Chemistry 1102Charlie BondMCS Rm 4.16/4.27Charles.Bond@uwa.edu.au

What is Organic Chemistry?Organic Reactions I IIAlkanes (Ch 21)Conformational Analysis (Ch 21)Stereochemistry I II III (Ch 22)Alkyl Halides I II (Ch 24)Alcohols and Ether I II (Ch 24)

Problems from Brown & LeMay

Ch 22 22.1 - 22.33 except 22.4-6, 22.17, 22.24,

22.25

What is stereochemistry? Chemistry is not flat. It occurs in 3 dimensions. There are limitations in how we present chemical

compounds and reactions on paper.

Need to learn to think in 3D. This is easier for some people than others.

What is stereochemistry? Stereochemistry: The branch of chemistry

that deals with spatial arrangements of atoms in molecules and the effects of these arrangements on the chemical and physical properties of substances.

You will cover E and Z isomers of alkenes later this is a kind of stereochemistry

OH OH

powerful, intensely green, grassy odor has a more fruity odor

Chirality A different kind of stereoisomerism which

is more 3-dimensional is chirality. Lord Kelvin 1884 I call any geometrical

figure chiral, and say it has chirality, if its image in a plane mirror cannot be brought to coincide with itself (from the Greek for hand)

1975 Nobel prize for Chemistry: Vladimir Prelog (http://hrcak.srce.hr/file/8822)

Chiral The two partner objects which are chiral

are called enantiomorphs or enantiomers.

Hands are the simplest examples

Objects which are not chiral are achiral.

Chirality in 2 Dimensions

Object Mirror Reflection Original Identical? Chiral/achiral Mirror symmetry

YYYNNNN

achiral

achiral

achiral

chiral

chiral

chiral

chiral

Tetris pieces:

Chirality in practise: Tetris

No matter how many times you rotate the blue piece, it will not fit.

It's enantiomorph, the purple piece will fit nicely in a couple of places.

In a 3D world you could just flip the blue piece over and it would look like the purple piece, but in Tetris (2D) world you can only rotate it.

In 2D, the blue and purple pieces are enantiomorphs.

Compare two scenarios in tetris:

=

Chirality in Practise: Letters Achiral: ACDEHIMOTUVWXY MOUTHY | YHTUOM Chiral: BFGJKLNPQRSZ GNP | PNG

ABBA AOXOMOXOA TOYS R US

Chirality in 3 Dimensions

Clayden et al Organic Chemistry Ch 16 on Stereochemistry: PDF currently available on www.oup.co.uk website.

Are all of these items chiral?

Back to Chemistry:Isomers

Enantiomers Enantiomers:Enantiomers: nonsuperposable mirror

images as an example of a molecule that exists as a

pair of enantiomers, consider 2-bromopentane

Enantiomers one way to see that the mirror image of 2-

butanol is not superposable on the original is to rotate the mirror image

Originalmolecule

OHC

H3C CH2CH3H

OHC

CH3HCH3CH2

OHC

H3C HCH2CH3

Mirrorimage Themirrorimagerotatedby180

180

rotatethemirrorimageby180abouttheCOHbond

Different molecules:

non-superimposable mirror images

Enantiomers.OHC

H3C CH2CH3H

OHC

H3C HCH2CH3

Theoriginalmolecule

Themirrorimageturnedby180

Enantiomers Molecules with superposable mirror images are said to be achiral. Achiral

molecules possess a plane of symmetry

As an example of an achiral molecule, consider 2-propanol notice that this molecule has no stereocentre

Originalmolecule Mirrorimage

OHC

H3C CH3H

OHC

CH3HH3C

Enantiomers The most common cause of enantiomerism in organic

molecules is the presence of a carbon with four different groups bonded to it a carbon with four different groups bonded to it is called a

stereocentre, a stereogenic centre or a chiral centre.stereocentre, a stereogenic centre or a chiral centre.

