1
Mirror
O O
N
S R
N
Two enantiomers differ by absolute configuration
OH HO
HN
NH
2
NH
2 NH
• A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomers
• Enantiomers have identical physical properties in an achiral environment
•
•
•
A molecule with
Enantiomers
2 stereogenic centres
(mirror images) still have can exist as identical
4 stereoisomers
physical properties
Diastereoisomers (non-mirror images) have different properties
O
2
N O
2
N enantiomers
CO
2
Me
O trans epoxide mp = 141°C
O
2
N
CO
2
Me
O diastereoisomers different mp enantiomers
O
2
N
CO
2
Me
O cis epoxide mp = 98°C
CO
2
Me
O
123.702 Organic Chemistry

2
NH
2
NH
2
NH
2
NH
2
NH
2
NH
2 diastereoisomers
2HCl chiral
2HCl solubility 0.1g/100ml EtOH different solubility seperable meso solubility 3.3g/100ml EtOH
• 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 Me
NH
2 syn same face
NH
2 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

3
OH
CHO
HO
OH OH
(2 R,3R,4R)-2,3,4,5-tetrahydroxypentanal ribose
OH
CHO
HO
OH OH
(2 R,3R,4R)-ribose
OH
CHO
HO
OH OH
(2 R,3R,4S)-arabinose
OH
CHO
HO
OH OH
(2 R,3S,4R)-xylose
OH
CHO
HO
OH OH
(2 R,3S,4S)-lyxose four diastereoisomers mirror plane
OH
CHO
HO
OH OH
(2 S,3S,4S)-ribose
OH
CHO
HO
OH OH
(2 S,3S,4R)-arabinose
OH
CHO
HO
OH OH
(2 S,3R,4S)-xylose
OH
CHO
HO
OH OH
(2 S,3R,4R)-lyxose 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
Problem is, the molecule will never have more than 2 n
2 n stereoisomers
stereoisomers but it might have less...
123.702 Organic Chemistry

4
OH
HO
2
C
CO
2
H
OH tartaric acid
HO
2
C
OH
OH
CO
2
H enantiomers
HO
2
C
OH
OH
CO
2
H diastereoisomers
HO
2
C
OH
OH
CO
2
H identical
HO
2
C
OH
OH
CO
2
H
OH
H
HO
2
C
H
2
O
C
O
2
H
O
H
2
C
O
CO
OH O
H C
2
O
H
C 2
CO
2
H
H
O
C
O
2
H
HO
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

5
• 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
HO
2
C OH
HO CO
2 rotate LHS
H plane of symmetry
• Another example...
H
Cl H
Cl chiral no plane of symmetry non-superimposable on mirror image
( but it is symmetric!
)
H
Cl Cl
H achiral plane of symmetry superimposable on mirror image
( meso )
123.702 Organic Chemistry

6
• Difference in diastereomers allows chiral derivatising agents to resolve enantiomers
R / S racemic mixture enantiomerically pure derivatising agent
R* mix tur e of dia ste reo iso mers
R – R * + S – R *
R pure enantiomer
R* cleave diastereoisomer diastere oisomers sepa rable S – R *
R – R * pure diastereoisomer
• Remember a good chiral derivatising agent should:
Be enantiomerically pure (or it is pointless)
• Coupling reaction of both enantiomers must reach
Coupling conditions should not
100% (if you are measuring ee) 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

7
OH
+
R / S
F
3
C OMe
CO
2
H
S
DCC, DMAP
CH
2
Cl
2
, –10°C
N
C
N
DCC - dicyclohexylcarbodiimide
F
3
C OMe
O
H
Me
O
R – S & S – S
• Popular derivatising agent for alcohols and amines is α -methoxyα trifluoromethylphenylacetic acid (MTPA) or Mosher’s acid
• Difference in nmr signals between diastereoisomers (above): 1 H nmr Δδ = 0.08 ( Me )
..................................................................................................
19 F nmr Δδ = 0.17 ( CF
3
)
• Typical difference in chemical shifts in
19
1 H nmr 0.15 ppm
F nmr gives one signal for each diastereoisomer
• No α -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

8
O
R / S
OH
NH
OTol
HO
2
C
OTol
CO
2
H
O NH
2
OTol
OH
O
2
C
CO
2
H
OTol
S diastereoisomer is insoluble so easily removed by filtration
NaOH
O
OH
NH
(–)-propranolol
β -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

9
• 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 ’ enantiomer - more stable (3 interactions)
‘ matched ’ enantiomer travels slowly racemic mixture in solution chiral stationary phase
‘ mis-matched ’ enantiomer - less stable (1 interaction)
‘ mis-matched ’ enantiomer readily eluted
123.702 Organic Chemistry

10
inject mixture on to column
R / S
R S
R
S chiral column prepared from a suitable chiral stationary phase
(many different types)
R
S
O
O
Si
O
O
Si
O
O
O
Si O
O
O
Si O
Si
O
Me
Si
Me
O
N
H silica
NO
2 chiral amine chiral stationary phase
NO
2
• 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
• 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
C
3
F
7
O
Eu( hfc )
3
O
Eu L
2
+ substrate Eu( hfc )
3
•••substrate
• Problems - as complexes are paramagnetic, line broadening is observed (especially on high field machines)
• Compound must contain
Accuracy is only ±2%
Lewis basic lone pair (OH, NH
2
, C=O, CO
2
H etc )
123.702 Organic Chemistry

12
O
O
O
N
Sm
3+
N
O
O
O
O
H
Me O
γ
α CO
2
H
β
NH
2
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 D
2
O at pH 9.4
123.702 Organic Chemistry

13
O
Bu
F
R / S
OEt lipase PS from Pseudomonas cepacia, 0.05M phosphate buffer, pH 7, 0.1M NaOH, 5°C
60% conversion
O
Bu
OEt
F
R
>99% ee soluble in organic phase
+
O
Bu
O
Na
F
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 diastereomeric interaction of enzyme lone pair with σ * orbital of C–F of ( S)enantiomer favoured over interaction with ( R)-enantiomer
O
H
Bu
O
F
H
N his
N H
O
R
O
Et
O
O ser
N
H
123.702 Organic Chemistry