1

Two chiral centres (diastereoisomers)

Mirror
O
N
HN

O
OH

HO

NH2

NH2

NH

Two enantiomers
differ by absolute configuration

A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomers

Enantiomers have identical physical properties in an achiral environment
A molecule with 2 stereogenic centres can exist as 4 stereoisomers
Enantiomers (mirror images) still have identical physical properties
Diastereoisomers (non-mirror images) have different properties
O2N

O2N
CO2Me

CO2Me

enantiomers

trans
epoxide
mp = 141C

O2N

diastereoisomers
enantiomers
different mp

cis
epoxide
mp = 98C

O2N
CO2Me
O

CO2Me
O

123.702 Organic Chemistry

Diastereoisomers
NH2

NH2

2HCl

NH2

NH2

2HCl

chiral
solubility 0.1g/100ml EtOH

NH2

diastereoisomers

NH2

2HCl

meso
solubility 3.3g/100ml EtOH

different solubility
seperable

Enantiomers differ only by their absolute stereochemistry (R or S etc)

Diastereoisomers differ by their relative stereochemistry
Relative stereochemistry - defines configuration with respect to any other

stereogeneic element within the molecule but does NOT differentiate enantiomers

In simple systems the two different relative stereochemistries are defined as below:
OH

OH
Me

NH2

syn
same face

Me
NH2

anti
different face

A molecule can only have one enantiomer but any number of diastereoisomers
The different physical properties of diastereoisomers allow us to purify them
The differences between diastereoisomers will be the basis for everything we do...
123.702 Organic Chemistry

Diastereoisomers II
OH
CHO

HO

OH OH
(2R,3R,4R)-2,3,4,5-tetrahydroxypentanal
ribose

OH

OH
CHO

HO
OH

(2R,3R,4R)-ribose

OH

OH

OH OH
(2S,3S,4S)-ribose

HO

OH

OH OH
(2S,3S,4R)-arabinose

HO

OH

(2R,3S,4S)-lyxose

OH
CHO

CHO

HO

OH

(2R,3S,4R)-xylose

OH
CHO

OH
CHO

HO

OH

(2R,3R,4S)-arabinose

OH
HO

CHO

HO

OH

OH

OH
CHO

OH OH
(2S,3R,4S)-xylose

HO

CHO

OH OH
(2S,3R,4R)-lyxose

four
diastereoisomers

mirror
plane
and their 4
enantiomers

If a molecule has 3 stereogenic centres then it has potentially 8 stereoisomers (4

diastereoisomers & 4 enantiomers)

If a molecule has n stereogenic centres then it has potentially 2n stereoisomers
Problem is, the molecule will never have more than 2n stereoisomers but it might
have less...

123.702 Organic Chemistry

Meso compounds
OH
HO2C

CO2H

OH
tartaric acid

OH

HO2C

CO2H
OH

2H

OH

CO2H

CO2H

HO2C

OH

H
O

2C

identical

CH
OO

OH

diastereoisomers

OH

CO2H

O
HC
O2
H

OH

enantiomers

HO2C

H
2
O
OC
H

OH

CO2H

H
O

HO2C

CO2H

OH

HO2C

HO2C

OH

OH

OH

Tartaric acid has 2 stereogenic centres.

But does it have 4 diastereoisomers?

2 diastereoisomers with different relative stereochemistry
2 mirror images with different relative stereochemistry
1 is an enantiomer
The other is identical / same compound
Simple rotation shows that the two mirror images are superimposable

123.702 Organic Chemistry

Meso compounds II
Meso compounds - an achiral member of a set of diastereoisomers that also

includes at least one chiral member

Simplistically - a molecule that contains at least one stereogenic centre but has a
plane of symmetry and is thus achiral
Meso compounds have a plane of symmetry with (R) configuration on one side and
(S) on the other
HO2C

OH

HO
CO2H
rotate LHS

HO

OH

HO2C

CO2H

plane of
symmetry

Another example...

Cl
Cl

chiral
no plane of symmetry
non-superimposable
on mirror image
(but it is symmetric!)