Chiral

Achiral

Enantiomers To summarize

an object that is nonsuperposable on its mirror image is chiralchiral (it shows handedness)

the most common cause of chirality among organic molecules is the presence of a carbon with four different groups bonded to it

we call a carbon with four different groups bonded to it a stereocentrestereocentre

an object that is superposable on its mirror image is achiralachiral (without chirality)

nonsuperposable mirror images are called enantiomersenantiomers

enantiomers, like gloves, always come in pairs

Drawing Enantiomers Following are four different representations for one of the

enantiomers of 2-butanol

both (1) and (2) show all four groups bonded to the stereocenter and show the tetrahedral geometry

(3) is a more abbreviated line-angle formula; although we show the H here, we do not normally show them in line-angle formulas

(4) is the most abbreviated representation; you must remember that there is an H present on the stereocentre

OHC

H3C CH2CH3H

OHC

H3C CH2CH3

HH OH OH

(1) (2) (3) (4)

Drawing Mirror Images on the left is one enantiomer of 2-butanol on the right are two representations for its

mirror image (in this case, its enantiomer)

Often, an asterisk (*) is used to indicate a stereocentre

OH OH OH

Oneenantiomerof2butanol

Alternativerepresentationsforitsmirrorimage

OH*

Indeterminate Chirality If we dont know the stereochemistry of a

compound, or we are talking about both enantiomers, We can use wiggly lines to represent the

ambiguity:

Identifying ChiralityQ. Which of the following molecules are chiral? Identify the stereogenic centre(s).

H2NF O CH3

OH

CH2CH3HO2CH

Cl

HIH

CO2H

BrH NH2

O

H H3C

CH3

Which is the odd one out?

Which is the odd one out?

Which is the odd one out?

Assigning ChiralityEnantiomers are different compounds.

So it is necessary to be able to describe the handedness (configuration) of stereogenic centres.Vladimir Prelog, along with Cahn and Ingold, developed a convention for assigning chiral centres as R or S. (They also invented the E,Z notation used for alkenes)

Consider the amino acid alanine:

1. Identify the stereogenic centre CO2

CH3

H3N

2. Draw the molecule to illustrate its tetrahedral nature. CO2H3N

CH3H

Assigning Chirality3. Assign priority to the 4 substituents.

3a. Priority increases with atomic number (1 is highest).

CO2H3N

CH3H1 2/3

4

3b. If two (or more) of the atoms attached to the stereogenic carbon are the same, consider the next atoms in the chain.

CO2H3N

CH3H1

2

4 3

Panic what is Priority? Priority rules

1. Priority is based on atomic number; the higher the atomic number, the higher the priority

2. If priority cannot be assigned on the basis of the atoms bonded directly to the double bond, look to the next set of atoms; priority is assigned at the first point of difference

(53)(35)(17)(16)(8)(7)(6)(1)

Increasingpriority

-H -CH3 -NH2 -OH -SH -Cl -Br -I

Increasingpriority

(8)(7)(6)(1)-CH2-OH-CH2-NH2-CH2-CH3-CH2-H

- 3. Atoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds

-CH=CH2

O-CH

O

HC

CO

CC-CH-CH2

istreatedas

istreatedas

Assigning Chirality4. Arrange the molecule so that the lowest priority substituent is

pointing away from you (into page).

5. Mentally, move from 1-2-3.

If rotation is clockwise

If rotation is anticlockwise

O2C NH3

H CH31

2

4 3

anticlockwise S-alanine

O2C NH3

H CH31

2

4 3

CO2H3N

CH3H1

2

4 3

flip horizontal

RS Remember: R is for Right

From the latin: Sinister, Rectus

Assigning R/S

H2NF O CH3

OH

CH2CH3HO2CH

Cl

HIH

CO2H

BrH NH2

O

H H3C

CH3

Brainbuster Is this compound chiral? If so, is it R or S?

NOTE: YOU WILL NOT BE EXAMINED ON THIS .

Enantiomers can be described as (+)/(-)In addition to R/S, you will encounter molecules labelled as (+)/(-).

Whereas R/S is based on geometry, (+)/(-) is based on a physical property of chiral compounds:

Optical Activity: the ability to rotate plane-polarised light.Two enantiomers will interact differently with polarised light, scattering it in opposite directions.

(A bit like bowling to left-handed or right-handed batsmen)

Optical Rotation The instrument that measures the angle of

rotation of plane-polarised light is called a polarimeter.

In order to quantify the observed rotation, , both the path length through the sample and the concentration of the sample need to be accounted for. The specific rotation [ ] can be calculated by:

20

Figure 22.12a

Unlike R/S. this property changes with solvent, temperature, concentration and wavelength of light used. Typical conditions are at 20C, in ethanol or chloroform with light of =589nm (e.g. sodium lamp D-line).

is the observed rotation in degrees, c is the concentration in g/mL and l is the length of the sample in dm (1dm=10cm=0.1m). These are bizarre units: the unit for [ ] is not normally stated.

