Unit One Part 8: stereochemistrygjr-–-

• Describe the difference between stereoisomers & structural isomers• Nomenclature used for double bonds (cis-trans or E-Z)• Predict conformations of cyclohexanes• Define chirality and recognise stereocentres• Understand enantiomers and diastereoisomers

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dr gareth rowlands; g.j.rowlands@massey.ac.nz; science tower a4.12http://www.massey.ac.nz/~gjrowlan

Isomerismgjr-–-

OH

cyclopentanolC5H10O

OH

(E)-pent-3-en-1-olC5H10O

O4-methoxybut-1-ene

C5H10O

O

3-methylbutan-2-oneC5H10O

HO H

(S)-pent-1-en-3-olC5H10O

2

structural isomers

enantiomers

diastereomers

different bond pattern

samebond pattern

non-superimposable mirror images

stereoisomers

ISOMERS

Structural isomers

Configurational isomerism or stereoisomerism gjr-–-

• The spatial arrangement of atoms in a molecule is its configuration • Configurational isomers have the same bonds• Configurational isomers can only be interconverted by breaking a bond• Easiest compounds to see this in are the alkenes...

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H

R H

R

Z or cisE or trans

H

R R

Hless stable

steric crowding

B

A C

D≠ A

B C

D

Atom connectivity identicalBut different configurationsKnown as diastereoisomers

They are different compounds

CO2Me

MeO2C

H

H

dimethyl fumaratetrans (E)mp 103°Cbp 193°C

H

MeO2C

H

CO2Me

dimethyl maleatecis (Z)

mp –19°Cbp 202°C

E and Z nomenclaturegjr-–-

• E-alkenes have the highest priority groups on the opposite sides• Z-alkenes have the highest priority groups on the same side

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H2C

CH3 > >CH3O

CH3 OH

C N ≡ CN

NNC

C

atom = Br>Cl>O>N>C>HAtomic number = 35, 17, 8, 7, 6 & 1

Priority rules1. Rank atoms attached to alkene in order of decreasing atomic number

2. If atoms are the same, move along substituent until a difference is found

.3. Multiple bonds are assumed to count as the same number of single bonds

C CCl

H3C CH3

CH2CH3

C CC

Br CH2CH3

CH2OHN

C CH3C C6H5

CH3H3CO

C CHO2C

Ph CH2OH

CHO

(Z)-3-hydroxymethyl-4-oxo-2-phenylbut-2-enoic acid

(E)-2-bromo-3-(hydroxymethyl)pent-2-enenitrile

(E)-3-methyl-4-phenylpent-3-en-2-one

(Z)-2-chloro-3-methylpent-2-ene

1 1

1

1 1

1

1 1

2 2

2

2 2

2

2 2

Cis–trans isomerism in cyclohexanesgjr-–-

HtBu

Me

HtBu

H

H

Me

bulky group equatorial favoured

tert-butyl group rarely is axial

• If two groups on a ring we must specify relative stereochemistry • Cis - both groups are on the same face• Trans - groups are on opposite faces

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Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cltrans-1,2-

dichlorocylohexane(anti)

cis-1,2-dichlorocylohexane

(syn)cis-1,2-

dichlorocylohexane(syn)

trans-1,2-dichlorocylohexane

(anti)

H

2Cl

H

1Cl

2Cl

H

H

1Cl

one conformation is disfavoured as it has two axial groups so maximum 1,3-diaxial interactions

H

1Cl

2Cl

H

1Cl

H

2Cl

H

both conformations have one axial substituent & are identical

X

Decalinsgjr-–-

• Another example of stereoisomers comes from fused bicyclic molecules• Like a double bond the substituents could be cis or trans • Like a double bond these two are not interconvertible unless a bond broken

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H

H

H

Htrans-decalin equatorial, equatorial

ring fusion

H

H

H

H

cis-decalin equatorial, axial ring fusion

Chiralitygjr-–-

• The most confusing form of stereochemistry• A chiral structure is one that is non-superimposble on its mirror image• Occurs in nature (snails, honeysuckle etc), man-made objects (propellers,

corkscrews etc) and in molecules...

