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Unit One Part 8:

stereochemistry

the lecture everyone


(but me) hates...

...How would you like to live in
Looking-glass House, Kitty? I
wonder if they'd give you milk in
there? Perhaps Looking-glass
milk isn't good to drink?
Alice's Adventures in Wonderland - Lew" Carroll

...How would you like to live in
Looking-glass House, Kitty? I
wonder if they'd give you milk inglass
there? Perhaps Looking-glass
its a good
question...and it
turns out ‘looking-
milk’ would not
be good for
Kitty...but why?
milk isn't good to drink?
Alice's Adventures in Wonderland - Lew" Carroll
Unit One
Part 8
stereoisomers
shape & chirality
isomers
happy with isomers
having the same
atoms...

structural
isomers

different
bond pattern
isomers

structural
isomers ...and structural
isomers have these
atoms arranged
differently (different
bonding)...

different
bond pattern
structural isomers
OH
all these have the
same formula but are
obviously (!) very
different
cyclopentanol
C5H10O

OH O
(E)-pent-3-en-1-ol 4-methoxybut-1-ene
C5H10O C5H10O
O

HO H

3-methylbutan-2-one (S)-pent-1-en-3-ol
C5H10O C5H10O
isomers

stereoisomers have
the same atoms and

structural
the same bonds...so
same number of C– stereoisomers
isomers
C, C–H etc bonds

diastereomers

same
bond pattern
isomers
...they only differ by how these
bonds are arranged in space
(how they are orientated
relative to each other)

structural stereoisomers
isomers

diastereomers

same
bond pattern
stereoisomerism
or configurational isomerism
A C A D

B D
≠ B C

alkenes are the easiest to


understand...these two have all the
same bonds but differ because D & C
are on different sides of the molecule
stereoisomerism
or configurational isomerism
A C A D

B D
≠ B C

these are NOT different


conformations...to change between
the two stereoisomers we have to
break a bond...
stereoisomerism
or configurational isomerism
A C A D

B D
≠ B C
break
double bond remember: we cannot
rotate double bonds...so
we must break the π
A C bond, then...

B D
stereoisomerism
or configurational isomerism
A C A D
...rotate central C–C

B D
≠ B
bond...

C
break
double bond

A C A D
B D B C
rotate
single bond
stereoisomerism
or configurational isomerism
A C A D

B D
≠ B C
break reform
double bond double bond

A C A D
B D B C
rotate
single bond
diastereoisomers
MeO2C H MeO2C CO2Me

H CO2Me H H
dimethyl fumarate dimethyl maleate
trans (E) cis (Z)
mp 103°C mp –19°C
bp 193°C bp 202°C
diastereoisomers are different
compounds with different chemical
and physical properties
cyclic molecules
& diastereoisomers
cyclic molecules can exist as
diastereoisomers depending
on the relative orientation of
substituents...

Cl

Cl

relative stereochemistry
change the relative
stereochemistry to give new
diastereoisomers
Cl Cl

Cl Cl
cis-1,2- trans-1,2-
dichlorocylohexane dichlorocylohexane
(syn) (anti)

Cl Cl

Cl Cl
trans-1,2- cis-1,2-
dichlorocylohexane dichlorocylohexane
(anti) (syn)
Cl Cl

Cl Cl
cis-1,2- trans-1,2-
dichlorocylohexane dichlorocylohexane
(syn) (anti)

Cl Cl

Cl Cl
trans -1,2-
here we have TWO diastereoisomers...
cis-1,2-
dichlorocylohexane dichlorocylohexane
either both the chlorines are on the same side
(anti ) are on opposite sides
or they (syn)
Cl Cl

Cl Cl
cis-1,2- trans-1,2-
dichlorocylohexane dichlorocylohexane
(syn) (anti)

Cl Cl

Cl Cl
cisslide...which
trans-1,2- two questions arise from this -1,2-
conformation of
dichlorocylohexane each diastereoisomer is
dichlorocylohexane
(anti) preferred (easy)...and, why have I draw four
(syn)
molecules (hard)?
what will the favoured
conformation be?
cis
Cl

