Isomers

Isomers
Isomers are molecules with identical formulas (e.g. C6H6) but distinct structures. The concept of isomerism was
introduced by Justus von Liebig.

constitutional Constitutional isomers are distinguished by a different

connectivity and hybridization of the atoms.

configurational Configurational isomers have the same connectivity but a

different arrangement of their atoms in space. They can only be
interconverted through a series of chemical reactions or
through processes with high energy barriers. They can be
generally separated since they are “configurationally stable”.
Distinguish between enantiomers and diastereomers stereoisomers

(absolute and relative configuration).

conformational Conformational isomers (conformers) interconvert rapidly via

bond rotations, inversions, and other and other processes with relatively low
energy barriers.

The distinction between configurational and conformational

isomers is somewhat fuzzy and depends on the temperature.
 Constitutional isomers

C5H12
n-pentane isopentane neopentane

C10H16 adamantane

OH

HO O
HO HO OH
OH
HO O HO OH
O O
HO O
C12H22O HO O OH OH
OH OH
saccharose lactose
HO

C20H20 pagodane dodecahedrane

 Stereoisomers
Stereoisomers have the same connectivity between atoms but a different layering of atoms in space.

Enantiomers are stereosisomers that are mirror images of each other but are not superimposable (because they are
chiral).

D-(–)-tartaric acid L- (+)-tartaric acid (–)-twistane (+)-twistane

Diastereomers are stereosisomers that are not enantiomers.

D-(–)-tartaric acid meso-tartaric acid (E)-alkene (Z)-alkene

Conformers are stereoisomers that can be easily interconverted through processes with low energy barriers (rotations,
inversions etc.) This depends, however, on the temperature.

axial equatorial s-cis s-trans

 Enantiomers
Enantiomers are stereoisomers that are mirror images of each other and are not superimposable. They are the two forms
of a chiral molecule. Enantiomers have opposite absolute configuration.

O O
Me Me
(S) (R)

O O

(–)-twistane (+)-twistane (S)-(+)-Wieland-Miescher ketone (R)-(–)-Wieland-Miescher ketone

O OMe
O OMe MeO O
N N N
OBz BzO OBz

(+)-cocaine (–)-cocaine

Establishing the absolute configuration is not straightforward. It can be done through correlation with a compound of
known absolute configuration, through derivatization with such a compound, and through anomalous X-ray scattering. The
absolute configuration cannot be easily determined through calculation of the optical rotation. The sign of the optical
rotation, (+), (–), does not correlate with the nomenclature [(R), (S), D, L, etc.]. If one enantiomer is levorotatory, (–), the
other must be dextrorotatory, (+).
 Enantiomers
Enantiomers can be constructed by flipping (not rotating!) the entire structure or by inverting each stereochemical
designator (dash, wedge, D, L):

Me O O Me Me O
(S) (R)
(S)
H (S) H (R)
H (R)

H
(R)
H H H
≡ H
(S)
H
HO OH HO

estrone ent-estrone

Me Me Me Me Me Me Me Me Me Me Me Me
O O

O OH O O OH O O O OH O O OH O O

COOH COOH
H OH HO H
L-tartaric acid D-tartaric acid
HO H H OH
COOH COOH
 Racemates
A racemate is a mixture of equal amounts of both enantiomers. Racemates are often formed in synthesis, when achiral
starting materials yield a chiral product in the absence of chiral information (catalyst, solvent etc.)

rac-twistane

OH OH
O O O O
HO OH OH
HO
rac-TTX HO OH HO OH
HN N OH OH N HN
H H
HN NH

Me O Me O

H H
rac-estrone
H H H H
HO HO

But: what does “racemic” really mean? Statistically, there’s an (N)1/2 excess of one enantiomer, so in one mole of
racemate there will be, on average, 7.8 x 1011 molecules of one enantiomer in excess. Relatively seen, this is
negligible, but it can be amplified out, e.g., with the Soai reaction.
 “You are now in the racemic series”
For convenience, often only one enantiomer is drawn and the other one is implied in a synthetic scheme. You always
have to be aware whether you are in the racemic series or in an enantiomeric series (and which one). This has
consequences when two chiral building blocks are linked or when chiral reagents are used.