Optical Rotation The optical isomer that rotates plane-polarised light in

a clockwise direction is called dextrorotatory. Given the symbols (+)-isomer

The optical isomer that rotates plane-polarised light in an anticlockwise direction is called levorotatory. Given the symbols (-)-isomer

An equal mix of (+) and (-) is known as a racemic mixture or racemate. Racemates have an observed rotation of 0o Usually given the symbols dl or ()

Enantiomers can be L or D To add to the alphabet soup, some compounds

are labelled L or D. This is archaeic notation, from many years ago. Before X-ray crystallography became

commonplace, chemists would work out the detailed structure of compounds by breaking them down into smaller pieces.

If a fragment resembled D-glyceraldehyde it would be labelled D etc etc.

It is only commonly now used with amino acids and sugars: all natural chiral amino acids are called L-.

R/S/+/-/L/D what the ?

Knowing which enantiomer you have is IMPORTANT as they are different molecules, so make sure you use the correct convention.

This is why Prelog was awarded a Nobel prize for systemising this mess.

Ghana is to change over to driving on the right. The change will be made gradually.

Life is chiral

Enzymes can (and usually do) discriminate between enantiomers.

They can do this because they are also chiral (and single enantiomers) . We will discuss this more in a later lecture.

H3C

CO2H

OHH

CH3

CO2H

HOH

(+)-lactic acidm.p. = 53 C[]D = +3.82

()-lactic acidm.p. = 53 C[]D = 3.82

lactatedehydrogenase

lactatedehydrogenase

H3C

CO2H

O

no reaction

substrate enzyme(Nature's catalyst) product

Racemates

The chemical product (2) contains an equal mixture of either enantiomer.A mixture of 50:50 of two enantiomers is called a racemic mixture, or racemateRacemates have no optical activity: the rotation caused by one enantiomer exactly cancels out that of the other.

H3C

CO2H

OHH

(S)-(+)-lactic acid

lactatedehydrogenaseH3C

CO2H

O

H3C

CO2H

no optical activityH3C

CO2H

ONaBH4

OH

() lactic acid

(1)

(2)

Physical Properties of Enantiomers

H3C

CO2H

no optical activity

OH( ) lactic acid

H3C

CO2H

OHH

CH3

CO2H

HOH

(+)-lactic acidm.p. = 53 C[ ]D = +3.82

()-lactic acidm.p. = 53 C[ ]D = 3.82

m.p. = 17 C?

It is important to know, if you are using a racemic mixture, an arbitrary mixture or an enantiomerically pure compound for a particular purpose as their physical properties may differ.

Chirality is important!O O

()-carvone(spearmint)

(+)-carvone(caraway)

(+)-limonene(orange smell)

()-limonene(lemon smell)

On this and following slides, make sure you can identify chiral centres and designate them R/S.

Importance of ChiralityChirality is of importance to organic chemistry for a number of

reasons:

Many reactions will produce mixtures of enantiomeric products which may need to be separated.

Many compounds made by synthetic organic chemistry are

designed to interact with living beings (antiseptics, antibiotics, drugs, cancer chemotherapeutics), and living beings are chiral.

H3C

CO2H

OHH CH3

CO2H

HOH

DOPA must be marketed as a single enantiomer, not a racemate.

Chirality is important!

L-DOPA (S)

HO

HO

NH2

CO2H

D-DOPA (R)toxic

HO

HO

NH2

CO2H

dopamine- deficient in

Parkinson's disease

HO

HO

NH2

DOPA-decarboxylase

Two enantiomers may exhibit different biological properties:Enantiopurity is important!

Racemate marketed as a palliative for morning sickness in the 1950s.

R enantiomer useful and harmless.

S enantiomer potent teratogen

NH

O

O

N

O

ONH

O

O

N

O

O

(R)-Thalidomide (S)-Thalidomide

Diastereomers(diastereoisomers)

Enantiomers & Diastereomers

For a molecule with 1 stereocenter, 21 = 2 stereoisomers are possible

It gets more interesting with combinations of chiral centres:

2,3,4-Trihydroxybutanal

For a molecule with 2 stereocenters, a maximum of 22 = 4 stereoisomers are possible:

HOCH2-CH-CH-CHOHOH

O* *

C

C

H OHCHO

OH

CH2OH

H

C

C

HHOCHO

HO

CH2OH

H H

CH2OH

HO

C

C

H OHCHO

C

C

HHOCHO

H

CH2OH

OH

Apairofenantiomers(Erythrose)

Apairofenantiomers(Threose)

22 = 4 stereoisomers

C

C

H OHCHO

OH

CH2OH

H

C

C

HHOCHO

HO

CH2OH

H H

CH2OH

HO

C

C

H OHCHO

C

C

HHOCHO

H

CH2OH

OH

Apairofenantiomers(Erythrose)

