(24) session 24 stereochemistry

5/9/2012

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Session 24

Organic Chemistry, UNAM School of Medicine1

StereochemistryStereochemistryStereochemistryStereochemistry

Dr L.H.A. Prins (Ph.D.)

Dept. of Pharmacy

UNAM

Learning Outcomes

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� By the end of this session, the student should be able to:

�Define stereochemistry, isomers, chiral centre, chiral

molecule, stereoisomers, enantiomers, diastereomers &

optical activity

�Understand the classification of isomers

�Understand the difference between structural isomers &

stereoisomers

� Identify asymmetric/chiral/stereocentres in compounds

Organic Chemistry, UNAM School of Medicine

5/9/2012

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Learning Outcomes… cont’d

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�Assign R,S configuration to chiral molecules (Cahn-Ingold-

Prelog)

� Identify optically active & optically inactive molecules

�Calculate the specific rotation of a given compound

�Draw perspective formulas of compounds

�Understand what a racemic mixture is & what meso

compounds are

�Understand the role of stereochemistry in drug action

(receptor bonding)


Definitions??Definitions??Definitions??Definitions??

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� Stereochemistry = The field of chemistry that deals with the

structures of molecules in three-dimensions

- Isomers = Compounds that have the same molecular formula but

which are not identical (have different structures)

- Chiral = Object/molecule that has a nonsuperimposable mirror

image

- Achiral = Object/molecule that has a superimposable mirror image

- Stereoisomers = Isomers that have their atoms connected in the

same order but have different three-dimensional arrangements


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Definitions??Definitions??Definitions??Definitions??

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- Asymmetric/Chiral centre = An atom (usually C) that is bonded to

four different groups & is therefore chiral

- Enantiomers/Optical isomers = Stereoisomers of a chiral substance

that have a mirror-image relationship

- Diastereomers = Stereoisomers that are not mirror-images (not

enantiomers)

- Optically active = Compound that rotates the plane of polarised

light. Chiral compounds are optically active

- Optically inactive = Compound that does not rotate the plane of

polarised light. Achiral compounds are optically inactive


Classification of isomersClassification of isomersClassification of isomersClassification of isomers

6 Organic Chemistry, UNAM School of Medicine

Isomers

Structural isomers

Skeletal Positional Functional

Stereo-isomers

Configurational

Diastereomers

Geometric isomers Meso compounds

Enantiomers

Conformational

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Structural isomersStructural isomersStructural isomersStructural isomers

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1. Skeletal isomers: Structural isomers that differ in the branching

of the aliphatic carbon chain

• Examples:


butane

isobutane

(2-methylpropane)

CH H

H

C C HCH

H

H

HH

H

(butane & isobutane = C4H10)


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2. Positional isomers: Structural isomers that differ in the

position of a FG or other substituent

• Examples:


1-chloropropane 2-chloropropane

1,2-dihydroxybenzene/o-hydroxyphenol

1,3-dihydroxybenzene/m-hydroxyphenol

1,4-dihydroxybenzene/p-hydroxyphenol

(1-chloropropane & 2-chloropropane = C3H7Cl)

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3. Functional isomers: Structural isomers that have different FG’s

• Examples:


methyl ethanoate/methyl acetate

propanoic acid/propionic acid

ethanol methoxy methane/dimethyl ether

(methyl ethanoate & propanoic acid = C3H6O2)

(ethanol & methoxy methane= C2H6O)

StereoisomersStereoisomersStereoisomersStereoisomers

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1. Conformational (rotational) isomers: Stereoisomers that

are able to undergo mutual conversion through rotation about a

single bond

• Example: Rotation around C-C single bonds in open-chain molecules


ethane

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• Example: Restricted rotation around C-C single bonds in cyclic molecules



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2. Configurational (non-rotational) isomers: Stereoisomers

that can only undergo mutual conversion by breaking bonds &

forming new bonds

• Examples:


trans-but-2-enedioic acid/fumaric acid

cis-but-2-enedioic acid/maleic acid

(2S)-2-hydroxypropanoic acid/(S)-lactic acid

(2R)-2-hydroxypropanoic acid/(R)-lactic acid

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Stereoisomers: ChiralityStereoisomers: ChiralityStereoisomers: ChiralityStereoisomers: Chirality

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� Why can’t you put your right shoe on your left foot?

� Why can’t you put your right glove on your left hand?