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Mirror image Left & right hands Non-superimposable

Enantiomers

Mirror plane

Chiral

gjr-–-

• This form of stereoisomerism arises from a lack of symmetry• The molecule & its mirror image are different• The molecule & its mirror image are known as enantiomers

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rotate

Mirror plane

Achiral

For those of a sick & twisted disposition more info on chirality & stereochemistry can be found at my website: http://www.massey.ac.nz/~gjrowlan/teaching.html

X

rotate

X

Enantiomers IIgjr-–-

• Most common form of chirality has a carbon atom with 4 different groups attached & is called central chirality

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NH

O O

HN

O

O

(R)-thalidomide(morning sickness)

Me2NMe

Ph O

EtO

darvonpainkiller

NHMeN

nicotinetoxin / stimulant

Me CO2H

NH2

L-alaninemammalian amino acid

• Many other forms of chirality including helical, axial & planar

PPh2PPh2

(R)-(+)-BINAP(R)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene

M-[8]helicene

FePh2PPh

(R)-2-phenyl-1-(diphenylphosphanyl)

ferrocene

Physical properties of enantiomersgjr-–-

• Enantiomers have identical physical properties such as mp, bp etc• They only differ in their interactions with other chiral entities

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α

light source

polariser plane polarised light

samplecell length l (dm)

readinglight (λ)

Ph CO2H

OHH

(R)-(-)-mandelic acid131-133°C[α]23 –153D

Ph CO2H

HHO

(S)-(+)-mandelic acid131-134°C[α]20 +154D

• Chiral compounds rotate the plane of polarised light (hence optical isomers)• As most biological systems are chiral, enantiomers can have different effects

O

H

(R)-carvonespearmint

O

H

(S)-carvonecaraway

H

(S)-limonenelemons

H

(R)-limoneneoranges

Two chiral centres (diastereoisomers)gjr-–-

enantiomerscis

epoxidemp = 98°C

• A molecule with 1 stereogenic centre exists as 2 enantiomers• Enantiomers have identical physical properties in an achiral environment

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NH2HN

N

O

OHNH2 NH

N

O

HOS R

Mirror

Two enantiomersdiffer by absolute configuration

O

CO2Me

O2N

O

CO2Me

O2N

enantiomerstrans

epoxidemp = 141°C

O

CO2Me

O2N

O

CO2Me

O2N

diastereoisomers

different mp

• A molecule with 2 stereogenic centres can exist as 4 stereoisomers• Enantiomers (mirror images) still have identical physical properties • Diastereoisomers (non-mirror images) have different properties

Chirality in our bodiesgjr-–-

• Common amino acids are all have the same stereochemistry (L or S)• Aspartame (sweetener) is a dipeptide (two amino acids) - two stereocentres• Potentially 4 compounds (n stereocentres can give 2n diastereoisomers)

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HO2C Me

NH2

HO2C

NH2

HO2C

NH2 N

HN

alanine phenylalanine histidine

H2N NH

CO2CH3

O

HO2C

• Insulin is made of 2 peptide chains - 1x30 amino acids & 1x21 amino acids• Potentially 2.25 x 1015 diastereoisomers• A relatively small protein is ribonuclease at 124 amino acids or• Potentially 2.13 x 1037 diastereoisomers

Chiral drugsgjr-–- 13

NH

HN

OH

Et OH

Et

Ethambutoltuberculostatic (anti-TB)

NH

HN

OH

EtOH

Et

(R,R)-enantiomercauses blindness

OHNH

Me Me

(–)-propanololβ-blocker for heart disease

(+)-propanololcontraceptive

OHHN

MeMe

NNS

N O NH

O

OH

(S)-timololhigh blood pressure

N NS

NONH

O

OH

(R)-timololglaucoma

Overviewgjr-–-

What have we learnt?• Molecules are three dimensional...and it makes a difference• The arrangement of atoms in space can form new isomers• Such isomers can only be interconverted by breaking bonds• Mirror images can have very different properties• Synthesis of single enantiomers is very important

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What's next?• A brief look at spectroscopy in many of its glorious forms• Starting with NMR or nuclear magnetic resonance spectroscopy• An idea of what information this tells us about protons in a molecule

dr gareth rowlands; g.j.rowlands@massey.ac.nz; science tower a4.12http://www.massey.ac.nz/~gjrowlan