Stereochemistry

Stereoisomers

• Molecules with the same connectivity but a different arrangement of atoms in 3 dimensional space (different configurations)

• Have the same physical and chemical properties

Constitutional isomers

• Have the same molecular formula but different connectivities (order in which the atoms are bonded to each other)

• Have very different physical and chemical properties

Why is it difficult to distinguish between some types of stereoisomers in the laboratory?

They often have the same physiochemical properties » same boiling point, melting point, solubility, polarity

Difference between constitutional isomers and stereoisomers

• Stereoisomers have different configuration and same connectivity

• Constitutional isomers have different connectivity

Which molecules show stereoisomerism?

• A Chiral molecule that is non-superimposable on its mirror image

• E.g. The 2 stereoisomers of alanine are non superimposable mirror images, therefore these are different compounds

A molecule is chiral if…

• It contains a tetrahedral, sp³ hybridised C with FOUR DIFFERENT GROUPS bonded to it

• This is called a chirality centre

• A molecule is chiral if because it contains a chirality centre

Steps for identifying chirality centres

• Discount any C that is not sp³ hybridised

• Discount any CH2s and CH3s

How to check if a molecule shows stereoisomerism

1. Check if the molecule has a chiral C

2. Draw the mirror image and see if they are non-superimposable

The 2 stereoisomers of alanine are shown.

Rotate the right hand molecule of alanine to demonstrate that it is non-superimposable with the other stereoisomer

• No matter how you rotate the structure, it will never be superimposable on its mirror image

• So the 2 stereoisomers are 2 different compounds

The 2 stereoisomers of lactic acid are shown.

Rotate the left hand molecule of lactic acid to demonstrate that it is non-superimposable with the other stereoisomer

Stereoisomers are…

ENTIRELY DIFFERENT MOLECULES

2 stereoisomers are also called

Enantiomers of one another

Define enantiomers

Non-superimposable mirror images that have OPPOSITE configuration at EVERY chirality centre

Draw the opposite enantiomer for 1-bromo-1-chloroethane

Is hexan-3-ol a chiral molecule?

If so draw an asterisk at the chiral/stereogenic centre

Yes

Is 1-bromo-1-methylcyclohexane a chiral molecule?

If so draw an asterisk at the chiral/stereogenic centre

• Ignore the CH2 carbons

• That just leaves C1, which is bonded to Br and CH3

• If we go around the ring clockwise, we have CH2CH2CH2CH2CH2

• And if we go anticlockwise, we also have CH2CH2CH2CH2CH2 » molecule is symmetrical

• So C1 is not a chirality centre and the molecule is achiral

If a molecule has a plane of symmetry…

• No chirality centres

• The molecule is achiral

Identify any stereogenic centres in carvone and mark them with asterisks

Identify the chirality centres in pseudoephedrine

Identify the chirality centres in tetrahydrocannabinol

When is a chiral molecule stereospecific?

Why is it important to be stereospecific when drawing chiral molecules

• When it shows how the 4 groups bonded to the stereogenic C atom are arranged in three dimensions

• Knowing how the bonds are arranged in a chiral molecule allows us to distinguish between enantiomers

How do we draw a chiral molecule stereospecifically?

Must draw the stereogenic C as tetrahedral

Draw the stereospecific structure of both enantiomers of hexan-3-ol from its bond-line formula shown

2 ways of drawing enantiomers

1. Reflecting the structure to form the mirror image

2. By swapping 2 groups then rotating the molecule

Draw the 2 enantiomers of bromo-chloro-ethane using the 2 different methods:

1. Mirror image

2. Swapping the substituents and rotating

Draw the individual enantiomers of promethiazide in any suitable stereospecific form

Why do we need a method of describing in words the configuration of different stereoisomers?

• The systematic name of a compound describes connectivity, but enantiomers have the SAME connectivity

• And we cannot use the same name to describe configuration for each enantiomer because they are DIFFERENT COMPOUNDS

What system do we use to describe the configuration of a chirality centre of 2 enantiomers

The Cahn-Ingold-Prelog

AKA

R-S convention

The 2 enantiomers of lactic acid are shown.

