1. Unit One Part 8:
stereochemistry
the lecture everyone
(but me) hates...

2. ‘
...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

3. ‘
...How would you like to live in
Looking-glass House, Kitty? I
there? Perhaps Looking-glass
glass
its a good
question...and it
wonder if they'd give you milk inturnsmilk’ ‘looking-
out
would not
be good for
Kitty...but why?
milk isn't good to drink?
Alice's Adventures in Wonderland - Lew" Carroll

4. Unit One
Part 8
stereoisomers
shape & chirality

5. isomers
happy with isomers
having the same
atoms...
structural
isomers
different
bond pattern

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

7. 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

8. 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

9. 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

10. 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

11. 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...

12. 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

13. 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

14. 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

15. 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

16. cyclic molecules
& diastereoisomers
cyclic molecules can exist as
diastereoisomers depending
on the relative orientation of
substituents...
Cl
Cl
relative stereochemistry

17. change the relative
stereochemistry to give new
diastereoisomers

18. 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)

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

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

21. what will the favoured
conformation be?

22. ax ax
Cl1 ax eq
eq eq
eq eq
Cl2 eq ax
ax ax
need to map skeletal representation
onto 3D representation

23. Cl1
Cl2
ax ax up up
eq up up
ax
eq eq down down
eq eq up up
eq ax down down
ax ax down down
bold is up
dashed is down

24. Cl1
Cl2
ax ax up up
eq up up
ax
eq eq down down
eq eq up up
eq ax down down
ax ax down down
Please remember that up and down
refers to which face of the molecule the
bold is up
substituent is whilst equatorial and axial
refer to their orientation
dashed is down

25. Cl1
Cl2
Cl 1 Cl1
H H
eq up
ax down
once the first substituent is in
place the other’s position is fixed

26. Cl1
randomly place a substituent in an
upwards position. In this case I’ve chosen
axial but I could have had an equatorial Cl2
upward substituent...
Cl 1 Cl1
H H
eq up
ax down
once the first substituent is in
place the other’s position is fixed

27. Cl1
Cl2
Cl 1
H
Cl 2
H
the second substituent
must be in an upwards
position

28. Cl1
Cl2
ax up
Cl 1 Cl 1
eq down
H H
the other conformation starts with
Cl1 equatorial

29. Cl1
Cl2
ax up
Cl 1 Cl 1
eq down
H H
if I had started with the first
the other conformation starts with
upward substituent equatorial we
would end up with the same
Cl1 equatorial
answer

30. Cl1
Cl2
Cl2
Cl 1
H
H

31. cis
Cl1
Cl2
Cl1
Cl2
2
H Cl1
Cl
H
H
H
always
axial
one
substituent

32. cis
Cl1
Cl2
Cl1
Cl2
2
H Cl1
Cl
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

33. cis
Cl1
Cl2
Cl1
Cl2
2
H Cl1
Cl
H
H
H
always
axial
one
BUT REMEMBER THIS IS ONLY
TRUE FOR 1,2-DISUBSTITUTED
SYSTEMS!!!!
substituent

34. ax ax
Cl1 ax eq
eq eq
eq eq
Cl2 eq ax
ax ax
need to map skeletal representation
onto 3D representation

35. Cl1
Cl2
Cl 1 Cl 1
H H
eq up
ax down
once the first substituent is in
place the other’s position is fixed

36. Cl1
Cl2
Cl1
H
H
Cl2

37. Cl1
Cl2
ax up
Cl 1 Cl 1
eq down
H H
the other conformation starts with
Cl1 equatorial

38. Cl1
Cl2
H
Cl 1
Cl2
H

39. 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?

40. trans Cl
Cl
2Cl
X
H
2Cl H
H
1Cl
H 1Cl
equatorialfavoured

41. H
H
tBu
H
H
HO t
Bu
OH
what happens if we have two
different substituents (two different
groups on the ring)?

42. 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

43. 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

44. Draw the two
conformations of:
Ph
following the guidelines above you
should be able to deduce the
orientation of any substituent and
hence draw the conformations

45. Ph can go in any Ph
down position:
ax ax up up
ax eq up up
eq eq down down
eq eq up up
eq ax down down
ax ax down down

46. Ph can go in any Ph
down position:
up H H
up up
down Ph Ph
up up up
down down
down down down
now methyl can only go in one place

47. Ph can go in any Ph
down position:
H
Ph
H
now methyl can only go in one place

48. second conformation Ph
has Ph in axial down
position:
ax ax up up
ax eq up up
eq eq down down
eq eq up up
eq ax down down
ax ax down down