Consider this Diels-Alder reaction. It is highly diastereoselective, but not enantioselective:

N O Me O O
cat. Et2AlCl
O N [Reference]
+ O
TMSO TMSO Me
Me

(80 %)
What authors really mean is:

N O Me O O Me O O
cat. Et2AlCl
O N N
+ O + O
TMSO TMSO Me TMSO Me
Me Me

There is no chiral information! (40 %) (40 %)

Racemic natural products
[Review]
A racemic natural product

O O
O O
O O
MeO OMe
OH HO

O O
O O

preuisolactone A

[Reference]
 Non-racemic (scalemic) mixtures and optical purity

enantiomeric excess, ee, e.e. [%major] - [% minor] = [(R-S)/(R+S)] x 100

enantiomeric ratio, er, e.r. [%major]/ [% minor]

racemic 0 % ee
scalemic = non-racemic
enantioenriched
enantiomerically pure
enantiopure
> 99.9 % ee
optically pure

Homochiral refers to two individual molecules with the same absolute configuration. It does not mean “enantiomerically
pure”. Heterochiral refers to individual molecules with the opposite absolute configurations.
 Diastereomers
Diastereomers are stereoisomers that are not enantiomers.

Diastereomers have different relative configuration. They can be formed both from enantiomerically pure compounds
and from racemates.

D-tartaric acid meso-tartaric acid an (E)-alkene a (Z)-alkene

O O
Me Me
O O
O O
O O
H H

a trans decalin a cis decalin exo-brevicomin endo-brevicomin

OH OH OH OH
OH HO
HO O HO O HO O 4 O
HO HO OH HO OH HO OH
HO HO 2 OH
OH
a-D-glucopyranose b-D-glucopyranose a-D-mannopyranose a-D-galactopyranose
 Diastereomers and epimers
Epimers are diastereomers with respect to one stereocenter.

Me Me Me
(S)
HO
Me
O O O NH2
Me Me Me
TBS
N O O
MeO Me
TBS
O O
TBS
Me Me Me
(R)
HO
Me
O O O NH2
Me Me Me
TBS
N O O
MeO Me
TBS
O O
TBS

Don’t say “a sterocenter racemizes”, it epimerizes. Racemization refers to the whole molecule.

O O
Me Me
NaOH
[Reference]
MeO dioxane, H2O MeO
H H
O O
 Diastereomers
Remember: a molecule with n stereocenters has 2n possible stereoisomers, provided meso compounds are not possible
and all sterocenters are independent of each other, which may not be the case in polycyclic compounds. As such,
palytoxin has 259 = 5.7 x 1017 stereoisomers, not counting double bond isomers. Half of them are diastereomers, which
come in pairs of enantiomers.
OH
HO OH
O O HO OH
OH
O HO
OH
O
H 2N Me
OH HO OH
OH OH
OH
OH
OH
HO OH O
O O Me OH HO OH
palytoxin
OH OH
HO N N O
H
H H OH OH OH
HO HO
Me
OH
OH O
Me O HO
O Me OH Me OH
OH H
O
OH
HO OH OH
HO OH [Wikipedia]
OH
 Enantiomers and diastereomers
enantiomers

OH COOH COOH OH
(S) Me H OH HO H (R) Me
HOOC (R) ≡ ≡ HOOC (S)

OH HO H H OH OH
Me Me

diastereomers diastereomers

OH COOH COOH OH
(R) Me H OH HO H (S) Me
HOOC (R)
≡ ≡ HOOC (S)

OH H OH HO H OH
Me Me

enantiomers
Enantiomers, diastereomers, and meso compounds
enantiomers

OH COOH COOH OH
(R) COOH H OH HO H (S) COOH
HOOC (R) ≡ ≡ HOOC (S)

OH HO H H OH OH
COOH COOH

diastereomers diastereomers

OH COOH COOH OH
(S) COOH H OH HO H (R) COOH
HOOC (R)
≡ ≡ ≡ HOOC (S)

OH H OH HO H OH
COOH COOH
identical

meso
 Conformers
Conformers are stereoisomers that can be interconverted through processes with low energy barriers (rotations,
inversions etc.) This depends on the temperature. Conformers that interconvert through bond rotations are also called
rotamers.
H CH3 H H
H 3C H 3C
H CH3
H H H H

gauche anti-periplanar s-cis s-trans

ringflip:
cyclohexane ring flip:

chair twist boat (enantiomers) chair

N N
ax.
eq.

conformational Enantiomers interconvert through Diastereomers interconvert through

anchor ring flip. nitrogen inversion and ring flip.