Which one is (S)-lactic acid and which is (R)-lactic acid?

1. Identify the 4 different substituents bonded to the chirality centre: CO2H, OH, CH3, H

2. Rank the substitutents in order of decreasing priority by ranking them according to atomic number. If the directly bonded atoms are the same move along to the next atom: OH > CO2H > CH3 > H

3. Draw the molecule with the lowest priority group behind the plane of the paper

4. If the lowest priority group is not already at the back: pick one of the bonds in the plane of the paper and keep that group fixed (not the lowest priority group as this is the one you want to move), rotate the other groups until the lowest priority one is at the back

5. Draw an arrow starting from the 1st to 2nd to 3rd highest priority substituent

6. If the arrow is anticlockwise = S configuration

7. If the arrow is clockwise = R configuration

Determine the configuration of the stereoisomer of alanine shown

• Anti-clockwise arrow

• So (S)-alanine

Determine the configuration of (-)-carvone

(R)-carvone

IF A SUBSTITUENT HAS A C=C IT HAS HIGHER PRIORITY THAN A C-C

How to draw a particular enantiomer when given the configuration (R or S)

1. Identify chirality centre

2. Rank the constituents

3. Place the lowest priority substituent in the back

4. Order the other substituents either clockwise (if R) or anticlockwise (if S) in order of priority (1, 2, 3, 4)

If asked to determine absolute configuration…

This is whether it is R or S

Draw the biologically active S enantiomer of ibuprofen

1. Identify chiral C

2. Order of priority is -COOH > aromatic ring > CH3 > H

3. Draw 3D structure with H at the back

4. Order the other 3 substituents anticlockwise (can be in the order that makes it the most easy to draw, just has to be anticlockwise)

Physical properties of enantiomers

• Same physical properties

• The molecules of each enantiomer pack together in the same way with the same intermolecular forces » so the density, melting point and boiling point for the S enantiomer will be the same as the R enantiomer

• The overall polarities of the 2 enantiomers are the same = same solubility

What is the only physical property enantiomers can be distinguished by?

Their interaction with plane polarised light

What happens if you pass plane polarised light through a solution of a chiral substance?

• ONLY chiral substances are optically active

• The substance will cause plane polarised light to be rotate through a certain angle (α)

• The angle by which the polarised light is rotated can be measured using another polarising filter on the other side of the sample which is turned until the light passes through it again » called a polarimeter

How can we classify chiral molecules based on how they rotate plane polarised light?

• If a substance causes plane-polarised light to rotate clockwise, α has a positive value

  » substance is dextrorotatory

  » (+)-name of substance e.g. (+)-carvone

• If plane polarised light rotated anticlockwise, α has a negative value

  » substance is levorotatory

  » (-)-name of substance e.g. (-)-carvone

What does the angle of rotation (α) depend on?

• Concentration (% or g/100mL)

• Path length (dm)

How to calculate the angle of rotation

[α] = 100α /concentration (% or g/100mL) x path length (dm)

[α] = 100α / c x l

• Measured at 25^oC, using light of wavelength 589.6 nm

What is the relationship between the rotation of plane polarised light pair of enantiomers?

Equal in magnitude but opposite in direction

The [α] value for (R)-lactic acid is -3.33^o. What is the [α] value for (S)-lactic acid?

+3.33^o

Chemical properties of enantiomers

• Same chemical properties

• Same polarity

• Same acidity » have same pKa

• Same reactivity

• However, react differently with other chiral molecules

Pharmacological activity of enantiomers (how do they act in the body)

• Target molecules in the body e.g. receptors and enzymes are usually proteins

• Proteins are chiral as made up of chiral amino acids

• They have specific binding sites where only drugs with a complementary shape can bind

• For a chiral drug, only one enantiomer will have the complementary shape to bind to the binding site

• So one enantiomer is active and the other is inactive

Why is it not good practise to administer an inactive enantiomer to a patient?