� Hands, feet, gloves & shoes have right-handed & left-handed forms

� Object that has a right-handed & left-handed form = chiral

� Chiral object – nonsuperimposable mirror image (mirror image is not

the same as itself)

� Achiral object – superimposable mirror image (mirror image is the

same as itself)


Stereoisomers: ChiralityStereoisomers: ChiralityStereoisomers: ChiralityStereoisomers: Chirality

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� Chiral object (does not have a plane of symmetry)

(nonsuperimposable mirror image)

� Achiral object (has a plane of symmetry)

(superimposable mirror image)


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Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons,

chirality centres, chirality centres, chirality centres, chirality centres, stereocentresstereocentresstereocentresstereocentres

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� Like objects, molecules can be chiral too

� Feature that most often is the cause of chirality in a molecule –

asymmetric C

� Asymmetric C = C atom that is bonded to 4 different groups


Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons,

chirality centres, chirality centres, chirality centres, chirality centres, stereocentresstereocentresstereocentresstereocentres

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� NB!!! – Only sp3 hybridised C atoms can be asymmetric

– sp2 & sp hybridised C atoms can’t have 4 groups attached to

them

� Asymmetric C – also known as a chirality centre (chiral centre)

� Atoms other than C, like N & P, can also be chirality centres – when

bonded to 4 different atoms/groups

� Chirality centre belongs to broader group known as stereocentres

(explained later)


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Stereoisomers: EnantiomersStereoisomers: EnantiomersStereoisomers: EnantiomersStereoisomers: Enantiomers

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� Compound with 1 asymmetric C can exist as 2 different

stereoisomers

� The 2 isomers - are similar to a left & right hand

- are nonsuperimposable mirror images (they are

different molecules)

� Nonsuperimposable mirror-image molecules = enantiomers

� Example:


Stereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomers

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� 2 methods of drawing enantiomers:

1. Perspective formulas (p. 207, Bruice – Self study!!!)

2. Fischer projections

� Perspective formula – show 2 of the bonds to asymmetric C in plane

of paper, 1 bond as solid wedge protruding out of paper & 1 bond as

hatched wedge extending behind plane of paper

� Example:


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Stereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomers

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� Fischer projection – represents an asymmetric C as the point of

intersection of 2 perpendicular lines. Horizontal lines represent bonds

that project out of plane of paper & vertical lines represent bonds that

extend back behind plane of paper

� C chain is always drawn vertically with C-1 at top of the chain

� Example:


Stereoisomers: Stereoisomers: Stereoisomers: Stereoisomers: StereocentresStereocentresStereocentresStereocentres

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� Stereocentre = an atom at which the interchange of 2 groups

produces a stereoisomer

� ∴Asymmetric C’s (+ other atoms) & C’s where interchange of 2

groups converts cis isomer to trans isomer (or Z isomer to E isomer),

are stereocentres


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Stereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomers

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� System necessary for indicating the configuration (arrangement)

of atoms/groups about the asymmetric C

� R/S naming system used

� For a pair of enantiomers with 1 asymmetric C, one enantiomer

will have R configuration & the other will have S configuration

� R/S naming system was developed by Cahn, Ingold & Prelog



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� Determining compound configuration containing 1 asymmetric C

(Cahn-Ingold-Prelog system):

1. Rank atoms/groups bonded to asymmetric C in order of priority

� Atomic numbers of atoms attached directly to asymmetric C determine

the relative priorities (Revisit Session 16, slides 20-22!!)


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2. Orient molecule so that atom/group with lowest priority is

directed away from you. Draw an imaginary arrow from

atom/group with highest priority to atom/group with next higher

priority

� Arrow points clockwise = R configuration

� Arrow points counterclockwise = S configuration



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� Remembering R/S:


= R configuration

= S configuration

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� Determining R/S configuration without mentally rotating the

molecule:

1. Rank atoms/groups bonded to asymmetric C in order of priority

2. If atom/group with lowest priority is bonded by hatched wedge,

draw arrow from atom/group with highest priority to atom/group

with 2nd highest priority & determine R/SOrganic Chemistry, UNAM School of Medicine


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3. If atom/group with lowest priority (4) is NOT bonded by hatched

wedge, switch two groups so group 4 is bonded by hatched wedge.

Proceed as in step 2 (previous slide)

NB!!! – Correct answer is then the opposite of that found!

