1
Chapter 5
Isomers
Constitutional Isomers
Stereoisomers
Cis/Trans
R/S
Enantiomers
Diastereomers
Chiral
Achiral
Stereocenter
Meso
Mirror image
Superimposable/Nonsuperimposable
Racemic/Racemate
Stereocenter
Plane of symmetry
Configuration
Enantioselective
Enzymes/Hydrolysis/Lipase
2
Stereochemistry
Chirality/Chiral/Enantiomers/Diastereomers/ Achiral
OH
Constitutional vs. Stereoisomers
OH
Constitutional isomers b/c OH is on different carbons in each molecule.
Different Connectivity.
1
OH 1
OH
R
S
2
3
2
3
Stereoisomers b/c all the connectivity is the same, it is just orientation that is
different. Specifically, these are enantiomers.
Biological chirality—limonene, carvone, thalomid
Stereogenic center vs chirality
History—van’t Hoff, Le Bel—the tetrahedral; Pasteur—Stereochemistry
Meso compounds—plane of symmetry
1 stereocenter can only be a pair of enantiomers
2 or more stereocenters is needed for diastereomers
2 stereoisomers that are mirror images of each other and nonsuperposable—enantiomers
2 molecules that are mirror images of each other and superposable—same molecule
2 stereoisomers that are not mirror images of each other—diastereomers
enantiomers
H
2
2
OH HO
Br
1 Br
3
same molecule
H
Br
1
mirror
1
Cl
mirror
S
S
OH
1
HO Cl
2
not mirror images, diastereomers
3
3
1
2
2
3
Br
Br
3
S
R
OH HO
3
2
Br
H
R
1
H
S
3
R/S nomenclature—Cahn, Ingold, Prelog
All 4 atoms attached to a stereocenter are assigned a priority from 1-4(a-d) based
on atomic number. The highest priority(largest atomic number) is assigned 1(a)
the lowest priority is assigned 4(d).
If 2 isotopes of the same element are attached the heavier isotope gets the
higher priority.
If 2 identical elements are on same stereocenter then you go to the next
carbon for each. You keep going out one carbon till you get to a
difference. Priority is then determined based on size of different groups.
Double bonds count twice. Triple bonds count three times.
Now rotate the lowest priority away from you. Follow 1 to 2 to 3(a to b to c). If
you go in a clockwise manner to go from 1 to 2 to 3(a to b to c), then the
enatiomer is R(rectus). If you go counterclockwise then the enantiomer is
S(sinister).
B
A
1Br
R
H
Br
3
2
3
Cl
1
OH
Br
H
S 1
2
3
1
H HO
1
R
Br
3
S
S
Br
1
1
R
d
Br
1
Cl
S
2
R
1
3
H Br H3CO Cl
OCH3
3
R
d
1
1
Br
Br
3
d
2
2
H OH
d
H OH
3
3
e
HO
2
3
R
O
HH
S
2
H 3CO Cl
e
H
R
3
1
3
2
2
OCH3 HO H
Br
HO
Br
S
Br
1 Br
2
2
F
E
D
3
2
OH
H
OH
3
C
2
Br
S
1
2
4
Label the stereocenters R or S in the following
HS Br
OH
H Br
Cl
CH3
Cl
Cl
Br
H
HO CCl 3
H
H
Br
F
H
H
HO
Cl
HO
CH3
Br
Br
OH
Br
H
H Br
F
H
OH
Cl
F
Br
Cl
Br
OH
OCH3
Et
H
HO
Cl
Br
OH
OH
5
KEY
3
3
OH
1
HS
Br
R
Cl
Br
H
2 Cl
2
CH3
3
HO
1
S
C Cl 3
2
1
R
2
1
3
Cl
S
CH3
R
Br
R
4
3H O
Br
1
1
H
R
1
4
H
Br
3
4
Br
1
OH
S
R
Br
3
Cl
2
2
R
3 R
2
HO
1 R
S
2
1
H
H
3
Br
1
3
S
2
H
F
S
3
1
H
3
2
1
3
2
S
OH
1
R 1
S
3
2
3
OH
S
1
Br
1
H
2
1
1
S
Br
S
3
HO
3
2
2
3
O CH 3
2
2
F
2
1
1
Et
1
OH
3
2
2
R
H
3
2
Cl
3
F
4
S
3
3
H
4
Cl
2
1 Cl
2
R
1
Br
3
2
OH
6
Properties of enantiomers
R/S have the same physical properties(bp/mp/solubility/IR/rate of reaction) because they
share the same environment. Most of the physical properties are based on
environment(intermolecular forces).
The have different properties with other chiral environments such as plane-polarized
light. Enantiomers rotate plane polarized light in the opposite direction but by the same
amount.
Single enantiomers are considered to be optically active. R/S mixtures are racemic.
