1

Enantiomeric excess
Optical purity - an outdated measurement of the enantiomeric excess (amount of
two enantiomers) in a solution / mixture
If a solution contains only one enantiomer, the maximum rotation is observed...

H NH2
CO2H

measure rotation
derive []D = +14 100% (+) enantiomer
100% of maximum
observed rotation

H2N H
CO2H

measure rotation
derive []D = -14 100% () enantiomer
100% of maximum
observed rotation

The observed rotation is proportional to the amount of each enantiomer present...

Advanced organic
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Enantiomeric excess II

= +
90% (+) enantiomer 10% anti- 90% clockwise 10% of major 80% of maximum
10% () enantiomer clockwise enantiomer is rotation observed
cancelled out

= +
60% (+) enantiomer 40% anti- 60% clockwise 40% of major 20% of maximum
40% () enantiomer clockwise enantiomer is rotation observed
cancelled out

= +
50% (+) enantiomer 50% anti- 50% clockwise 50% of major 0% of maximum
50% () enantiomer clockwise enantiomer is rotation observed
cancelled out
Advanced organic
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Enantiomeric excess III

Previous slide indicates that a polarimeter measures difference in the amount of
each enantiomer
Racemate (racemic mixture) - 1 to 1 mixture of enantiomers (50% of each)
Racemisation - converting 1 enantiomer to a 1:1 mixture of enantiomers
Optical rotation very unreliable so use new methods to measure amounts and use
the value enantiomeric excess
Enantiomeric excess (% ee) = [R] [S] = %R %S
[R] + [S]
How do we measure enantiomeric excess?
Problem - all the physical properties of enantiomers are identical (in an achiral
environment) except rotation of plane polarised light
Solution - the interaction of a chiral molecule with other chiral compounds is
different depending on the enantiomer used...
Imagine you have a mixture of left and right-handed gloves and you are asked to
separate them...suddenly there is a power cut, and you are left in a darkened room.
How would you do it? Use just one hand and try the gloves on...

Advanced organic
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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

matched matched
enantiomer - more enantiomer
stable (3 interactions) travels slowly

mis-matched mis-matched
enantiomer - less enantiomer
stable (1 interaction) readily eluted

racemic mixture chiral stationary

in solution phase
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Chiral chromatography
R/S
inject mixture
on to column
RS
R O
O O
S chiral column O
Si O
Si O H
O N
prepared from a Si O
O Si
Me
R suitable chiral
stationary phase
O
O
Si O
Me
Si
O
NO2

(many different types)

S
NO2
silica chiral amine
R 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
Advanced organic
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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 + substrate Eu(hfc)3substrate
O EuL2
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%

Advanced organic
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Chiral shift reagents II

O O
O Sm3+ O CO2H

O N N O
NH2
H L-valine
O Me O

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
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Chiral derivatising agents

A racemic mixture of enantiomers can be converted to a mixture of
diastereoisomers by covalently attaching a second, enantiomerically pure unit
The advantage of this over the previous methods is there is normally larger signal
separation in nmr
There is no reversibility
Diastereoisomers can often be separated by normal, achiral chromatography

OH O O
MeO
Me CO2H MeO MeO
DCC, DMAP, Me Me
OH DCM, rt, 24h O O
= + + +
OH

() mixture of enantiomerically 2 diastereoisomers

racemate enantiomers pure

To understand why diastereoisomers are useful we need to do some more revision...

Advanced organic
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Two chiral centres

Mirror
O O
enantiomers
N
S R N different absolute
OH HO configuration
HN NH2 NH2 NH

A molecule with one stereogenic centre exists as two stereoisomers or enantiomers

The two enantiomers differ by their absolute configuration
A molecule with two stereogenic centres can exist as four stereoisomers
OH OH

each molecule has

an enantiomer
NH2 NH2
(1R,2R) (1S,2S)
other stereoisomers that
are not mirror images
are diastereoisomers
OH OH

each molecule has

an enantiomer
NH2 NH2
(1R,2S) (1S,2R)

A molecule can have one enantiomer but any number of diastereoisomers

Advanced organic
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Diastereoisomers
OH OH OH OH
same relative different relative
stereochemistry stereochemistry
/ configuration / configuration
NH2 NH2 NH2 NH2
diastereoisomers diastereoisomers

Diastereoisomers can have the same relative stereochemistry

The stereoisomers above differ only by their absolute stereochemistry
Or they can have different relative stereochemistry
Relative stereochemistry - defines configuration with respect to any other
stereogenic element within the molecule but does NOT differentiate between
enantiomers
In simple systems the two different relative stereochemistries are defined as below
OH OH

NH2 NH2
syn anti
same face different face

Occasionally you will see the terms erthyro & threo - depending on the convention
...used, these can mean two either relative stereochemistry so I will not use them!
Advanced organic
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Diastereoisomers II
OH
CHO
HO
OH OH
(2R,3R,4R)-2,3,4,5-tetrahydroxypentanal
ribose

OH OH OH OH
CHO CHO CHO CHO
HO HO HO HO four
diastereoisomers
OH OH OH OH OH OH OH OH
(2R,3R,4R)-ribose (2R,3R,4S)-arabinose (2R,3S,4R)-xylose (2R,3S,4S)-lyxose
mirror
plane
OH OH OH OH
CHO CHO CHO CHO
HO HO HO HO and their 4
enantiomers
OH OH OH OH OH OH OH OH
(2S,3S,4S)-ribose (2S,3S,4R)-arabinose (2S,3R,4S)-xylose (2S,3R,4R)-lyxose

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...
Advanced organic
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Meso compounds
OH
HO2C
CO2H
OH
tartaric acid

OH OH OH
HO2C HO2C HO2C
CO2H CO2H CO2H

H
OH OH OH

2
O

2H
H
OC
diastereoisomers

CH
OO
enantiomers identical

H
O
2C

HC
O2
O
O
OH
OH OH

H
CO2H
HO2C HO2C HO2C
CO2H CO2H
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
Advanced organic
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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 OH

HO CO2H HO2C CO2H

rotate LHS
plane of
symmetry

Another example...