Cl

1Cl
2Cl

H 1Cl
2Cl

H
H
H
always

axial
one
substituent
cis
Cl

Cl

1Cl
2Cl

H 1Cl
2Cl

H
H
H
always

axial
in this example...both

one
conformations of the cis
diastereoisomer are identical...both
have one axial & one equatorial
substituent
substituent
trans Cl

Cl

2Cl
H
2Cl H
H
1Cl
H 1Cl

for the trans diastereomer the two


conformations are very different...one
has two axial substituents and the other
has two equatorial substituents...which
is preferred?
trans Cl

Cl

2Cl

X
H
2Cl H
H
1Cl
H 1Cl

equatorialfavoured
H
H
tBu
H
H
HO t
Bu
OH

what happens if we have two


different substituents (two different
groups on the ring)?
this one favoured as big tert-butyl
group is equatorial...minimises 1,3-
diaxial interactions

H
H
tBu
H
H
HO t
Bu
OH

equatorial
largest group
favours
H
Me
tBu Me H

H tBu

H
true for all substitution patterns
(it doesn’t matter where you put
the big group it will be equatorial

equatorial
largest group
favours
decalins fused ring system found in
many natural products (such
H as steroids) can exist as two
diastereoisomers...

2 H

stereoisomers
trans-decalins
H H

H H
trans-decalin equatorial, equatorial
ring fusion

they cannot undergo ring


flip so they are stuck in
these conformations
cis-decalins
H H

H
cis-decalin equatorial, axial
ring fusion
the one you all hate...
isomers

structural stereoisomers
isomers

diastereomers enantiomers

same
bond pattern
isomers

structural stereoisomers
isomers
a special kind of (pain)
stereosiomer...a pair of
enantiomers are identical in
always except...

diastereomers enantiomers

same
bond pattern
...an object that is
nonsuperposable on
its mirror image...
chirality in nature

chirality
in nature
chirality in nature

chirality
our hands are
mirror images...

in nature
chirality
in nature
chirality they look identical

in nature
(barring scars etc)
chirality
but can never
occupy the same
space...they are

in nature
chiral
chirality
snail shells are
either clockwise or

in nature
anti-clockwise...

photograph: Willi Rolfes


chirality
...and clockwise snails
will only mate with

in nature
clockwise snails....

photograph: Willi Rolfes


chiral
objects

windmills and
propellers are left or
right handed as are...
chiral
objects corkscrews
molecules can be left
or right handed

chiral molecules
Achiral compounds
Mirror
plane

if we take a molecule
and its...
Achiral compounds
Mirror
plane

...mirror image...and
we then start to...
Achiral compounds
Mirror
plane

rotate

...rotate that molecule


Achiral compounds
Mirror
plane
Achiral compounds
Mirror
plane

rotate
Achiral compounds
Mirror
plane

...we can get to a point


were the molecules are
identical and can be...
Achiral compounds
Mirror
plane
Achiral compounds
Mirror
plane

superposed upon each


other...then those
molecules are achiral
Chiral compounds
Mirror
plane

rotate

...it doesn’t matter how


many times and
directions you rotate a
chiral object...
Chiral compounds
Mirror
plane

it can never be
superposed...
the two isomers are called
enantiomers

such mirror images


are called...
they are identical in all ways...
physical properties
NMR (see lecture 9) identical for
both enantiomers as is the melting
points and all standard chemical
E-300
180 160 reactions
140 120 100 80 60 40

H OH

Ph CO2H
(R)-(-)-mandelic acid
mp 131-133°C
HO H

Ph CO2H
(S)-(+)-mandelic acid
mp 130-132°C
9 8 7 6 5 4 3 2
but they do differ
under certain
circumstances
(otherwise why would
we care...)

except
two properties...
physical properties
α

light light (λ) polariser plane sample reading


source polarised light cell length l (dm)

H OH HO H

Ph CO2H Ph CO2H
(R)-(-)-mandelic acid (S)-(+)-mandelic acid
[α]23
D –153 [α]23
D +153
physical properties
α

each enantiomer rotates plane


polarised light in a different
direction and more importantly...

