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Unit One Part 8:stereochemistry
the lecture everyone (but me) hates...
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 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 in there? Perhaps Looking-glass milk isn't good to drink?
‘.’
its a good question...and it
turns out ‘looking-glass milk’ would not
be good for Kitty...but why?
stereoisomersshape & chirality
8Unit OnePart
structural isomers
isomers
bond patterndifferent
happy with isomers having the same
atoms...
structural isomers
isomers
bond patterndifferent
...and structural isomers have these
atoms arranged differently (different
bonding)...
OH
cyclopentanolC5H10O
OH(E)-pent-3-en-1-ol
C5H10O
O4-methoxybut-1-ene
C5H10OO
3-methylbutan-2-oneC5H10O
HO H
(S)-pent-1-en-3-olC5H10O
structural isomersall these have the
same formula but are obviously (!) very
different
diastereomers
stereoisomersstructural isomers
isomers
bond patterns a m e
stereoisomers have the same atoms and the same bonds...so same number of C–
C, C–H etc bonds
diastereomers
stereoisomersstructural isomers
isomers
bond patterns a m e
...they only differ by how these bonds are arranged in space
(how they are orientated relative to each other)
B
A C
D≠ A
B C
D
stereoisomerismor configurational isomerism
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
B
A C
D≠ A
B C
D
stereoisomerismor configurational isomerism
these are NOT different conformations...to change between the two stereoisomers we have to
break a bond...
B
A C
D≠ A
B C
D
stereoisomerismor configurational isomerism
break double bond
A CB D
remember: we cannot rotate double bonds...so
we must break the π bond, then...
B
A C
D≠ A
B C
D
stereoisomerismor configurational isomerism
break double bond
A CB D
rotate single bond
A DB C
...rotate central C–C bond...
B
A C
D≠ A
B C
D
stereoisomerismor configurational isomerism
break double bond
reform double bond
A CB D
rotate single bond
A DB C
CO2Me
MeO2C
H
H
dimethyl fumaratetrans (E)mp 103°Cbp 193°C
H
MeO2C
H
CO2Me
dimethyl maleatecis (Z)
mp –19°Cbp 202°C
diastereoisomers
diastereoisomers are different compounds with different chemical
and physical properties
cyclic molecules& diastereoisomers
relative stereochemistry
Cl
Cl
cyclic molecules can exist as diastereoisomers depending on the relative orientation of
substituents...
change the relative stereochemistry to give new
diastereoisomers
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
trans-1,2-dichlorocylohexane
(anti)cis-1,2-
dichlorocylohexane(syn)
cis-1,2-dichlorocylohexane
(syn)trans-1,2-
dichlorocylohexane(anti)
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
trans-1,2-dichlorocylohexane
(anti)cis-1,2-
dichlorocylohexane(syn)
cis-1,2-dichlorocylohexane
(syn)trans-1,2-
dichlorocylohexane(anti)
here we have TWO diastereoisomers...either both the chlorines are on the same side
or they are on opposite sides
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
trans-1,2-dichlorocylohexane
(anti)cis-1,2-
dichlorocylohexane(syn)
cis-1,2-dichlorocylohexane
(syn)trans-1,2-
dichlorocylohexane(anti)
two questions arise from this slide...which conformation of each diastereoisomer is
preferred (easy)...and, why have I draw four molecules (hard)?
what will the favoured conformation be?
Cl1
Cl2
need to map skeletal representation onto 3D representation
axax
eqeq
axax
ax
ax
eqeq
eqeq
bold is updashed is down
axax
eqeq
axax
ax
ax
eqeq
eqeq
Cl1
Cl2
downdown
updown
upup
up
down
up
down
up
down
bold is updashed is down
axax
eqeq
axax
ax
ax
eqeq
eqeq
Cl1
Cl2
downdown
updown
upup
up
down
up
down
up
down
Please remember that up and down refers to which face of the molecule the substituent is whilst equatorial and axial
refer to their orientation
once the first substituent is in place the other’s position is fixed
Cl1
Cl2
ax
eqH
Cl1
down
upH
Cl1
once the first substituent is in place the other’s position is fixed
Cl1
Cl2
ax
eqH
Cl1
down
upH
Cl1
randomly place a substituent in an upwards position. In this case I’ve chosen axial but I could have had an equatorial
upward substituent...
