Page 1
5/9/2012
1
Session 24
Organic Chemistry, UNAM School of Medicine1
StereochemistryStereochemistryStereochemistryStereochemistry
Dr L.H.A. Prins (Ph.D.)
Dept. of Pharmacy
UNAM
Learning Outcomes
2
� 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
Page 2
5/9/2012
2
Learning Outcomes… cont’d
3
�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)
Organic Chemistry, UNAM School of Medicine
Definitions??Definitions??Definitions??Definitions??
4
� 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
Organic Chemistry, UNAM School of Medicine
Page 3
5/9/2012
3
Definitions??Definitions??Definitions??Definitions??
5
- 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
Organic Chemistry, UNAM School of Medicine
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
Page 4
5/9/2012
4
Structural isomersStructural isomersStructural isomersStructural isomers
7
1. Skeletal isomers: Structural isomers that differ in the branching
of the aliphatic carbon chain
• Examples:
Organic Chemistry, UNAM School of Medicine
butane
isobutane
(2-methylpropane)
CH H
H
C C HCH
H
H
HH
H
(butane & isobutane = C4H10)
Structural isomersStructural isomersStructural isomersStructural isomers
8
2. Positional isomers: Structural isomers that differ in the
position of a FG or other substituent
• Examples:
Organic Chemistry, UNAM School of Medicine
1-chloropropane 2-chloropropane
1,2-dihydroxybenzene/o-hydroxyphenol
1,3-dihydroxybenzene/m-hydroxyphenol
1,4-dihydroxybenzene/p-hydroxyphenol
(1-chloropropane & 2-chloropropane = C3H7Cl)
Page 5
5/9/2012
5
Structural isomersStructural isomersStructural isomersStructural isomers
9
3. Functional isomers: Structural isomers that have different FG’s
• Examples:
Organic Chemistry, UNAM School of Medicine
methyl ethanoate/methyl acetate
propanoic acid/propionic acid
ethanol methoxy methane/dimethyl ether
(methyl ethanoate & propanoic acid = C3H6O2)
(ethanol & methoxy methane= C2H6O)
StereoisomersStereoisomersStereoisomersStereoisomers
10
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
Organic Chemistry, UNAM School of Medicine
ethane
Page 6
5/9/2012
6
StereoisomersStereoisomersStereoisomersStereoisomers
11
• Example: Restricted rotation around C-C single bonds in cyclic molecules
Organic Chemistry, UNAM School of Medicine
StereoisomersStereoisomersStereoisomersStereoisomers
12
2. Configurational (non-rotational) isomers: Stereoisomers
that can only undergo mutual conversion by breaking bonds &
forming new bonds
• Examples:
Organic Chemistry, UNAM School of Medicine
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
Page 7
5/9/2012
7
Stereoisomers: ChiralityStereoisomers: ChiralityStereoisomers: ChiralityStereoisomers: Chirality
13
� 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)
Organic Chemistry, UNAM School of Medicine
Stereoisomers: ChiralityStereoisomers: ChiralityStereoisomers: ChiralityStereoisomers: Chirality
14
� Chiral object (does not have a plane of symmetry)
(nonsuperimposable mirror image)
� Achiral object (has a plane of symmetry)
(superimposable mirror image)
Organic Chemistry, UNAM School of Medicine
Page 8
5/9/2012
8
Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons,
chirality centres, chirality centres, chirality centres, chirality centres, stereocentresstereocentresstereocentresstereocentres
15
� 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
Organic Chemistry, UNAM School of Medicine
Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons, Stereoisomers: Asymmetric carbons,
chirality centres, chirality centres, chirality centres, chirality centres, stereocentresstereocentresstereocentresstereocentres
16
� 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)
Organic Chemistry, UNAM School of Medicine
Page 9
5/9/2012
9
Stereoisomers: EnantiomersStereoisomers: EnantiomersStereoisomers: EnantiomersStereoisomers: Enantiomers
17
� 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:
Organic Chemistry, UNAM School of Medicine
Stereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomers
18
� 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:
Organic Chemistry, UNAM School of Medicine
Page 10
5/9/2012
10
Stereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomersStereoisomers: Drawing enantiomers
19
� 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:
Organic Chemistry, UNAM School of Medicine
Stereoisomers: Stereoisomers: Stereoisomers: Stereoisomers: StereocentresStereocentresStereocentresStereocentres
20
� 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
Organic Chemistry, UNAM School of Medicine
Page 11
5/9/2012
11
Stereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomers
21
� 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
Organic Chemistry, UNAM School of Medicine
Stereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomers
22
� 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!!)
Organic Chemistry, UNAM School of Medicine
Page 12
5/9/2012
12
Stereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomers
23
� Determining compound configuration containing 1 asymmetric C
(Cahn-Ingold-Prelog system):
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
Organic Chemistry, UNAM School of Medicine
Stereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomers
24
� Determining compound configuration containing 1 asymmetric C
(Cahn-Ingold-Prelog system):
� Remembering R/S:
Organic Chemistry, UNAM School of Medicine
= R configuration
= S configuration
Page 13
5/9/2012
13
Stereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomers
25
� 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
Stereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomers
26
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!