light light (λ) polariser plane sample reading


source polarised light cell length l (dm)

H OH HO H

Ph CO2H Ph CO2H
(R)-(-)-mandelic acid (S)-(+)-mandelic acid
[α]23
D –153 [α]23
D +153
other chiral objects
other chiral objects
...how they interact with other chiral
objects is very different (imagine trying to
put your left foot in your right shoe...its a
tad more difficult than putting the right
foot in the right shoe)
we are chiral
we are chiral
so chiral molecules will
interact with us in
different ways...
smell

CH3 CH3

H H
CH3 H3C
(S)-limonene (R)-limonene
lemons oranges
taste

CH3 CH3
O O

H H
CH3 H3C
(R)-carvone (S)-carvone
©Patrick J. Lynch 2006 spearmint caraway
taste

CH3 CH3
O O

H H
...but these differences are
trivial compared to... CH3 H3C
(R)-carvone (S)-carvone
©Patrick J. Lynch 2006 spearmint caraway
chirality and drugs
Me Me
Me2N NMe2

Ph O O Ph
O O
Et Et
darvon novrad
painkiller cough-suppressant
chirality and drugs
Me Me
Me2N NMe2

Ph O O Ph
O O
Et Et
darvon novrad
painkiller cough-suppressant

both are commercially available and look


what those comical chemists have done
with the names!
drugs that target bacterial
alanine won’t hurt us (but
cause bacteria to burst!)

Me CO2H Me CO2H

NH2 NH2

L-alanine D-alanine
mammalian amino acid bacterial cell wall
chirality and drugs
O O
H H
N N

O O
O N O O N O
H H
(R)-thalidomide (S)-thalidomide
(morning sickness) (teratogenic)
but we have to be very careful otherwise
we can have horrific problems such as the
limbless children born because of the use
of thalidomide
www.massey.ac.nz/~gjrowlan/teaching.html

more information about chirality


can be found on my web site (if
you’re sad or sick of mind)
why does nature only
produce one enantiomer?

not part of the


course but a
wonderful
philosophical
question...
Me CO2H
a molecule with one carbon
atom with four different
groups coming off it can exist

NH2 as 2 enantiomers

1
2 =2
stereoisomers
O
H2N
N CO2CH3
H
a molecule with two carbon
HO2C atoms each with four different
aspartame
2
2 =4
groups coming off them can
exist as 4 stereoisomers

stereoisomers
if it has three atoms
(stereocentres) with 4 different

OH groups then it can have 8


stereoisomers...

CHO
HO
OH OH

3
2 =8
stereoisomers
insulin
(monomer)
has 51 stereocentres so it can exist
as a large number of stereoisomers

51
2 = 2.25 x 1015
stereoisomers
insulin
(monomer)

we have seen the problems


with just a 50:50 choice
(does it smell of lemons or
oranges?)

51
2 = 2.25 x 1015
stereoisomers
insulin
(monomer)
so we must have a single form of
insulin so it always does the same
thing...but insulin ain’t particularly
big...

51
2 = 2.25 x 1015
stereoisomers
DNA
polymerase
this number is
meaningless to me!

342

342
>2 = >8.96 x 10102

stereoisomers
DNA
polymerase

342

but it gets
worse...consider
our genes...

342
>2 = >8.96 x 10102

stereoisomers
46 46 chromosomes
comprising of...
and each base pair is
two molecules with three
stereocentres...so we
have a possibility of...
OH N
O
O N
NH
N
HO NH2

>3 billion
base pairs
Benny Herudek 3D Hifi - High Fidelity 3d Graphics Solutions

29,000,000,000 = ∞
stereoisomers
Benny Herudek 3D Hifi - High Fidelity 3d Graphics Solutions

if we produce just one


isomer then we don’t
have this problem...

29,000,000,000 = ∞
stereoisomers
?
of course, why we have one enantiomer and
not its mirror image is another question
entirely...one which I will not comment on in
order to avoid offending the religious
amongst you...
what have
....we learnt?

•t h e s h a pe
of molecules
• chirality
©bioneural.net

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