Cl1
Cl2
H
Cl2H
Cl1
the second substituent must be in an upwards
position
the other conformation starts with Cl1 equatorial
Cl1
Cl2
ax
H
Cl1
eq
up
H
Cl1
down
the other conformation starts with Cl1 equatorial
Cl1
Cl2
ax
H
Cl1
eq
up
H
Cl1
down
if I had started with the first upward substituent equatorial we
would end up with the same answer
Cl1
Cl2
Cl2
H
Cl1
H
cis
axialalways
onesubstituent
Cl1
Cl2
H
Cl1
Cl2
H
Cl1
H
Cl2
H
cis
axialalways
onesubstituent
Cl1
Cl2
H
Cl1
Cl2
H
Cl1
H
Cl2
H
in this example...both conformations of the cis
diastereoisomer are identical...both have one axial & one equatorial
substituent
cis
axialalways
onesubstituent
Cl1
Cl2
H
Cl1
Cl2
H
Cl1
H
Cl2
H
BUT REMEMBER THIS IS ONLY TRUE FOR 1,2-DISUBSTITUTED
SYSTEMS!!!!
Cl1
Cl2
need to map skeletal representation onto 3D representation
axax
eqeq
axax
ax
ax
eqeq
eqeq
Cl1
Cl2
ax
eqH
Cl1
once the first substituent is in place the other’s position is fixed
down
upH
Cl1
Cl1
Cl2
Cl2
H H
Cl1
up
H
Cl1
down
ax
H
Cl1
eq
the other conformation starts with Cl1 equatorial
Cl1
Cl2
Cl1
Cl2
H
H
Cl1
Cl2
H
2Cl
H
1Cl
2Cl
H
H
1Cl
trans Cl
Cl
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?
H
2Cl
H
1Cl
2Cl
H
H
1Cl
trans
equatorialfavoured
XCl
Cl
HtBu
OH
HtBu
HH
HO
what happens if we have two different substituents (two different
groups on the ring)?
HtBu
OH
H
equatoriallargest group favours
tBu
HH
HO
this one favoured as big tert-butyl group is equatorial...minimises 1,3-
diaxial interactions
HtBu
Me
H
equatoriallargest group favours
tBu
H
H
Me
true for all substitution patterns (it doesn’t matter where you put the big group it will be equatorial
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
Ph can go in any down position:
Ph
axax
eqeq
axax
ax
ax
eqeq
eqeq
downdown
updown
upup
up
down
up
down
up
down
Ph can go in any down position:
Ph
Ph
H
down
updowndown
upPh
Hup
up
down
up
down
up
down
now methyl can only go in one place
Ph can go in any down position:
Ph
now methyl can only go in one place
Ph
H
H
second conformation has Ph in axial down position:
Ph
axax
eqeq
axax
ax
ax
eqeq
eqeq
downdown
updown
upup
up
down
up
down
up
down
Ph
now methyl can only go in one place
second conformation has Ph in axial down position:
downPh
Hdown
upup
up
down
up
down
up
down
Ph
H
up
down
Ph
now methyl can only go in one place
second conformation has Ph in axial down position:
Ph
HH
Ph
HHPh
H
H
favoured conformation has large group equatorial
decalinsH
H2 stereoisomers
fused ring system found in many natural products (such as steroids) can exist as two
diastereoisomers...
trans-decalinsH
H
H
Htrans-decalin equatorial, equatorial
ring fusion
they cannot undergo ring flip so they are stuck in
these conformations
H
H
H
H
cis-decalin equatorial, axial ring fusion
cis-decalins
the one you all hate...
diastereomers
stereoisomersstructural isomers
isomers
bond patterns a m e enantiomers
diastereomers
stereoisomersstructural isomers
isomers
bond patterns a m e enantiomers
a special kind of (pain) stereosiomer...a pair of
enantiomers are identical in always except...
...an object that is nonsuperposable on its mirror image...
chirality in nature
chirality in nature
chirality in nature
chirality in nature
our hands are mirror images...
chirality in nature
chirality in nature
they look identical (barring scars etc)
chirality in nature
but can never occupy the same space...they are
chiral
chirality in nature
photograph: Willi Rolfes
snail shells are either clockwise or
anti-clockwise...
chirality in nature
photograph: Willi Rolfes
...and clockwise snails will only mate with clockwise snails....
chiral objects
windmills and propellers are left or right handed as are...
chiral objects corkscrews
chiral moleculesmolecules can be left
or right handed
Mirror plane
Achiral compounds
if we take a molecule and its...