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4. In drawing the arrow from group 1 to 2, you can draw past the

group with lowest priority (4), but never past the group with next

lowest priority (3)

Determining R/S configuration of compounds drawn as Fischer

projections – Self study!!!

(Organic Chemistry, Paula Y. Bruice, 4th Ed, p. 190-191)


Enantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activity

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� Enantiomers have similar physical properties (boiling points,

melting points, solubilities, density)

� One of the properties enantiomers do not share is the way they

interact with polarised light

� What is polarised light??

� Normal light – electromagnetic waves oscillating in all directions

� Polarised light – electromagnetic waves oscillating only in a single

plane

– produced by passing normal light through a polariser

such as a polarised lens (like Polaroid® sunglasses)


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29 Organic Chemistry, UNAM School of Medicine


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� Polarised light passing through a solution of achiral molecules,

emerges from the solution with its plane of polarisation unchanged

� Achiral compound doesn’t rotate the plane of polarisation

� ∴Achiral compound = Optically inactive


____________

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� Polarised light passing through a solution of chiral molecules, emerges

from the solution with its plane of polarisation changed

� Chiral compound rotates the plane of polarisation

clockwise/counterclockwise

� ∴Chiral compound = Optically active


___________


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� If one enantiomer rotates polarisation plane clockwise, its mirror

image will rotate polarisation plane the same amount

counterclockwise

� Optically active compound that rotates plane of polarisation clockwise

– dextrorotatory, indicated by (+) or d

� Optically active compound that rotates plane of polarisation

counterclockwise – levorotatory, indicated by (-) or l

NB!!! – Don’t confuse R/S with (+)/(-)

– R enantiomer may be (+) or (-)

– S enantiomer may be (+) or (-)


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� Degree to which an optically active compound rotates the plane of

polarisation – measured with instrument called polarimeter

� Optically active molecules - characterised by their specific

rotation [α]



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� Specific rotation ( ) can be calculated from the observed rotation

(α) using the following formula:


[ ]lxc

=Τλ

ααT is the temp in °C

λλλλ is the wavelength in nm

αααα is the measured rotation in degrees

l is the path length in decimeters

c is the concentration in grams per mL

[ ] rotationspecificT=λα

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Enantiomers: Racemic mixtureEnantiomers: Racemic mixtureEnantiomers: Racemic mixtureEnantiomers: Racemic mixture

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� Mixture of equal amounts of 2 enantiomers – racemic mixture/racemate

� Example: Mixture of equal amounts of (R)-(−)-lactic acid & (S)-(+)-lactic acid

� Racemic mixtures – optically inactive, because for every molecule in a racemic mixture that rotates the plane of polarisation in one

direction there is a mirror-image molecule (enantiomer) that rotates the plane in the opposite direction

� Symbol (±) – used to specify a racemic mixture� Example: (±)-2-bromobutane = mixture of (+)-2-bromobutane &

equal amount of (–)-2-bromobutane


Stereoisomers: Stereoisomers: Stereoisomers: Stereoisomers: DiastereomersDiastereomersDiastereomersDiastereomers

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� Molecules with more than 1 chirality centre have mirror image

stereoisomers that are enantiomers

� In addition they can have stereoisomeric forms that are not mirror

images, called diastereomers

� A compound can have maximum 2n stereoisomers (provided it

doesn’t have any other stereocentres!)

� n = # of asymmetric C’s


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� Example:

� 1&2/3&4 = Nonsuperimposable mirror images

= Enantiomers

� 1&3/1&4/2&3/2&4 = Not identical & not mirror images

= DiastereomersOrganic Chemistry, UNAM School of Medicine


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� Diastereomers = Stereoisomers that are not enantiomers

(stereoisomers that are not mirror images)

� Enantiomers: - Identical physical properties (except for

interaction with polarised light)

- Identical chemical properties

� Diastereomers: - Different physical properties

- Different chemical properties


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DiastereomersDiastereomersDiastereomersDiastereomers: : : : MesoMesoMesoMeso compoundscompoundscompoundscompounds

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� Some compounds with 2 asymmetric C’s have only 3 stereoisomers

� Example:

� “Missing” isomer = mirror image of 1

(1 & its mirror image are the same molecule!)Organic Chemistry, UNAM School of Medicine

DiastereomersDiastereomersDiastereomersDiastereomers: : : : MesoMesoMesoMeso compoundscompoundscompoundscompounds

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� Stereoisomer 1 – Called a meso compound