Apairofenantiomers(Threose)

HOCH2-CH-CH-CHOHOH

O* *

R

R

R

S

S

S

S

R

Meso Compounds Meso compound:Meso compound: an achiral compound

possessing two or more stereocenters E.g. tartaric acid

C

C

H OH

COOH

OH

COOH

H

C

C

HHO

COOH

HO

COOH

H

C

C

H OH

COOH

H

COOH

HO

C

C

HHO

COOH

H

COOH

OH

ApairofenantiomersAmesocompound(planeofsymmetry)

R

S

S

R

R

R

S

S

m.p.=173 C

[ ] = +12.7

m.p.=173 C

[ ] = -12.7

m.p.=147C

[ ] = 0

Meso CompoundsTartaric acid has two stereocenters2n = 4, but only three stereoisomers exist

Meso CompoundsThe RS and SR compounds are identical meso compounds

Summary

Cyclic Molecules

2-Methylcyclopentanol 2 stereocenters; a maximum of 4

stereoisomers how many exist?

cis2Methylcyclopentanol trans2Methylcyclopentanol

H3C

HO

CH3

OH

H3C

HO

CH3

OH

Cyclic Molecules

1,2-Cyclopentanediol 2 stereocenters = a maximum of 4

stereoisomers how many exist?

HO

HO

OH

OH

HO

HO

OH

OHcis1,2Cyclopentanediol trans1,2Cyclopentanediol

Cyclic Molecules

4-Methylcyclohexanol how many stereoisomers are possible?

OHH3C OHH3C

cis4Methylcyclohexanol trans4Methylcyclohexanol

Three Or More Stereocenters how many stereocenters are present in the

molecule on the left? how many stereoisomers are possible? one of the possible stereoisomers is menthol assign an R or S configuration to each

stereocenter in menthol

2Isopropyl5methylcyclohexanol

OH

Menthol

OH

Three Or More Stereocentres Cholesterol

on the left is the carbon skeleton of cholesterol

how many stereocentres are present? how many stereoisomers are possible?

HO HOThisisthestereoisomerfoundin

humanmetabolism

H

H

H

Thecarbonskeletonofcholesterol

H

Thiostrepton 216 Thiostrepton is an antibiotic compound produced by some

streptomycete bacteria. Only one stereoisomer is produced:

DNA DNA is chiral: there are deoxyribose sugars in its structure:

A filament of duplex DNA has around 20 billion stereogenic centres per metre. (You have ~2m DNA per cell and ~1013 cells in your body)

Lactate Dehydrogenase

LDH is a protein found in humans, composed of around 330 chiral aminoacids. Of 2330 possible stereoisomers, only 1 is produced.

Lactate Dehydrogenase

O

CO2Hpyruvic acid

NaBH4CO2H

lactic acid

HO H

CO2Hlactic acid

H OH+

Hattack of H from behind attack of H from in front

O

CO2HNADH

CO2HS-(+)-lactic acid (only)

H OH

enzyme(both enantiopure)

Chemical Synthesis

DEMO

Chirality in the Biological World because enzymes are chiral substances, most either produce or react with

only substances that match their stereochemical requirements

Schematic diagram of the surface of an enzyme capable of distinguishing between enantiomers

Virus Particle

http://www.stanford.edu/group/virus/polyoma/2005/SV40%20Large.jpg

This virus particle is made up from around 400 copies of a protein, which is itself made up of 100s of chiral aminoacids.

Of ~210,000 stereoisomers, only one exists.

You need to Appreciate all forms of isomerism: Constitutional isomerism, StereoisomerismChirality and enantiomerism: be able to recognise chiral and achiral molecules and stereogenic centres Represent enantiomers. Be able to assign absolute configuration (R/S). Appreciate optical activity and the lack of it with achiral compounds and racemic

mixtures. Do calculations of optical activity measurements.Be able to recognise diastereomers and meso compounds.Understand the importance of configuration to biological activity.

Look in Brown & LeMay and MasteringChemistry for plenty of example questions.

Look in any Organic chemistry text for a compound and see if you can determine its stereochemistry.

Problems Draw a constitutional

isomer and a stereoisomer of this compound

Problems How many

stereogenic centres do each of these compounds have?

Assign R or S to them.

(a)H Cl

OHH

(b)

NH3+O-

O(c)

Problems

Are these compounds

(B)isomers?

(C)Stereoisomers?

(D)A pair of enantiomers?

(E) Chiral?

(F) Diastereomers?

(G)Optically active?

Problems

Assign R/S to these compounds:

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