Mirror plane
Achiral compounds
...mirror image...and we then start to...
Mirror plane
rotate
Achiral compounds
...rotate that molecule
Mirror plane
Achiral compounds
Mirror plane
rotate
Achiral compounds
Mirror plane
Achiral compounds
...we can get to a point were the molecules are identical and can be...
Mirror plane
Achiral compounds
Mirror plane
Achiral compounds
superposed upon each other...then those
molecules are achiral
Chiral compoundsMirror plane
rotate
...it doesn’t matter how many times and
directions you rotate a chiral object...
Chiral compoundsMirror plane
it can never be superposed...
the two isomers are called enantiomers
such mirror images are called...
they are identical in all ways...
12 11 10 9 8 7 6 5 4 3 2 1 0
240 220 200 180 160 140 120 100 80 60 40 20 0CDCl3+DMSO-d6 QE-300
physical properties
(R)-(-)-mandelic acidmp 131-133°C
Ph CO2H
H OH
(S)-(+)-mandelic acidmp 130-132°C
Ph CO2H
HO H
NMR (see lecture 9) identical for both enantiomers as is the melting points and all standard chemical
reactions
excepttwo properties...
but they do differ under certain circumstances
(otherwise why would we care...)
(R)-(-)-mandelic acid[α]23 –153D
Ph CO2H
H OH
(S)-(+)-mandelic acid[α]23 +153D
Ph CO2H
HO H
α
light source
polariser plane polarised light
samplecell length l (dm)
readinglight (λ)
physical properties
(R)-(-)-mandelic acid[α]23 –153D
Ph CO2H
H OH
(S)-(+)-mandelic acid[α]23 +153D
Ph CO2H
HO H
α
light source
polariser plane polarised light
samplecell length l (dm)
readinglight (λ)
physical propertieseach enantiomer rotates plane
polarised light in a different direction and more importantly...
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 chiralso chiral molecules will interact with us in different ways...
CH3
(S)-limonenelemons
CH3
HCH3
HH3C
(R)-limoneneoranges
smell
taste
©Patrick J. Lynch 2006
(R)-carvonespearmint
(S)-carvonecaraway
CH3 CH3
HCH3
HH3C
O O
taste
©Patrick J. Lynch 2006
(R)-carvonespearmint
(S)-carvonecaraway
CH3 CH3
HCH3
HH3C
O O
...but these differences are trivial compared to...
chirality and drugs
Me2NMe
Ph O
EtO
darvonpainkiller
NMe2
Me
PhO
EtO
novradcough-suppressant
chirality and drugs
Me2NMe
Ph O
EtO
darvonpainkiller
NMe2
Me
PhO
EtO
novradcough-suppressant
both are commercially available and look what those comical chemists have done
with the names!
Me CO2H
NH2
D-alaninebacterial cell wall
Me CO2H
NH2
L-alaninemammalian amino acid
drugs that target bacterial alanine won’t hurt us (but cause bacteria to burst!)
NH
O O
HN
O
O
(R)-thalidomide(morning sickness)
NH
OO
HN
O
O
(S)-thalidomide(teratogenic)
chirality and drugs
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
NH2
21 = 2stereoisomers
a molecule with one carbon atom with four different
groups coming off it can exist as 2 enantiomers
H2N NH
CO2CH3
O
HO2C aspartame
22 = 4stereoisomers
a molecule with two carbon atoms each with four different groups coming off them can
exist as 4 stereoisomers
23 = 8stereoisomers
HOCHO
OH OH
OHif it has three atoms
(stereocentres) with 4 different groups then it can have 8
stereoisomers...
251 = 2.25 x 1015
stereoisomers
insulin (monomer)has 51 stereocentres so it can exist as a large number of stereoisomers
251 = 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?)
251 = 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...
>2342 = >8.96 x 10102
stereoisomers
DNA polymerase
342
this number is meaningless to me!
>2342 = >8.96 x 10102
stereoisomers
DNA polymerase
342
but it gets worse...consider
our genes...
46 46 chromosomes comprising of...
O N
HO
OH N
NNH
NH2
O
>3 billion base pairs
and each base pair is two molecules with three
stereocentres...so we have a possibility of...
29,000,000,000 = ∞ stereoisomers
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...
?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...
•the shape of molecules
•chirality
what have....we learnt?
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