulco, G.; Riccio, R. Chem. Rev. 2007, 107, 3744.
General methods
JBCA (J-based configuration analysis)
see, Murata, M. J. Org. Chem. 1999, 64, 866.
UDB (Universal NMR Database)
see, Kishi, Y. Org. Lett. 1999, 1, 2177 and 2188.
Use of quantum mechanical calculation
1,2- or 1,3-diols (diamine)
Protect the diol with acetone (or 2,2-dimethoxy propane, phosgene etc.) to give the
corresponding acetonide. Analyze the resulting cyclic acetal with NOESY, nOe difference
spectrum, HH coupling constrants etc.
1,3-diols
Acetonides of syn-1,3-diols have chair conformation, while those of anti-1,3-diols prefer twist
boat conformation. Therefor, the relative configuration of 1,3-diols can be elucidated with the
13
C NMR resonances of the methyl groups of their acetonides.
Me Me
98.1 0.83
R1
OH OH
O
=
Me 30.0 0.15
O
O
R2
O
R1
R2
Me 19.4 0.21
R1
R2
syn-1,3-diol
100.6 0.25
H
Me Me
1
R
OH OH
O
O Me
R12
Me
24.6 0.76
O
O
=
O
R
O Me
R1
R2
2
R
Me
R1
R2
H
anti-1,3-diol

OCH3

OCH3 ?
CH 3

Vicinal HH coupling ( JHH)

In general, the coupling constant between the two alkenyl the alkenyl protons is 1013 Hz when
the protons are arranged with cis configuration. In the trans isomer, the coupling constant is
1517 Hz.
The above rule is useful only when a carbon atom attaches to each alkenyl carbon.
Heteroatom substituents causes decrease in the coupling constant.
H
H
H
C
3J
3J
HH = 1013 Hz
HH = 1517 Hz
C
C
C
H
ii) Saturated four- and five-membered ring
NOESY or nOe difference spectrum
Use only transannular nOe. Sometimes, nOe is observed between vicinal hydrogens with
trans configurations, because these protons couple with each other.
b
d
The nOe between a and d (red) is reliable for determing the
a
relative configulation.
The nOe between a and b (blue) should be avoid to use for the
purpose, because an nOe is sometimes observed between a and c.
c
iii) Saturated six-membered ring
Chemical shift
In general, an axial proton appears in higher field (ca. 0.5 ppm) than its corresponding
equatorial proton.
Vicinal HH coupling
3
2
Karplus equation: JHH = A cos + B cos + C (: dihedral angle)
(e.g. A = 9.4, B = 1.4, C = 0.4 (for hydrocarbons))
3
3
3
JHaxHax is 814 Hz, because dihedral angle for HaxCCHax is 180. JHaxHeq and JHeqHeq
is 24 Hz, because the related dihedral angles are 60.
Higher magnetic field NMR spectrometer should be used for assigning the relative configuration
of cyclohexane derivative. Assign as many paeks as possible by using not only 1D-NMR but
also HH cosy, HMBC. HSQC etc.
Assign the stereochemistry by using each coupling constant in a similar way to solving a
puzzle.

10

4) Effect of * or n* interaction
3
3
Conformation involved with C(sp )C(sp ) bond is affected by the hyperconjugation between
vicinal CX bonds. In the hyperconjugation, one of the orbital of CX bond donates electrons
to *-orbital of another CX.
Electron donating ability: nN > nO > CC, CH > CX (X: N > O > S > Hal)
Electron accepting ability: C=O > *CHal > *CO > *CN > *CC, *CH
Gauche effect: In some compounds, gauche conformer is preferable to anti conformer.
H
H
H
CH2FCH 2F:
F
H
H
H
H
F
F
F
H
E = 2.02.6 kcal/mol

(4) Conformation of organic compounds

(a) Acyclic saturated compounds
1) Ethane
The staggered conformer ( = 60 or
180) is more stable than the eclipsed

one ( = 0 or 120) (E = 2.9 kcal

/mol).
The ecripsed conformer is a transition
The * interation
state and not energy minimum.
between the vicinal
The CH*CH interaction stabilizes CH bonds.
the staggered conformer.
The steric repulsion between the vicinal protons
scarcely contributes to rotational barrier.