Polarimeter—light is first passed through a polarizer which allows only one band of light
through. Then the light passes through the chiral environment of the enantiomer. Finally
the light lands on the detector. By where it lands on the 360
degree detector the amount of deflection is calculated.
If the light is rotated clockwise, the value will be (+). This is called Dextrorotatory
(dexter—right).
If the light is rotated counterclockwise, the value will be (-). This is called Levorotatory
(laevus—left).
The degree of rotation is given the term specific rotation, α.
[α]25 D
D refers to the light source. D = D line of Na(589.6 nm)
R/S has no relation to (+/-). R can be (+) in some molecules and (-) in others.
Racemic mixtures give 0o reading. The R and S forms cancel each other out.
Pure R will give one reading(+30 for ex.). Pure S will give opposite reading(-30).
Mixtures of R/S will give readings from +30 to –30 depending on concentrations of R
and S.
100% R give +30. 50% R/50% S gives 0. 100% S gives –30.
Racemic mixtures(50/50) can be referred to as R/S 2-butanol or (+/-) 2-butanol.
In most journals, scientific, medical and pharmaceutical, the %ee(enantiomeric excess) is a
vital statistic when referring to a reaction. You will see entries such as—“…The reaction was
carried out under typical conditions to give a 78 % yield an enantiomeric excess of 98%.”
7
% ee = [(moles of excess enantiomer – moles of other enantiomer)/total moles] x 100.
OR
%ee = (observed specific rotation/specific rotation of pure enantiomer) x 100
Enantiomeric excess—if ee = 50 % that means 50% is racemic and the other 50% is pure
enatiomer(50 + ½ of 50 = 75). Therefore 50 % ee means 75% of one enatiomer
and 25 % of the other enantiomer.
A. Given the ee
If a molecule is in the R form at 90%ee, what is the % of R and S? 90%ee means 90%
pure R and 10%(100-90) a mixture of R and S; therefore it is 95% R(90% + ½ of 10%)
and 5% S (½ of 10%)
82%ee S means 91% S(82 + ½ of 18) and 9% R(½ of 18).
71%ee R means 85.5% R(71 + ½ of 29) and 14.5 S(½ of 29)
B. Given the %
If a molecule is 20% R and 80% S, what is the ee?
ee = 80 – 20 = 60 % ee
If a molecule is 43% R and 57% S, what is the ee?
ee = 57 – 43 = 14 % ee
C. Given the optical rotation.
If the specific rotation of a molecule with R designation is + 45 and a mixture of R/S of
that molecule gives an observed rotation of + 25, what is the % R, % S and the ee?
ee = observed/specific x 100; ee = 25/45 x 100 = 56% ee; since it is 56% ee, that
means 56% R, and 44% R/S mixture; therefore, R = 78%(56 + ½ of 44) and S =
22%(½ of 44)
If the specific rotation of a molecule with R designation is + 45 and a mixture of R/S of
that molecule gives an observed rotation of - 25, what is the % R, % S and the ee?
ee = observed/specific x 100; ee = 25/45 x 100 = 56% ee; since it is 56% ee, that
means 56% S, and 44% R/S mixture; therefore, S = 78%(56 + ½ of 44) and R =
22%(½ of 44)
Since the observed rotation is the opposite sign of the specific rotation that means
that the major isomer is the opposite of the specific rotation isomer. IE since +45 =
R, then –25 is predominately S.
8
Most reactions yield a racemic form of the final product. If a reaction yields one enantiomer
in excess of the other the reactions is called enantioselective. These are highly desirable. In
biochemistry, you will study many enantioselective reactions driven by enzymes.
Chiral Drugs—many drugs are chiral. In their chirality it is often one of the 2 enantiomers
that does all the work, while the other is inert or even toxic.
Ibuprofen, Methyldopa, Penicillamine, FDA, pharmaceuticals, Glaxo Prilosec/Nexium
Diastereomers—chiral molecules with more than one stereocenter.
2N = number of stereoisomers possible(where N = # of stereocenters).
A molecule with 2 stereocenters(22 = 4) would have 4 possible stereoisomers(A, B, C
and D). A and B are enantiomers of each other. C and D are enantiomers of each
other(because they are mirror images). A and C, A and D, B and C, B and D are
diastereomers of each other because they are not mirror images.
Diastereomers have different physical properties from each other. I.E. A and B melt at
same temperature. C and D melt at same temperature. But the A/B temperature is
different from the C/D temperature.
Many times the true amount of stereoisomers is less than the maximum. This is due to
meso compounds(which are achiral).
Meso comopunds have a plane of symmetry which destroys chirality.
If A had a plane of symmetry it would be meso. Therefore B would be meso and
actually A and B would be the same thing. Therefore C and D would be enantiomers
of each other and they would both be diastereomers of A/B, where A/B is the same.
