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Unit One Part 8: stereochemistry

Describe the difference between stereoisomers & structural isomers
Nomenclature used for double bonds (cis-trans or E-Z)
Predict conformations of cyclohexanes
Define chirality and recognise stereocentres
Understand enantiomers and diastereoisomers

dr gareth rowlands; g.j.rowlands@massey.ac.nz; science tower a4.12

http://www.massey.ac.nz/~gjrowlan

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Isomerism
different bond
pattern

structural
isomers
diastereomers

ISOMERS
stereoisomers

same
bond pattern

enantiomers
non-superimposable
mirror images

Structural isomers
OH
OH

(E)-pent-3-en-1-ol
C5H10O

O
HO H

O
cyclopentanol
C5H10O

4-methoxybut-1-ene
C5H10O

3-methylbutan-2-one
C5H10O

(S)-pent-1-en-3-ol
C5H10O

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Configurational isomerism or stereoisomerism

The spatial arrangement of atoms in a molecule is its configuration
Configurational isomers have the same bonds
Configurational isomers can only be interconverted by breaking a bond
Easiest compounds to see this in are the alkenes...
A

MeO2C

Atom connectivity identical

But different configurations
Known as diastereoisomers
They are different compounds

H
CO2Me

dimethyl fumarate
trans (E)
mp 103C
bp 193C

less stable
steric crowding

E or trans

Z or cis

MeO2C
H

CO2Me
H

dimethyl maleate
cis (Z)
mp 19C
bp 202C

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E and Z nomenclature
E-alkenes have the highest priority groups on the opposite sides
Z-alkenes have the highest priority groups on the same side
Priority rules
1. Rank atoms attached to alkene in order of decreasing atomic number
atom = Br>Cl>O>N>C>H
Atomic number = 35, 17, 8, 7, 6 & 1

2. If atoms are the same, move along substituent until a difference is found
H2
C

CH3

>

CH3

CH3

>

OH

.3. Multiple bonds are assumed to count as the same number of single bonds
C N

1 Cl
2

H3C

1 CH2CH3

C C

CH3

(Z)-2-chloro-3methylpent-2-ene

N C

1CHO
HO2C 1
C C 2
2
Ph
CH2OH

(Z)-3-hydroxymethyl-4-oxo-2phenylbut-2-enoic acid

C N
N C

N
1CH OH
C2
2
C C 2
1
Br
CH2CH3
(E)-2-bromo-3(hydroxymethyl)
pent-2-enenitrile

H3C

2
H3C

O
2 CH
3

C C

C6H5
(E)-3-methyl-4phenylpent-3-en-2-one

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Cistrans isomerism in cyclohexanes

Cl
Cl
cis-1,2dichlorocylohexane
(syn)

Cl

Cl

Cl
trans-1,2dichlorocylohexane
(anti)

Cl

Cl
trans-1,2dichlorocylohexane
(anti)

Cl
cis-1,2dichlorocylohexane
(syn)

If two groups on a ring we must specify relative stereochemistry

Cis - both groups are on the same face
Trans - groups are on opposite faces
1Cl

2Cl

2Cl

H
H
both conformations have one axial
substituent & are identical

Me

2Cl

1Cl

2ClH

1Cl

H
bulky group equatorial
favoured

1Cl

one conformation is disfavoured as it has two

axial groups so maximum 1,3-diaxial interactions

H
tBu

Me

H
H

tBu

tert-butyl group
rarely is axial

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Decalins
H

H
H

H
trans-decalin

H
equatorial, equatorial
ring fusion

H
cis-decalin

equatorial, axial
ring fusion

Another example of stereoisomers comes from fused bicyclic molecules

Like a double bond the substituents could be cis or trans
Like a double bond these two are not interconvertible unless a bond broken

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Chirality

Mirror image

Left & right hands

Non-superimposable

The most confusing form of stereochemistry

A chiral structure is one that is non-superimposble on its mirror image
Occurs in nature (snails, honeysuckle etc), man-made objects (propellers,
corkscrews etc) and in molecules...