Anomeric effect: The ratio of - and -glucose is 38:62 in water. The unusual ratio (A value of
OH is 0.60) is caused by anomeric effect, the interaction between nO and *CO orbital.
nO
HO
HO
O
O
O
HO
HO
OH
*CO
HO
HO
HO
HO
OH
OH
-glucose
-glucose

2) Butane
Butane has two energy minima: one is anti, and the
other is gauche.
Anti conformer is more stable than gauche one (E =
0.9 kcal /mol).
Each conformer, including unstable conformers, can be
named with the dihedral angle as shown below.
R
R
a: synperiplanar (ecripsed, 30 < < 30)
a
C
A
b
b
b: synclinal (gauche, 30 < < 90 ())
c: anticlinal (90 < < 150 ())
c
c
d
d: antiperiplanar (anti, 150 < < 180 ())
B

(b) Acyclic unsaturated compounds

1) XCH2CH=Y (Y = CH2, O)
3
Energy minima appear when the C(sp )X (or H) bond overlaps to the C=Y bond in the Newman
2
projection. Another conformer, in which the CX bond overlaps to the C(sp )H bond, is a
torsional barrier.
Steric repulsion between X and Y is often considerable in the eclipsed conformer (1,3-allylic
strain). Therefore, the gauche conformer is generally preferable to the eclipsed one.
Y
YX
YH
Y
H

3) Pentane
In the conformational analysis of pentane, the free rotations of C2C3 and C3C4 should be
considered.

H
bisecting
(rotational barrier)

H
H

H
gauche

H
eclipsed

H
FelkinAnh-type

(a stable confomer) (less stable than gauche)

(not stable)

The gauche or ecripsed conformation is stable in substituted benzenes.

Allylic strain:

1,2-allylic strain (A(1,2)-strain)

R
R
R
H
H
H
H
R
Conformer aa is the most stable conformer of pentane.
+
+
Conformers g g and g g are the least stable.
The energies of these
conformers has been estimated to lie over 3.3 kcal/mol above that of
conformer aa.
The steric repulsion is called 'syn-pentane interaction'.

1,3-allylic strain (A(1,3)-strain)

H
H
R

H
R

R
H

2) X=CHCH=Y
In general, s-trans conformer is more stable than s-cis, when there is no steric repulsion in the
conjugated molecule.
However, gauche conformer is preferable to s-cis one, if X and/or Y have a substituent and both
double bonds have Z-configuration.
syn-pentane interaction

11

chair

H
Y

s-trans

s-cis

gauche

half-chair

twist boat

3) Carboxamides
CN bond of carboxamide possesses double bond character, because structure 2 remarkably
contributes to the resonance hybrid. Therefore, the rotation of CN bond is relatively slow.
In NMR analysis, a set of signals are often observed because the ZE isomerization of amide is
slow in NMR time scale.
O
Me
O
O
Me
R3
O
R3
N
N
N+
N
Me
H
H
H
R1
R2
R1
R2
1
2
E = 21.3 kcal/mol
E = 20.6 kcal/mol

equatorial

boat
R

1,3-diaxial interaction

axial

Stability of conformer of substituted 6-membered rings is affected by A-value, 1,3-diaxial

interaction, and the presence of gauche conformation etc.
Fused ring systems
Bicyclic system of cis-fused cyclohexane, such as cis-decaline, is possible to invert.
ring inversion of the trans-isomer is impossible.

In contrast,

(c) 4-Membered rings

In 4-membered rings, planar structure is unfavorable because torsional strain is maximum.
Puckered structure is preferable to planar one in order to escape the strain. The 4-membered
ring is released from the ecripsed conformation.
The angle of pucker is 28 and the barrier of ring inversion is 1.45 kcal/mol in cyclobutane.
5

2
4

5
E = 1.45 kcal/mol

1
6

half-chair
In 1,6-disubstituted cyclohexenes, substituent R' at the 6-position induces considerable
(1,2)
A -strain if it occupies the pseudo-equatorial position. To avoid the strain, R' tends to occupy
the psudo-axial position.
R'
R'
A(1,2)-strain
R
H
R H
more stable

(d) 5-Membered rings

Conformation analysis of 5-mambered rings is significantly complicated as compared to those of 4and 6-membered rings, because their conformation is very flexible.
Stable conformations of cyclopentane are envelope and half-chair conformations. The former is
more stable than latter, but the energy difference of both conformers is very small (0.5 kcal/mol).
The envelope conformer is Cs-symmetry, and the half-chair conformer is C2-symmetry.
Equilibrium between envelope and half-chair conformers is remarkably affected by substituents.

3) Cyclohexanone
Cyclohexanones prefer chair conformation.
planar structure of carbonyl group.

C2

envelope

trans-decaline

2) Cyclohexene
The most stable conformation of cyclohexene is half-chair.
pseudo-axial
=
pseudo-equatorial
=

cis-decaline

half-chair

(e) 6-Membered rings

1) Saturated rings
Stable conformations of saturated 6-membered rings are chair and twist boat. Boat
configuration is the transition state of the interconversion between two twist boat conformers.
In most cases, chair conformer is more stable than twist boat conformer. Rarely, twist boat is
preferable to chair in order to avoid large 1,3-diaxial interaction.

12

Their conformations are affected by the dipole and