H
Cl

Cl

achiral
plane of symmetry
superimposable on
mirror image
(meso)

123.702 Organic Chemistry

Chiral derivatising agents

Difference in diastereomers allows chiral derivatising agents to resolve enantiomers
enantiomerically pure
derivatising agent

mixture of
diastereoisomers

R*
+

RR*

R/S

SR*

racemic
mixture

R*

R
pure
enantiomer

diastereoisomers
separable

SR*

RR*
cleave
diastereoisomer

pure
diastereoisomer

Remember a good chiral derivatising agent should:

Be enantiomerically pure (or it is pointless)
Coupling reaction of both enantiomers must reach 100% (if you are measuring ee)
Coupling conditions should not racemise stereogenic centre
Enantiomers must contain point of attachment
Above list probably influenced depending whether you are measuring %ee or
preparatively separating enantiomers

123.702 Organic Chemistry

Chiral derivatising agents: Moshers acid

F3C

OH

OMe

R/S

CO2H

DCC, DMAP
CH2Cl2, 10C

F3C

OMe H
O

Me

RS & SS

DCC - dicyclohexylcarbodiimide

Popular derivatising agent for alcohols and amines is -methoxy-

trifluoromethylphenylacetic acid (MTPA) or Moshers acid

Difference in nmr signals between diastereoisomers (above): 1H nmr = 0.08 (Me)
..................................................................................................19F nmr = 0.17 (CF3)
Typical difference in chemical shifts in 1H nmr 0.15 ppm
19F nmr gives one signal for each diastereoisomer
No -hydrogen so configurationally stable
Diastereoisomers can frequently be separated

In many cases use of both enantiomers of MTPA can be used to determine the

absolute configuration of a stereocentre (73JACS512, 73JOC2143 & 91JACS4092)

123.702 Organic Chemistry

Chiral derivatising agents: salts

OTol
HO2C
O

CO2H

NH
OH

OTol

OTol

NH2
O2C

OH

CO2H
OTol

R/S

S diastereoisomer is insoluble so easily removed by filtration

NaOH

NH
OH

()-propranolol
-blocker

No need to covalently attach chiral derivatising group can use diastereoisomeric

ionic salts
Benefit - normally easier to recover and reuse reagent
Use of non-covalent interactions allows other methods of resolving enantiomers...
123.702 Organic Chemistry

Resolution of enantiomers: chiral chromatography

Resolution - the separation of enantiomers from either a racemic mixture or

enantiomerically enriched mixture

Chiral chromatography - Normally HPLC or GC
A racemic solution is passed over a chiral stationary phase
Compound has rapid and reversible diastereotopic interaction with stationary phase
Hopefully, each complex has a different stability allowing separation

racemic mixture
in solution

chiral stationary
phase

matched
enantiomer - more
stable (3 interactions)

matched
enantiomer
travels slowly

mis-matched
enantiomer - less
stable (1 interaction)

mis-matched
enantiomer
readily eluted

123.702 Organic Chemistry

10

Chiral chromatography
inject mixture
on to column

R/S
RS
R
S
R
R

chiral column
prepared from a
suitable chiral
stationary phase
(many different types)

O
O
O
Si O
Si O
O
O
O
Si
Me
Si O
Si
Si O
O
Me
O

silica

NO2

NO2
chiral amine
chiral stationary phase

Measurements of ee by HPLC or GC are quick and accurate (0.05%)

Chiral stationary phase may only work for limited types of compounds
Columns are expensive (>1000)
Need both enantiomers to set-up an accurate method
123.702 Organic Chemistry

11

NMR spectroscopy: chiral shift reagents

Chiral paramagnetic lanthanide complexes can bind reversibly to certain chiral

molecules via the metal centre

Process faster than nmr timescale and normally observe a downfield shift (higher
ppm)
Two diastereomeric complexes are formed on coordination; these may have different
nmr signals

C3F7
O
O EuL2

substrate

Eu(hfc)3substrate

Eu(hfc)3

Problems - as complexes are paramagnetic, line broadening is observed (especially

on high field machines)
Compound must contain Lewis basic lone pair (OH, NH2, C=O, CO2H etc)
Accuracy is only 2%

123.702 Organic Chemistry

12

Chiral shift reagents II

O
Sm3+

O
O
O

N
H
Me

O
O

CO2H
NH2

L-valine

New reagents are being developed all that time that can overcome many of these
problems
1H NMR spectra (400 MHz) of valine (0.06 M, [D]/[L] = 1/2.85) in D2O at pH 9.4

123.702 Organic Chemistry

13

Enzymatic resolution
lipase PS from Pseudomonas
cepacia, 0.05M phosphate buffer,
pH 7, 0.1M NaOH, 5C

O
Bu

OEt
F
R/S

60% conversion

O
Bu

O
+

OEt

Bu

Na

O
F

R
>99% ee
soluble in
organic phase

S
69% ee
soluble in
aqueous phase

Enzymes are very useful for the resolution of certain compounds

Frequently they display very high selectivity
There can be limitations due to solubility, normally only one enantiomer exists and
can be too substrate specific
Below is the rationale for the selectivity observed above...
enzyme
H
O

H
O

Bu
O

diastereomeric interaction of enzyme

lone pair with * orbital of CF of (S)enantiomer favoured over interaction
with (R)-enantiomer

N
H

his
O

R
O
O
Et

ser

123.702 Organic Chemistry