� Even though a meso compound has asymmetric C’s, it is achiral

because it has a plane of symmetry

� Meso compound – Recognised by 2 attributes:

1. Has 2 or more asymmetric C’s

2. Has a plane of symmetry


Meso compound = An achiralcompound that has chirality centres

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RRRR////SSSS nomenclature for isomers with 2 or nomenclature for isomers with 2 or nomenclature for isomers with 2 or nomenclature for isomers with 2 or

more asymmetric C’more asymmetric C’more asymmetric C’more asymmetric C’ssss

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� Follow the same rules as those for compounds with one asymmetric

C (Slides 22-23 & 25-27)

� Apply these rules to each of the asymmetric C’s individually

� Example:

� Group priorities at C-2: OH = 1, C-3 = 2, CH3 = 3, H = 4


1

2 3

4



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� Because lowest priority group is bonded by

a hatched wedge – immediately assign configuration

� Group priorities at C-3: Br = 1, C-2 = 2, CH3 = 3, H = 4

� Because lowest priority group is NOT bonded by a hatched wedge –temporarily switch 2 groups

� The stereoisomer is named:

(2S,3R)-3-bromo-2-butanol


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� The 4 stereoisomers of 3-bromo-2-butanol are named as follows:

� NB!! – Enantiomers have opposite configurations at both asymmetric C’s

–Diastereomers have same configuration at one asymmetric C & opposite configuration at the other asymmetric C


DiastereomersDiastereomersDiastereomersDiastereomers: Geometric isomers: Geometric isomers: Geometric isomers: Geometric isomers

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� Geometric isomers/cis-trans isomers = diastereomers that

differ in their cis-trans arrangement on a ring or double bond

(Session 16, slides 13-23!!)

� Examples:


cis – Highest priority groups on same side of double bond/ringtrans – Highest priority groups on opposite sides of double bond/ring

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Biological activity: Biological activity: Biological activity: Biological activity: ConfigurationalConfigurationalConfigurationalConfigurational isomersisomersisomersisomers

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� Enantiomers

� Can have the same physiological activities, different degrees of the

same activity or very different activities� Example: Binding of enantiomers to receptors

- Receptor = protein than binds a particular molecule- Because a receptor is chiral it will bind one enantiomer better

than the other



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- Different physiological properties may be associated with each

enantiomer, for example S-thalidomide (highly teratogenic) & R-thalidomide (safe sedative)


S-thalidomide R-thalidomide

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� Diastereomers

�Diastereomers have different physical & chemical properties

� Their solubility in biological solvents differ, leading to a difference

in absorption & transport through the human body

� Their penetration of chiral biological membranes differ, leading to a

difference in distribution through the human body

�Diastereomer with highest solubility & biological membrane

penetration will therefore reach the target receptor the soonest,

resulting in a faster onset of action


Quiz: Stereochemistry

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1. w


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2. w



50

3. w


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4. w



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5. The observed rotation of 2.0 g of a compound in 50 mL of

solution in a polarimeter tube 50 cm long is + 13.4°. What is the specific rotation of the compound?

[ ]lxc

=Τλ

αα


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Thank you

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END


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�Quiz answers:

1. w

� Compounds b, d & e do not have asymmetric carbons.

*

* *


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�Quiz answers:

2. w

R

R

1

2

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1

2

34


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�Quiz answers:

3. w

� The 2 compounds in a are enantiomers of one another

� The 2 compounds in b are enantiomers of one another

S

1 2

3

4

1

2

34

R

1

2

3

4

SR

1

23

4


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�Quiz answers:

4. w

� Fischer projections: Clockwise specifies R if the lowest priority

substituent is on a vertical bond!

S

1

2

3

4

R

1

2

3

4


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�Quiz answers:

5. w

� αααα = + 13.4°� l = 50 cm = 5 dm

� c = 2 g/50 mL = 0.04 g/mL

� ∴ = (+ 13.4°)(5 dm) x (0.04 g/mL)

= 67

[ ]lxc

=Τλ

αα


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� Additional reading on Stereochemistry:

�Organic Chemistry, Paula Y. Bruice (4th Ed)

�Chapter 5

� Pages 182 - 215

�Organic Chemistry, John McMurry (7th Ed)

�Chapter 9

� Pages 289 - 331


(24) session 24 stereochemistry

Health & Medicine

Transcript of (24) session 24 stereochemistry