Lecture8: 123.101

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


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


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


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


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


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


(anti)cis-1,2-



(syn)trans-1,2-


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


(anti)cis-1,2-



(syn)trans-1,2-


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


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


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


down

upH

Cl1

Cl1

Cl2

Cl2

H H

Cl1

up

H

Cl1

down

ax

H

Cl1

eq


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

Ph

H

down

updowndown

upPh

Hup

up

down

up

down

up

down

now methyl can only go in one place


Ph


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



downPh

Hdown

upup

up

down

up

down

up

down

Ph

H

up

down

Ph



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


isomers

bond patterns a m e enantiomers

diastereomers


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

...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...

Lecture8: 123.101

Education

Transcript of Lecture8: 123.101