Page 14
5/9/2012
14
Stereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomersStereoisomers: Naming enantiomers
27
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)
Organic Chemistry, UNAM School of Medicine
Enantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activity
28
� 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)
Organic Chemistry, UNAM School of Medicine
Page 15
5/9/2012
15
Enantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activity
29 Organic Chemistry, UNAM School of Medicine
Enantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activity
30
� 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
Organic Chemistry, UNAM School of Medicine
____________
Page 16
5/9/2012
16
Enantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activity
31
� 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
Organic Chemistry, UNAM School of Medicine
___________
Enantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activity
32
� 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 (-)
Organic Chemistry, UNAM School of Medicine
Page 17
5/9/2012
17
Enantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activity
33
� 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]
Organic Chemistry, UNAM School of Medicine
Enantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activityEnantiomers: Optical activity
34
� Specific rotation ( ) can be calculated from the observed rotation
(α) using the following formula:
Organic Chemistry, UNAM School of Medicine
[ ]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
Page 18
5/9/2012
18
Enantiomers: Racemic mixtureEnantiomers: Racemic mixtureEnantiomers: Racemic mixtureEnantiomers: Racemic mixture
35
� 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
Organic Chemistry, UNAM School of Medicine
Stereoisomers: Stereoisomers: Stereoisomers: Stereoisomers: DiastereomersDiastereomersDiastereomersDiastereomers
36
� 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
Organic Chemistry, UNAM School of Medicine
Page 19
5/9/2012
19
Stereoisomers: Stereoisomers: Stereoisomers: Stereoisomers: DiastereomersDiastereomersDiastereomersDiastereomers
37
� 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
Stereoisomers: Stereoisomers: Stereoisomers: Stereoisomers: DiastereomersDiastereomersDiastereomersDiastereomers
38
� 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
Organic Chemistry, UNAM School of Medicine
Page 20
5/9/2012
20
DiastereomersDiastereomersDiastereomersDiastereomers: : : : MesoMesoMesoMeso compoundscompoundscompoundscompounds
39
� 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
40
� 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
Organic Chemistry, UNAM School of Medicine
Meso compound = An achiralcompound that has chirality centres
Page 21
5/9/2012
21
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
41
� 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
Organic Chemistry, UNAM School of Medicine
1
2 3
4
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
42
� 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
Organic Chemistry, UNAM School of Medicine
Page 22
5/9/2012
22
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
43
� 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
Organic Chemistry, UNAM School of Medicine
DiastereomersDiastereomersDiastereomersDiastereomers: Geometric isomers: Geometric isomers: Geometric isomers: Geometric isomers
44
� 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:
Organic Chemistry, UNAM School of Medicine
cis – Highest priority groups on same side of double bond/ringtrans – Highest priority groups on opposite sides of double bond/ring
Page 23
5/9/2012
23
Biological activity: Biological activity: Biological activity: Biological activity: ConfigurationalConfigurationalConfigurationalConfigurational isomersisomersisomersisomers
45
� 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
Organic Chemistry, UNAM School of Medicine
Biological activity: Biological activity: Biological activity: Biological activity: ConfigurationalConfigurationalConfigurationalConfigurational isomersisomersisomersisomers
46
- Different physiological properties may be associated with each
enantiomer, for example S-thalidomide (highly teratogenic) & R-thalidomide (safe sedative)
Organic Chemistry, UNAM School of Medicine
S-thalidomide R-thalidomide
Page 24
5/9/2012
24
Biological activity: Biological activity: Biological activity: Biological activity: ConfigurationalConfigurationalConfigurationalConfigurational isomersisomersisomersisomers
47
� 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
Organic Chemistry, UNAM School of Medicine
Quiz: Stereochemistry
48
1. w
Organic Chemistry, UNAM School of Medicine
Page 25
5/9/2012
25
Quiz: Stereochemistry
49
2. w
Organic Chemistry, UNAM School of Medicine
Quiz: Stereochemistry
50
3. w
Organic Chemistry, UNAM School of Medicine
Page 26
5/9/2012
26
Quiz: Stereochemistry
51
4. w
Organic Chemistry, UNAM School of Medicine
Quiz: Stereochemistry
52
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
Organic Chemistry, UNAM School of Medicine
Page 27
5/9/2012
27
Thank you
53
END
Organic Chemistry, UNAM School of Medicine
54
�Quiz answers:
1. w
� Compounds b, d & e do not have asymmetric carbons.
*
* *
Organic Chemistry, UNAM School of Medicine
Page 28
5/9/2012
28
55
�Quiz answers:
2. w
R
R
1
2
34
1
2
34
Organic Chemistry, UNAM School of Medicine
56
�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
Organic Chemistry, UNAM School of Medicine
Page 29
5/9/2012
29
57
�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
Organic Chemistry, UNAM School of Medicine
58
�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
Organic Chemistry, UNAM School of Medicine
Page 30
5/9/2012
30
59
� 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
Organic Chemistry, UNAM School of Medicine