Sometimes the opposite enantiomer is toxic e.g. thalidomide

Relative configuration

What is the standard to which other compounds are compared to?

• Glyceraldehyde

• The configuration of substituents in (+)-glyceraldehyde is called the ‘D’ configuration

• The configuration of substituents in (-)-glyceraldehyde is called the ‘L’ configuration

Relative configuration

How is glyceraldehyde used as a standard to describe other enantiomers?

• Compounds that are chemically similar to D-glyceraldehyde = D configuration

• Compounds that are chemically similar to L-glyceryladehyde = L configuration

All amino acids found in proteins are __ configuration

L configuration

All the carbohydrates found in nature are __ configuration

D configuration

Compounds with only 1 chirality centre only have…

• 2 stereoisomers

• The R enantiomer and the S enantiomer (which are non-superimposable mirror images of each other)

How do we stereospecifically represent compounds that have MORE THAN ONE chirality centre? E.g. ephedrine

• The structure contains TWO chirality centres (C1 and C2)

• C1 could be R or S configuration and C2 could also be R or S configuration

• This gives a total of 4 possible stereoisomers:

  (1R,2R)-, (1R,2S)-, (1S,2S)-, (1S,2R)-

• Start with the stereoisomer that has R configuration at each chirality centre » (1R,2R)-ephedrine

• If we draw the mirror image of this » (1S,2S)-ephedrine

• If we change the configuration of C1 only, by swapping the 2 substituents (the order of substituents now goes anticlockwise) » (1S,2R)-ephedrine

• If we draw the mirror image of this » (1R,2S)-ephedrine

What is the relationship between all the stereoisomers of a compound with MORE THAN ONE chirality centre

E.g. for a compound with TWO chirality centres

• (1R,2R) and (1S,2S) are enantiomers

• (1S,2R) and (1R,2S) are enantiomers

• So the 4 stereoisomers exist as 2 pairs of enantiomers

• The stereoisomers that are not enantiomers of each other [e.g. (1R,2R) and (1R,2S), (1S,2S) and (1S,2R) etc] are diastereoisomers of each other

• These are stereoisomers that differ in configuration at one or more chirality centre but are NOT mirror images of each other

Draw any stereoisomer of 2-bromo-3-chlorobutane in a suitable stereospecific form and determine its absolute configuration. Draw its enantiomer and any diastereoisomer and write down their absolute configurations

If you’re confused about how swapping the 2 substituents on C1 changes the configuration from R to S even though it seems like the substituents still go in a clockwise order:

If you hold a group in the plane of the paper fixed and you rotate the substituents so the H is at the back, you’ll find IT DOES GO IN AN ANTICLOCKWISE ORDER YIPPEE !!!!!

Diastereoisomers

Stereoisomers that differ in configuration at one or more stereogenic centres but are NOT mirror images of each other

Physical properties of diastereoisomers

e.g. (1R,2R) and (1R,2S)

e.g. (1S,2S) and (1S,2R)

e.g. (1R,2R) and (1S,2R)

e.g. (1S,2S) and (1R,2S)

• Diastereoisomers are completely different compounds

• Different melting points, boiling points, solubilities and reactivities

• Diastereoisomers are optically active and differ in the direction AND angle they rotate plane polarised light

If a compound has TWO chirality centres…

• Maximum of 4 possible stereoisomers

• RR, SS, RS, SR

Formula for calculating maximum number of stereoisomers

2ⁿ

n = number of chirality centres

WHEN WILL A COMPOUND NOT BE CHIRAL

• If it has a plane of symmetry

• These are called meso compounds

How many stereoisomers are possible for a molecule with 2 stereogenic centres?

2³ = 8

The open chain form of glucose is shown. What is the maximum total number of stereoisomers possible for this sugar?

