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Home , Enantiomer, Racemic mixture

1 Two chiral centres (diastereoisomers) Mirror O O Two N S R N OH HO differ by absolute configuration

HN NH2 NH2 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 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

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

O2N O2N

CO2Me CO2Me

O O 123.702 Organic 2 Diastereoisomers

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

• Enantiomers differ only by their absolute (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 are defined as below:

OH OH Me Me

NH2 NH2 syn anti same face different face

• A molecule can only have one 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 Diastereoisomers II

OH CHO HO OH OH (2R,3R,4R)-2,3,4,5-tetrahydroxypentanal

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... 123.702 Organic Chemistry 4 Meso compounds

OH

HO2C CO2H OH

OH OH OH

HO2C HO2C HO2C

CO2H CO2H CO2H

H 2

OH OH O OH

C H H

O H 2 OO

diastereoisomers C

enantiomers identical H O

C

C H 2

H 2 O

O O O

OH OH H H

2

H O C

2

C O HO2C HO2C H

CO2H CO2H H

OH OH O

• 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 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)

123.702 Organic Chemistry 6 Chiral derivatising agents

• Difference in allows chiral derivatising agents to resolve enantiomers

enantiomerically pure mixture of derivatising agent diastereoisomers R* R / S R–R* + S–R* diastereoisomers separable S–R* R*

R R–R* 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 123.702 Organic Chemistry 7 Chiral derivatising agents: Mosher’s acid

OH F3C OMe DCC, DMAP F3C OMe H CH2Cl2, –10°C O Me + CO2H O N C R / S S N R–S & S–S

DCC - dicyclohexylcarbodiimide

• 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) 19 ...... F 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)

123.702 Organic Chemistry 8 Chiral derivatising agents: salts

OTol

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

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

NaOH

O NH OH

(–)- 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 of enantiomers: chiral • 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 123.702 Organic Chemistry 10 Chiral chromatography

R/S inject mixture on to column R S R O O O Si O S Si O chiral column O H O O Si N prepared from a Si O Me Si O Si NO2 R suitable chiral O Me O stationary phase O (many different types)

NO2 S 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

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 + substrate Eu(hfc)3•••substrate 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%

123.702 Organic Chemistry 12 Chiral shift reagents II

O O 3+ O Sm O γ α CO2H O N N O β NH2 H O Me O 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 O cepacia, 0.05M phosphate buffer, O O pH 7, 0.1M NaOH, 5°C Bu Bu + Bu OEt OEt O Na 60% conversion F F F R / S R S >99% ee 69% ee soluble in soluble in organic phase aqueous phase

• 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...

H N N H R O O Bu O O O Et his N diastereomeric interaction of enzyme H F H lone pair with σ* orbital of C–F of (S)- O enantiomer favoured over interaction ser with (R)-enantiomer 123.702 Organic Chemistry