CH 3
CH 3
CH 3
H
OH H O
H
H
H
OH H O
H
HO
CH 3
A
CH 3
B
CH 3
OH
H
HO
H
H
OH
CH 3
CH 3
C
D
Fischer projections are often used to look for meso. Fischer’s are also often used in
carbohydrate che mistry. In Fischer projections the compound can be rotated in the
plane of the paper but it can NOT be flipped.
Nomenclature of diastereomers is the same as for enantiomers. Each stereocenter is
given a R/S designation.
9
Cyclic compounds
Cyclopentane(the 2 substituents must be the same)
1,2 disubstituted
Planes of symmetry
no plane of symmetry
cis is meso
H3C
trans is a pair of enantiomers
H3C
H3C
H3C
cis and trans are diastereomers
trans
cis
diastereomers
enantiomers
same
1,3 disubstituted
Planes of symmetry
no plane of symmetry
cis is meso
trans is a pair of enantiomers
cis and trans are diastereomers
trans
diastereomers
cis
enantiomers
same
If the substituents are different then 1,2 cis and 1,3 cis are pairs of enantiomers instead of the
same. 1,2 trans and 1,3 trans are still pairs of enantiomers and still diastereomers of the cis.
no plane of symm etry
Br
Cl
Br
no pla ne of symm etry
Cl
Br
diastereom ers
cis
e nantiomers
Cl
Cl
trans
e nantiomers
Br
10
Cyclohexane(the 2 substitue nts must be the same)
1,2 disubstituted
cis is a pair of rapidly intraconverting enantiomers(mimics meso)
they are considered conformational isomers
trans if a pair of enantiomers
cis and trans are diastereomers of each other
1,3 disubstituted
cis is meso
trans if a pair of enantiomers
cis and trans are diastereomers of each other
1,4 disubstituted
cis is meso
trans is meso
cis and trans are diastereomers of each other
cis
cis
cis
cis
cis
trans
all have planes of symmetry
If the substituents are different then 1,2 cis, 1,3 cis, 1,4 cis and 1,4 trans are pairs of
enantiomers instead of the same. 1,2 trans and 1,3 trans are still pairs of enantiomers and still
diastereomers of the cis.
11
Chemical Reactions
One of the goals of orga nic chemist is to create enantioselective reactions so that pure
chemicals can be obtained. One way to do this is to create a pure isomer and then
keep it unchanged.
Retention of Configuration—if a chemical reactions proceeds without breaking the
bonds of the stereocenter it is said to have retention of configuration
When a reaction proceed through retention of configuration, the R/S designation and
the optical rotation may stay the same or it may change.
Inversion of Configuration—if a reaction proceeds through the stereocenter it can
quite often invert the stereochemistry of the stereocenter.
Racemization—most often if a reaction proceeds through the stereocenter it will
racemize the mixture
Absolute/Relative Configurations
Absolute—the stereochemistry is known for all stereocenters.
Relative—the stereochemistry of all stereocenters is relative to the original
stereocenter which is unknown.
See the glyceraldehyde example
Resolution
Pasteur—by crystallization of diastereomers
1848—separation of (+/-) tartaric acid. Led to the field of stereochemistry.
Modern—by separation of diastereomers based on different physical properties which
could include mp, crystallization, solubility. Chromatography is most often
used(HPLC). Enzymes are very useful also.
Stereocenters other than carbon
4-bonded atoms such as Si, Ge, N and S can be stereocenters.
Chiral molecules that don’t have stereocenters
Allene b/c of out of plane double bonds has chirality(build a model).
12
A. Given the ee
If a molecule is in the R form at 90%ee, what is the % of R and S?
90%ee means 90% pure R and 10%(100-90) a mixture of R and S;
therefore it is 95% R(90% + ½ of 10%) and 5% S (½ of 10%)
Other examples:
82%ee S means 91% S(82 + ½ of 18) and 9% R(½ of 18).
71%ee R means 85.5% R(71 + ½ of 29) and 14.5 S(½ of 29)
B. Given the %
If a molecule is 20% R and 80% S, what is the ee?
ee = 80 – 20 = 60 % ee
If a molecule is 43% R and 57% S, what is the ee?
ee = 57 – 43 = 14 % ee
C. Given the optical rotation.
If the specific rotation of a molecule with R designation is + 45 and a mixture of R/S of that molecule gives
an observed rotation of + 25, what is the % R, % S and the ee?
ee = observed/specific x 100; ee = 25/45 x 100 = 56% ee;
since it is 56% ee, that means 56% R, and 44% R/S mixture;
therefore, R = 78%(56 + ½ of 44) and S = 22%(½ of 44)
If the specific rotation of a molecule with R designation is + 45 and a mixture of R/S of that molecule gives
an observed rotation of - 25, what is the % R, % S and the ee?
ee = observed/specific x 100; ee = 25/45 x 100 = 56% ee;
since it is 56% ee, that means 56% S, and 44% R/S mixture;
therefore, S = 78%(56 + ½ of 44) and R = 22%(½ of 44)
Since the observed rotation is the opposite sign of the specific rotation that means that the major
isomer is the opposite of the specific rotation isomer. IE since +45 = R, then –25 is predominately S.