• 4 chirality centres

• 2⁴ = 16

Cis-trans isomerism

• Type of stereoisomer

• Same connectivity, but different arrangement of their groups in space (different configuration)

Why do cis-trans isomers have different configurations?

• Because there is no free rotation about the carbon-carbon double bond

• So it is not possible to convert one isomer into another without breaking and reforming bonds

Why are cis-trans isomers technically diastereoisomers?

They differ in configuration but are NOT mirror images

Why is cis-but-2-ene and trans-but-2-ene not optically active?

• They have symmetry and so are superimposable on their own mirror images

• So these molecules are achiral and do not rotate plane polarised light

Why are cis and trans molecules always achiral

• We only use the prefixes cis and trans when each C in C=C is bonded to a H and one other group

• This means they will always be symmetrical and non-superimposable on their mirror image

Properties of cis-trans isomers

• Cis-trans isomers are diastereoisomers

• So have DIFFERENT physical, chemical and pharmacological properties

Differences in the properties of trans-fatty acids and cis-fatty acids

• Trans-fatty acids:

  » have linear chains which can pack together more easily = higher melting point

  » more stable than cis-fatty acids as the substituents are further away from each other in space so there is repulsion

• Cis-fatty acids:

  » the cis double bond results in a bend in the chain, causing less efficient packing = lower melting point

When is the only time you use cis and trans?

When each C in the double bond has a HYDROGEN and one other substituent

SAME SIDE HIGHEST PRIORITY SUBSTITUENTS =

CIS

OPPOSITE SIDE HIGHEST PRIORITY SUBSTITUENTS =

TRANS

What do we use if each C in the C=C is not bonded to a H?

E and Z

The oestrogen receptor antagonist tamoxifen is used in breast cancer. Only the stereoisomer shown is pharmacalogically active. Determine whether it has E or Z configuration

1. Identify where the C=C is and whether each C is bonded to 2 different groups

2. Find the highest priority group for each C in C=C

3. Both on the same side

4. (Z)-tamoxifen

Categorise all the different types of isomers

When a reaction with a chiral molecule takes place, what does the configuration of the molecule depend on?

• Depends on the part of the molecule at which the reaction takes place

• If the reaction is away from the chirality centre = the configuration of the product will be the same as the substrate (retention of configuration)

• If the reaction takes place at the chirality centre = different configuration in the product to the substrate

Chiral compounds that undergo S_N2 nucleophilic substitution will always result in…

• Inversion of configuration

• This is because the nucleophile must attach from the side of the molecule opposite from the side which the leaving group departs

• E.g. configuration will change from R to S

Draw the S_N2 nucleophilic substitution mechanism for (R)-2-bromobutane reaction with hydroxide

• One-step reaction

• Attack of the nucleophile occurs simultaneously with the loss of the leaving group

• Inversion of configuration means (R)-2-brompropane is converted to (S)-butan-2-ol

2-bromobutane ALWAYS UNDERGOES

S_N2 NUCLEOPHILIC SUBSTITUTION

Draw the nucleophilic substitution mechanism for the reaction between (R)-3-bromo-3-methylhexane and hydroxide

• Tertiary alkyl halide = S_N1

• Two-step process

• Leaving group leaves during RDS forming carbocation intermediate

• Nucleophile attacks the +ve C

What is racemisation?

The process by which a single stereoisomer is converted into a 1:1 mixture of enantiomers

How can an S_N1 nucleophilic substitution result in a racemic mixture?

• The nucleophile can attack the +ve carbocation from either the right or the left

• There is an equal chance of either happening so an equal amount of each enantiomer is formed

• This forms a racemic mixture

Why do racemic mixtures show no optical activity

• Mixture contains an equal concentration of the 2 enantiomers

• The clockwise rotation of the dextrorotatory enantiomer and the anticlockwise rotation og the levorotatory enantiomer cancel each other out

What is the process where 2 enantiomers are separated from a racemic mixture called?

Resolution of the enantiomers

Describe what it means by chemical reactions in the body being stereoselective

Why are they stereoselective?