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Enantiomers
This form of stereoisomerism arises from a lack of symmetry
The molecule & its mirror image are different
The molecule & its mirror image are known as enantiomers

Achiral

Chiral

Mirror
plane

Mirror
plane
rotate

For those of a sick & twisted disposition more info on chirality & stereochemistry
can be found at my website: http://www.massey.ac.nz/~gjrowlan/teaching.html

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Enantiomers II
Most common form of chirality has a carbon atom with 4 different groups
attached & is called central chirality
Me

Me2N

H
Ph O
O
Et
darvon
painkiller

Me
N

H
O

N
O
H
(R)-thalidomide
(morning sickness)

CO2H

N
NH2

Me

nicotine
toxin / stimulant

L-alanine

mammalian amino acid

Many other forms of chirality including helical, axial & planar

Ph

PPh2

Ph2P

PPh2

(R)-(+)-BINAP
(R)-2-(diphenylphosphino)-1-(2-(diphenyl
phosphino)naphthalen-1-yl)naphthalene

M-[8]helicene

Fe

(R)-2-phenyl-1(diphenylphosphanyl)
ferrocene

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Physical properties of enantiomers

Enantiomers have identical physical properties such as mp, bp etc
They only differ in their interactions with other chiral entities
H

OH

Ph

CO2H

(R)-(-)-mandelic acid
131-133C
23
[]D
153

light
source

light ()

polariser

sample
cell length l (dm)

plane
polarised light

reading

HO

Ph

CO2H

(S)-(+)-mandelic acid
131-134C
20 +154
[]D

Chiral compounds rotate the plane of polarised light (hence optical isomers)
As most biological systems are chiral, enantiomers can have different effects
O

H
(R)-carvone
spearmint

H
(S)-carvone
caraway

H
(S)-limonene
lemons

H
(R)-limonene
oranges

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Two chiral centres (diastereoisomers)

Mirror
O
N
HN

O
OH

HO

NH2

NH2

NH

Two enantiomers
differ by absolute configuration

A molecule with 1 stereogenic centre exists as 2 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

enantiomers

trans
epoxide
mp = 141C

O2N

diastereoisomers
enantiomers
different mp

cis
epoxide
mp = 98C

O2N
CO2Me
O

CO2Me
O

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Chirality in our bodies

HO2C

Me
NH2

alanine

HO2C

H
N

HO2C
NH2

phenylalanine

NH2

histidine

Common amino acids are all have the same stereochemistry (L or S)

Aspartame (sweetener) is a dipeptide (two amino acids) - two stereocentres
Potentially 4 compounds (n stereocentres can give 2n diastereoisomers)

O
H2N

N
H

CO2CH3

HO2C

Insulin is made of 2 peptide chains - 1x30 amino acids & 1x21 amino acids
Potentially 2.25 x 1015 diastereoisomers
A relatively small protein is ribonuclease at 124 amino acids or
Potentially 2.13 x 1037 diastereoisomers

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Chiral drugs
Et

H
N

N
H

OH

OH

Et

OH

H
N

N
H

Et

NH
Me

()-propanolol
-blocker for heart disease

OH

(R,R)-enantiomer
causes blindness

Ethambutol
tuberculostatic (anti-TB)

OH
Me

Et

HN
Me

Me

OH

(+)-propanolol
contraceptive

O
N

O
OH

N
H

N
H

OH
N

S
(S)-timolol
high blood pressure

N
S

(R)-timolol
glaucoma

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Overview

What have we learnt?

Molecules are three dimensional...and it makes a difference
The arrangement of atoms in space can form new isomers
Such isomers can only be interconverted by breaking bonds
Mirror images can have very different properties
Synthesis of single enantiomers is very important

What's next?
A brief look at spectroscopy in many of its glorious forms
Starting with NMR or nuclear magnetic resonance spectroscopy
An idea of what information this tells us about protons in a molecule

dr gareth rowlands; g.j.rowlands@massey.ac.nz; science tower a4.12

http://www.massey.ac.nz/~gjrowlan