H Cl H H
Cl H Cl Cl

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

Advanced organic
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Meso compounds III

EtO2C CO2Et EtO2C CO2Et

Me Me Me Me

plane of symmetry no plane of

meso symmetry
achiral chiral

One compound displays two CH3 peaks in 1H nmr; the other just one peak. Which
...one is which?
The meso compound shows two peaks for the cis and anti CH3 (wrt to CO2Et)
This compound is achiral
The chiral ester shows only one peak because it is symmetrical
It has a C2 axis of symmetry
This molecule is chiral but symmetrical

EtO2C CO2Et EtO2C CO2Et

Me Me Me Me
plane of axis of
symmetry symmetry

Advanced organic
15

Enantiomers vs. diastereoisomers

Two enantiomers have identical physical properties in an achiral environment
Two diastereoisomers have different physical properties

O2N O2N

CO2Me CO2Me

O O
diastereoisomers
trans cis
enantiomers epoxide enantiomers epoxide
mp = 141C mp = 98C
different mp
O2N O2N

CO2Me CO2Me

O O

Different physical properties, such as crystallinity or polarity allow diastereoisomers

to be separated
NH2 NH2 NH2 NH2 NH2 NH2
diastereoisomers

2HCl 2HCl 2HCl

chiral different solubility meso
solubility 0.1g/100ml EtOH seperable solubility 3.3g/100ml EtOH

Advanced organic
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Chiral derivatising agents II

This difference allows chiral derivatising agents to resolve enantiomers

enantiomerically pure mixture of

derivatising agent diastereoisomers
R*
R/S RR* + SR*
racemic
mixture
diastereoisomers
separable SR*
R*
R RR*
pure cleave pure
enantiomer diastereoisomer 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
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Chiral derivatising agents: Moshers acid

OH F3C OMe DCC, DMAP F3C OMe H

CH2Cl2, 10C O Me
+ CO2H
O
N
R/S S C RS & SS
N

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)

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Chiral derivatising agents: salts

OTol
HO2C
O NH CO2H OTol
O NH2
OH OTol O2C
OH CO2H
OTol

R/S S diastereoisomer is insoluble so easily removed by filtration

NaOH

O 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
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Enzymatic resolution
lipase PS from Pseudomonas
O cepacia, 0.05M phosphate buffer, O O
Bu pH 7, 0.1M NaOH, 5C Bu Bu
+ Na
OEt OEt O
60% conversion
F F F
R/S R S
>99% ee 69% ee
soluble in soluble in
organic phase 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 R
N N H
O O
Bu O
O
O
Et
diastereomeric interaction of enzyme H F his N
H
lone pair with * orbital of CF of (S)- O
enantiomer favoured over interaction ser
with (R)-enantiomer
Advanced organic
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Stereoselective synthesis
The term asymmetric synthesis should be used with caution. As we shall see, a
number of important chiral compounds are symmetric!!
As such this course will primarily focus on diastereoselective or enantioselective
synthesis or the synthesis of chiral molecules
Chiral compounds can be prepared in a number of ways:
Enantiospecific synthesis; the chiral pool

O HONO OH O
H2O
OH O O
H2N H N2 H H2O
H
(S)-leucine retension inversion

HO H OH
HO H
(S)-()-ipsenol inversion

Use enantiomerically pure starting material and stereospecific reactions

Good - if a cheap, readily available source of chirality exists
Problems - often results in long, tortuous syntheses
.......................suitable material not always available
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Stereoselective synthesis
Chiral auxiliaries

couple to form new

chiral compound
substrate substrate
(achiral) + chiral (achiral) chiral
auxiliary auxiliary

product
overall diastereoselective
reaction reaction chiral
auxiliary

resolve other
diastereoisomer
product cleave chiral product
(chiral) auxiliary
+ chiral chiral
auxiliary auxiliary

Chiral auxiliary - allows enantioselective synthesis via diastereoselective reaction

Add chiral unit to substrate to control stereoselective reaction
Can act as a built in resolving agent (if reaction not diastereoselective)
Problems - need point of attachment
....................adds additional steps
....................cleavage conditions must not damage product!
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Stereoselective synthesis II
Chiral reagents

chiral reagent substrate

interacts with (achiral)
achiral substrate reaction product
substrate (chiral)
(achiral) + chiral
+ dead
reagent reagent
chiral
reagent
chiral
complex

Chiral reagent - stereochemistry initially resides on the reagent

Advantages - No coupling / cleavage steps required
........................Often override substrate control
........................Can be far milder than chiral auxiliaries
Disadvantages - Need a stoichiometric quantity (not atom economic)
.............................Frequently expensive
.............................Problematic work-ups
Advanced organic
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Stereoselective synthesis III

substrate
(achiral) substrate
(achiral) chiral
catalyst

chiral
catalyst

product
(chiral)
chiral
catalyst

product
(chiral)

Chiral catalysis - ideally a reagent that accelerates a reaction (without being

destroyed) in a chiral environment thus permitting one chiral molecule to generate
millions of new chiral molecules...
Advanced organic
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substrate
(achiral) chiral
auxiliary

chiral
reagent

product

chiral
auxiliary

Advanced organic