• They only work on one stereoisomer and produce products that are single stereoisomers

• This is because chemical reactions are only catalysed by enzymes which have a specific active site so only a single stereoisomer can bind

Consequences of chemical reactions in the body being stereoselective

1. Molecules produced by biosynthesis are usually single stereoisomers e.g. the only isomer of lactic acid produced by anaerobic respiration is (S)-lactic acid

2. Often one enantiomer will be a substrate for an enzyme and the other will not » if a drug is administered as a racemic mixture, the enantiomers will have different activity and will be metabolised differently

Salbutamol

How many chirality centres?

How is the drug administered?

Characteristics of each enantiomer

• 1 chirality centre

• Salbutamol is administered as a racemic mixture

• Only the R enantiomer is biologically active and is metabolised more quickly

• The S enantiomer can cause inflammation

Penicillamine

How many chirality centres?

How is the drug administered?

• Amino acid that contains 1 chirality centre

• Administered as a single enantiomer, (S)-penicillamine, as the R enantiomer is highly toxic

Methamphetamine

How many chirality centres?

Characteristics of each enantiomer

• 1 chirality centre

• The R enantiomer is used in OTC nasal decongestant remedies

• The S enantiomer is crystal meth

EQ:

Determine if the following pairs of molecules are identical or enantiomer of one another

A)

• Br is in the same place in both

• All the rest of the groups are in the same order

• So the 2 molecules are identical

  OR

• If you rotate the molecules to put the lowest priority substituent at the back

• Both molecules will have S configuration

• So they are identical

B)

• Rotate molecules to put lowest priority substituent at the back

• One molecule is S configuration and the other is R

• So they are enantiomers

EQ:

Draw the biologically active S enantiomer of fluoxetine.

How will the physical and chemical properties of (S)-fluoxetine compare to those of (R)-fluoxetine

• Identical physiochemical properties

• Except they rotate plane polarised light in opposite directions and react differently with other chiral molecules

EQ:

250mg of (S)-ibuprofen was dissolved in methanol to produce 10mL of solution. When this solution was analysed at 25^oC in a 20cm path length polarimeter, the observed optical rotation, a, was measured at +2.7^o. Calculate the value of [a]²⁵ for (S)-ibuprofen.

Predict the value of [a]²⁵ for (R)-ibuprofen and a racemic mixture of ibuprofen.

Concentration of (S)-ibuprofen: 250mg = 0.25g in 10mL = 2.5g/100mL

Path length = 20/10 = 2dm

[a]²⁵ (S)-ibuprofen = 100a/cl = 100 × 2.7 / 2.5 × 2 = +54^o

[a]²⁵ (R)-ibuprofen = -54^o

[a]²⁵ racemic mixture = 0^o

EQ:

Draw the mechanism of the SN2 reaction between (S)-2-bromopentane and sodium hydroxide.

Give the name, including the absolute configuration, of the product that is formed

R-pentan-2-ol

EQ:

Advantages and disadvantages of manufacturing and formulating a drug as a single active enantiomer

• + inactive enantiomer may contribute to unwanted effects

• - synthesis and isolation of single enantiomer may be difficult and costly

EQ:

Do diastereoisomers always rotate the plane of polarised light in opposite directions?

NO

When there is an aromatic ring with 1 heteroatom in it

None of the Cs are chiral !!!

IF A QUESTION ASKS WHAT IS THE MAXIMUM NUMBER OF STEREOISOMERS..

1. CHECK FOR CHIRALITY CENTRES FOR RS ENANTIOMERS

2. CHECK FOR C=C DOUBLE BONDS FOR EZ IZOMERS

EQ:

What is the maximum number of stereoisomers possible for isoallyl alanine?

4

Whenever deciding whether a molecule is R or S configuration..

ALWAYS DRAW THE DASH AND WEDGE ON THE LEFT SIDE

EQ:

How would the substitution reaction shown affect the configuration of the substrate?

• Tertiary alkyl halide

• So undergoes SN1

• Racemisation