H CH3

H
H H
Most conformers of this n-alkane are chiral!
 Atropisomers
Atropisomers are separable stereoisomers due to hindered rotations about single bonds or hindered inversions. The rate
of interconversion and the ability to separate and isolate atropisomers depend on the temperature. They can be
enantiomers or diastereomers.

CN CN
OMe OMe
O O
enantiomeric biaryls [Reference]
O MeO

OMe OMe O OMe OMe

OMe
O O

H 2N O H 2N O
H H
N N
diastereomeric biaryls
F F
OH atropisomers in drug development: [Reference]
OH
O O
N N
O O
N N

F F

enantiomeric cyclononadienes [Reference]

O O
O
 Atropisomers and binaphthyls

OH rotation H OH rotation OH
looks like an S H
OH OH OH

(S)-BINOL (S)-BINOL

θ = 94° θ = 0° θ = – 94°

1 3
OH OH

4 OH 3 2 OH 1

The substituents closer to you have higher priority

Then the substituents away from you.
2 4

Binaphthyls of this type are often configurationally stable (BINOL, BINAP etc.)
 Topicity

Greek τόπος, topos = place, site

homotopic mutual labeling gives the same molecule

enantiotopic mutual labeling leads to enantiomers

diastereotopic mutual labeling leads to diastereomers

 Topicity

OH OH OH
COOH COOH COOH
homotopic HOOC HOOC HOOC
OH OH OH
comes with Cn same

OH OH OH

enantiotopic

comes with s, Sn OH OH OH
enantiomers

diastereotopic CH3 NH2 CH3 NH2 CH3 NH2

H 3C COOH H 3C COOH H 3C COOH

diastereomers
 Homotopicity
Mutual labeling (derivatization) yields the same molecule. This is usually associated with C2 symmetry.
The two sites are related through an axis of rotation.

HO Me Me
OH PPh3
OH PPh3
HO O O O

CH3 CH3 O OH
O MeOOC
O N O
N NPh
N N H O
MeOOC OH O

But sometimes with dihedral symmetry:

H
H H

H H
H
 Enantiotopicity
Mutual flagging (derivatization) yields enantiomers. This is usually associated with Cs symmetry
(but sometimes applies to centrosymmetric molecules). The two sites are related through a reflection or rotation-reflection.

OAc O O
H H Me H
OH
O O
Me
O O O H
OAc

OH
OAc Me O
COOH AcO
HOOC
O O O
OH H H
O Me Me
Me
meso-tartaric acid O H H
O O O nonactin O
OH H H
HO
OH O O Me
Me Me O
OH O H H
HOOC O O O
COOH
O Me
These molecules are substrates for desymmetrization.
 Diastereotopicity
Mutual flagging (derivatization) gives diastereomers. Very common.

Me O
NH2 Me NH2
H H Me
Me
COOH Me COOH
Me Me Me

Me H OH
H O H
N H HO O
HO OH
O O OH
Me
H H

O O
O
OH OH O
O N O
O
H H O O
Me Me Me O
 The usefulness of topicity in synthesis
Homotopic functional groups need not be distinguished (but mind the stoichiometry):

Me Me
O KHMDS, PhN(Tf)2 TfO
C2 C1 [Reference]
O ca. 1 equiv. O
Me Me

Enantiotopic functional groups can be distinguished with a chiral reagent or catalyst:

OH OH
pig liver esterase
O COOEt (chiral catayst) O COOEt
Cs C1 [Reference]
H 2O
HO HO
COOEt COOH

In principle, every reaction can be rendered asymmetric through desymmetrization:

FG chiral FG*
reagent

or
catalyst
FG FG
 Topicity and NMR spectra
Enantiotopic and homotopic groups reduce the signal set in an NMR spectrum.

Enantiotopic and homotopic groups can be distinguished with a chiral shift reagent.
 The nonstereogenic, chirotopic center
consider this reduction:

nonstereogenic
O OH OH OH chirotopic
Me Me NaBH4 Me Me Me Me Me Me center
≡ ≡
O O O O O O O O

comes with pseudo Cn-axes:

H
O
Al
O OEt OH OH
O

Me O Me Me Me
(S)-BINAL-H) baconipyrone

reduces the number of intermediates and transition states that must be considered in asymmetric synthesis:

Ph2 L Ph2 L
P S P H
M ≡ M
P H P S
Ph2 L Ph2 L