Two chiral centres (diastereoisomers) - Massey Universitygjrowlan/stereo2/lecture2.pdf · Two...
Transcript of Two chiral centres (diastereoisomers) - Massey Universitygjrowlan/stereo2/lecture2.pdf · Two...
123.702 Organic Chemistry
enantiomerscis
epoxidemp = 98°C
Two chiral centres (diastereoisomers)
• A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomers• Enantiomers have identical physical properties in an achiral environment
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NH2HN
N
O
OHNH2 NH
N
O
HOS R
Mirror
Two enantiomersdiffer by absolute configuration
O
CO2Me
O2N
O
CO2Me
O2N
enantiomerstrans
epoxidemp = 141°C
O
CO2Me
O2N
O
CO2Me
O2N
diastereoisomers
different mp
• 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
123.702 Organic Chemistry
Diastereoisomers
• 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:
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NH2 NH2 NH2 NH2
2HCl 2HClchiral
solubility 0.1g/100ml EtOH
NH2 NH2
2HClmeso
solubility 3.3g/100ml EtOH
diastereoisomers
different solubilityseperable
MeOH
NH2
MeOH
NH2
synsame face
antidifferent 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
HOCHO
OH OH
OH
(2R,3R,4R)-2,3,4,5-tetrahydroxypentanalribose
Diastereoisomers II
• 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...
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HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
HOCHO
OH OH
OH
(2R,3R,4R)-ribose (2R,3R,4S)-arabinose (2R,3S,4R)-xylose (2R,3S,4S)-lyxose
(2S,3S,4S)-ribose (2S,3S,4R)-arabinose (2S,3R,4S)-xylose (2S,3R,4R)-lyxose
four diastereoisomers
and their 4 enantiomers
mirror plane
123.702 Organic Chemistry
Meso compounds
• Tartaric acid has 2 stereogenic centres. But does it have 4 diastereoisomers?
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HO2CCO2H
OH
OH
tartaric acid
HO2C CO2HOH
OHHO2C CO2H
OH
OH
HO2C CO2HOH
OHHO2C CO2H
OH
OH
diastereoisomersenantiomers identical
HO2C CO2HOH
OHHO2C
CO2HOH
OH
HO2C
CO2H
OH
OH
HO2C
CO2H
OH
OH
• 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
HO2C
OH
CO2H
HO OH
CO2H
HO
HO2C
plane of symmetry
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
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rotate LHS
HO2C
CO2HHO
OH
• Another example...
ClH
ClH
achiralplane of symmetrysuperimposable on
mirror image(meso)
ClH
HCl
chiralno plane of symmetrynon-superimposable
on mirror image(but it is symmetric!)
123.702 Organic Chemistry
R
R*
pure enantiomer
cleave diastereoisomer
S–R*
R–R*
diastereoisomers separable
pure diastereoisomer
R–R* + S–R*
mixture of diastereoisomers
R*
enantiomerically pure derivatising agent
R / Sracemic mixture
Chiral derivatising agents
• 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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• Difference in diastereomers allows chiral derivatising agents to resolve enantiomers
123.702 Organic Chemistry
Chiral derivatising agents: Mosher’s acid
• Popular derivatising agent for alcohols and amines is α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) or Mosher’s acid
• Difference in nmr signals between diastereoisomers (above): 1H nmr Δδ = 0.08 (Me)..................................................................................................19F nmr Δδ = 0.17 (CF3)
• Typical difference in chemical shifts in 1H nmr 0.15 ppm• 19F 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)
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OH+ CO2H
F3C OMe
R / S S
DCC, DMAP CH2Cl2, –10°C
F3C OMeO
O
MeH
R–S & S–S
DCC - dicyclohexylcarbodiimide
NC
N
123.702 Organic Chemistry
Chiral derivatising agents: salts
• 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...
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OOH
NH
R / S
HO2CCO2H
OTol
OTol
OOH
NH2O2C
CO2HOTol
OTol
S diastereoisomer is insoluble so easily removed by filtration
NaOH
OOH
NH
(–)-propranololβ-blocker
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
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racemic mixture in solution
‘matched’ enantiomer - more
stable (3 interactions)
‘mis-matched’ enantiomer - less
stable (1 interaction)
‘matched’ enantiomer
travels slowly
‘mis-matched’ enantiomer
readily eluted
chiral stationary phase
123.702 Organic Chemistry
Chiral chromatography
• 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
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SiN
H
ONO2
NO2
SiOSi
Si OO
O
O
OSi
OSiO
O
O
O
O
MeMe
silica chiral aminechiral stationary phase
R S
R/S
RS
S
R
inject mixture on to column
chiral column prepared from a suitable chiral
stationary phase (many different types)
R
123.702 Organic Chemistry
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
• 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%
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O EuL2O
C3F7
+ substrate
Eu(hfc)3
Eu(hfc)3•••substrate
123.702 Organic Chemistry
Chiral shift reagents II
• 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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CO2H
NH2L-valine
αβ
γ
O
O N N O
OMeH
OO
OOSm3+
123.702 Organic Chemistry
Enzymatic resolution
• 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...
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BuOEt
O
F
lipase PS from Pseudomonas cepacia, 0.05M phosphate buffer,
pH 7, 0.1M NaOH, 5°C
60% conversionBu
OEt
O
F
BuO
O
F
Na+
R / S R>99% ee
soluble in organic phase
S69% ee
soluble in aqueous phase
NNH
ONH
OH
OR
OEt
his
ser
OBu
FH
O
enzyme
diastereomeric interaction of enzyme lone pair with σ* orbital of C–F of (S)-enantiomer favoured over interaction
with (R)-enantiomer