Unit One Part 8:stereochemistry the lecture everyone (but me) hates...
‘...How would you like to live inLooking-glass House, Kitty? Iwonder if theyd give you milk inthere? Perhaps Looking-glassmilk isnt good to drink?Alices Adventures in Wonderland - Lew" Carroll
‘...How would you like to live inLooking-glass House, Kitty? Ithere? Perhaps Looking-glass glass its a good question...and itwonder if theyd give you milk inturnsmilk’ ‘looking- out would not be good for Kitty...but why?milk isnt good to drink?Alices Adventures in Wonderland - Lew" Carroll
Unit OnePart 8stereoisomersshape & chirality
isomers happy with isomers having the same atoms...structural isomers differentbond pattern
isomersstructural isomers ...and structural isomers have these atoms arranged differently (different bonding)... differentbond pattern
structural isomers OH all these have thesame formula but are obviously (!) very different cyclopentanol C5H10O OH O (E)-pent-3-en-1-ol 4-methoxybut-1-ene C5H10O C5H10O O HO H3-methylbutan-2-one (S)-pent-1-en-3-ol C5H10O C5H10O
isomers stereoisomers have the same atoms andstructural the same bonds...so same number of C– stereoisomers isomers C, C–H etc bonds diastereomers samebond 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 samebond pattern
stereoisomerismor 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
stereoisomerismor 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...
stereoisomerismor conﬁgurational isomerism A C A D B D ≠ B C breakdouble bond remember: we cannot rotate double bonds...so we must break the π A C bond, then... B D
stereoisomerismor conﬁgurational isomerism A C A D ...rotate central C–C B D ≠ B bond... C breakdouble bond A C A D B D B C rotate single bond
stereoisomerismor conﬁgurational isomerism A C A D B D ≠ B C break reformdouble 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 Clrelative stereochemistry
change the relativestereochemistry 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- TWO diastereoisomers... cis-1,2- here we have dichlorocylohexanedichlorocylohexaneare on the same side either both the chlorines (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 cis-1,2- trans-1,2- two questions arise from this slide...which conformation of each diastereoisomer is dichlorocylohexanedichlorocylohexane (easy)...and, why have I draw four preferred (anti) (syn) molecules (hard)?
Cl1 Cl2 ax ax up up eq up up ax eq eq down downeq eq up up eq ax down down ax ax down down bold is up dashed is down
Cl1 Cl2 ax ax up up eq up up ax eq eq down downeq 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
Cl1 Cl2 Cl 1 Cl1 H H eq up ax down once the ﬁrst substituent is inplace the other’s position is ﬁxed
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 inplace the other’s position is ﬁxed
Cl1 Cl2 Cl 1 H Cl 2 Hthe second substituentmust be in an upwards position
Cl1 Cl2 ax up Cl 1 Cl 1 eq down H Hthe other conformation starts with Cl1 equatorial
Cl1 Cl2 ax up Cl 1 Cl 1 eq down H H if I had started with the firstthe other conformation starts with upward substituent equatorial we would end up with the same Cl1 equatorial answer
Cl1 Cl2Cl2 Cl 1 H H
cis Cl1 Cl2 Cl1 Cl2 2 H Cl1 Cl H H H always axial one substituent
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
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
Cl1 Cl2 Cl 1 Cl 1 H H eq up ax down once the ﬁrst substituent is inplace the other’s position is ﬁxed
Cl1 Cl2 Cl1 H HCl2
Cl1 Cl2 ax up Cl 1 Cl 1 eq down H Hthe other conformation starts with Cl1 equatorial
Cl1 Cl2H Cl 1Cl2 H
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 BuOH what happens if we have twodifferent 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 equatoriallargest groupfavours
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 equatoriallargest groupfavours
Draw the twoconformations 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 Phdown position: ax ax up up ax eq up up eq eq down downeq eq up up eq ax down down ax ax down down
Ph can go in any Phdown position: up H H up up down Ph Phup up up down down down down downnow methyl can only go in one place
Ph can go in any Phdown position: H Ph Hnow methyl can only go in one place
second conformation Phhas Ph in axial downposition: ax ax up up ax eq up up eq eq down downeq eq up up eq ax down down ax ax down down
second conformation Phhas Ph in axial downposition: up up up up updown down down H up H down down Ph down Phnow methyl can only go in one place
second conformation Phhas Ph in axial downposition: H H Phnow methyl can only go in one place
H Ph H HH Phfavoured conformation has large group equatorial
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 H cis-decalin equatorial, axial ring fusion
isomersstructural stereoisomers isomers a special kind of (pain) stereosiomer...a pair of enantiomers are identical in always except... diastereomers enantiomers samebond pattern
...an object that isnonsuperposable onits mirror image...
chirality in naturechiralityin nature
chirality in naturechirality our hands are mirror images...in nature
chirality they look identicalin nature (barring scars etc)
chirality but can never occupy the same space...they arein 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 orright handed as are...
molecules can be left or right handedchiral 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 enantiomerssuch 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 chemicalE-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...)excepttwo properties...
physical properties α light light (λ) polariser plane sample readingsource 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
physical properties α each enantiomer rotates plane polarised light in a different direction and more importantly... light light (λ) polariser plane sample readingsource 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
other chiral objects
other chiral objects ...how they interact with other chiralobjects is very different (imagine trying toput 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
chirality and drugs Me MeMe2N NMe2 Ph O O Ph O O Et Et darvon novrad painkiller cough-suppressant
chirality and drugs Me MeMe2N 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-alaninemammalian 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 onlyproduce 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 21=2stereoisomers
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 stereoisomersstereoisomers
if it has three atoms (stereocentres) with 4 different OH groups then it can have 8 stereoisomers... CHO HO OH OH 23=8stereoisomers
insulin (monomer) has 51 stereocentres so it can exist as a large number of stereoisomers 251 = 2.25 x 1015stereoisomers
insulin (monomer) we have seen the problems with just a 50:50 choice (does it smell of lemons or oranges?) 251 = 2.25 x 1015stereoisomers
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 1015stereoisomers
DNA polymerase this number is meaningless to me! 342>2342 = >8.96 x 10102stereoisomers
DNA polymerase 342 but it gets worse...consider our genes...>2342 = >8.96 x 10102stereoisomers
46 46 chromosomes comprising of...
and each base pair istwo 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 questionentirely...one which I will not comment on in order to avoid offending the religious amongst you...