49. second conformation Ph
has Ph in axial down
position:
up up up
up up
down down down
H up H
down down
Ph down Ph
now methyl can only go in one place

50. second conformation Ph
has Ph in axial down
position:
H
H
Ph
now methyl can only go in one place

51. H
Ph H
H
H Ph
favoured conformation has large
group equatorial

52. decalins fused ring system found in
many natural products (such
H as steroids) can exist as two
diastereoisomers...
2 H
stereoisomers

53. trans-decalins
H H
H H
trans-decalin equatorial, equatorial
ring fusion
they cannot undergo ring
flip so they are stuck in
these conformations

54. cis-decalins
H H
H
H
cis-decalin equatorial, axial
ring fusion

55. the one you all hate...

56. isomers
structural stereoisomers
isomers
diastereomers enantiomers
same
bond pattern

57. isomers
structural stereoisomers
isomers
a special kind of (pain)
stereosiomer...a pair of
enantiomers are identical in
always except...
diastereomers enantiomers
same
bond pattern

58. ...an object that is
nonsuperposable on
its mirror image...

59. chirality in nature
chirality
in nature

60. chirality in nature
chirality
our hands are
mirror images...
in nature

61. chirality
in nature

62. chirality they look identical
in nature
(barring scars etc)

63. chirality
but can never
occupy the same
space...they are
in nature
chiral

64. chirality
snail shells are
either clockwise or
in nature
anti-clockwise...
photograph: Willi Rolfes

65. chirality
...and clockwise snails
will only mate with
in nature
clockwise snails....
photograph: Willi Rolfes

66. chiral
objects
windmills and
propellers are left or
right handed as are...

67. chiral
objects corkscrews

68. molecules can be left
or right handed
chiral molecules

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

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

71. Achiral compounds
Mirror
plane
rotate
...rotate that molecule

72. Achiral compounds
Mirror
plane

73. Achiral compounds
Mirror
plane
rotate

74. Achiral compounds
Mirror
plane
...we can get to a point
were the molecules are
identical and can be...

75. Achiral compounds
Mirror
plane

76. Achiral compounds
Mirror
plane
superposed upon each
other...then those
molecules are achiral

77. Chiral compounds
Mirror
plane
rotate
...it doesn’t matter how
many times and
directions you rotate a
chiral object...

78. Chiral compounds
Mirror
plane
it can never be
superposed...

79. the two isomers are called
enantiomers
such mirror images
are called...

80. they are identical in all ways...

81. 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

82. but they do differ
under certain
circumstances
(otherwise why would
we care...)
except
two properties...

83. 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 –153
D [α]23 +153
D

84. 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 –153
D [α]23 +153
D

85. other chiral objects

86. 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)

87. we are chiral

88. we are chiral
so chiral molecules will
interact with us in
different ways...

89. smell
CH3 CH3
H H
CH3 H3C
(S)-limonene (R)-limonene
lemons oranges

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

91. 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

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

93. 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!

94. 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

95. 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

96. 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)

97. why does nature only
produce one enantiomer?
not part of the
course but a
wonderful
philosophical
question...

98. Me CO2H
a molecule with one carbon
atom with four different
groups coming off it can exist
NH2 as 2 enantiomers
21=2
stereoisomers

99. O
H2N
N CO2CH3
H
a molecule with two carbon
HO2C atoms each with four different
aspartame
22=4
groups coming off them can
exist as 4 stereoisomers
stereoisomers

100. if it has three atoms
(stereocentres) with 4 different
OH groups then it can have 8
stereoisomers...
CHO
HO
OH OH
23=8
stereoisomers

101. insulin
(monomer)
has 51 stereocentres so it can exist
as a large number of stereoisomers
251 = 2.25 x 1015
stereoisomers

102. insulin
(monomer)
we have seen the problems
with just a 50:50 choice
(does it smell of lemons or
oranges?)
251 = 2.25 x 1015
stereoisomers

103. insulin
(monomer)
so we must have a single form of
insulin so it always does the same
thing...but insulin ain’t particularly
big...
251 = 2.25 x 1015
stereoisomers

104. DNA
polymerase
this number is
meaningless to me!
342
>2342 = >8.96 x 10102
stereoisomers

105. DNA
polymerase
342
but it gets
worse...consider
our genes...
>2342 = >8.96 x 10102
stereoisomers

106. 46 46 chromosomes
comprising of...

107. 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

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

109. 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

110. ?
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...

111. what have
....we learnt?
•t h e shape
of molecules
• chirality
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