13
1. What is the % R and S of the following?
88 %ee R
25 % ee S
42 % ee R
91 % ee R
68 % ee S
2. What is the % ee for the following?
90 % R 10 % S 40 % R 60 % S 70 % R 30 % S
85 % R 15 % S 74 % R 26 % S
3. If the observed rotation is +35 and the pure R rotates at +43, what is the % ee, % R and % S?
4. If the % ee = 50%R and pure S rotates at –20, what is the observed rotation?
5. (2S, 3R, 4R, 5S)-2,3,4,5-tetrachlorononane is made in the lab using stereospecific reactions. What is the
stereochemistry of the enantiomer of that molecule? What is the stereochemistry of one of the diastereomers?
How many possible stereoisomers are there for this molecule?
6. Four stereoisomers of dibromopentane are isolated. RR
RR has the same bp as
SS has the same solubility as
RS
SR
SS
RS has a different bp from
7. In the following pairs, label them as the same molecule, enantiomers or diastereomers.
a . _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _
H
Br
OH
Br
H 3C
Br
H
HO
CH
HO
H
b . _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ __
3
H
H
Cl
c . _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _
HO
Br
H 3C
Cl
H
Br
Br
H
d. _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _
H 3C H 2 C
C H3
H3C
C H2C H3
( 2 R , 3 R ) - 2 , 3 - d ic h lo r o p e n t a n e a n d
e . _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _
( 2 S , 3 R ) - 2 , 3 - d ic h l o r o p e n ta n e
HO
H
C H 2O H
C H2O H
H
HO
f. _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ __
14
1. What is the % R and S of the following?
88 %ee R—this means 88% R and 12%(R/S mix) therefore 88% R and (6% R/6%S) or 94% R and 6% S
25 % ee S—this means 25% S and 75%(R/S mix) therefore 25% S and (37.5% R/37.5%S) or 62.5% S and 37.5% R
42 % ee R—this means 42% R and 58%(R/S mix) therefore 42% R and (29% R/29%S) or 71% R and 29% S
91 % ee R—this means 91% R and 9%(R/S mix) therefore 91% R and (4.5% R/4.5%S) or 95.5% R and 4.5% S
68 % ee S—this means 68% S and 32%(R/S mix) therefore 68% S and (16% R/16%S) or 84% R and 16% S
2. What is the % ee for the following?
90 % R 10 % S—90-10 = 80% ee R
40 % R 60 % S—60-40 = 20% ee S
70 % R 3 % S—70-30 = 40% ee R
85 % R 15 % S—85-15 = 70% ee R
74 % R 26 % S—74-26 = 48% ee R
3. If the observed rotation is +35 and the pure R rotates at +43, what is the % ee, % R and % S?
% ee = obs/sp x 100 = 35/43 x 100 = 81% ee R
81 % ee R—this means 81% R and 19%(R/S mix) therefore 81% R and (9.5% R/9.5%S) or
90.5% R and 9.5% S
4. If the % ee = 50%R and pure S rotates at –20, what is the observed rotation?
Pure S = -20 then R = +20
% ee = obs/sp x 100; 50 = x/+20 x 100; 50 = 100x/20; (50)(20) = 100 x; 1000 = 100 x;
x = 10, therefore the observed rotation is +10
5. (2S, 3R, 4R, 5S)-2,3,4,5-tetrachlorononane is made in the lab using stereospecific reactions. What is the
stereochemistry of the enantiomer of that molecule? What is the stereochemistry of one of the diastereomers?
How many possible stereoisomers are there for this molecule?
Enantiomer
2R, 3S, 4S, 5R
Possible isomers 2N = 24 = 16
Diastereomer
2R, 3R, 4R, 5S
2S, 3S, 4R, 5S
2S, 3R, 4S, 5S
2S, 3R, 4R, 5R
2S, 3S, 4S, 5R
2R, 3R, 4S, 5R
2R, 3S, 4R, 5R
2R, 3S, 4S, 5S
2R, 3S, 4R, 5S
2R, 3R, 4S, 5S
2R, 3R, 4R, 5R
2S, 3R, 4S, 5R
2S, 3S, 4R, 5R
2S, 3S, 4S, 5S
15
6. Four stereoisomers of dibromopentane are isolated. Fill in the blanks using the 4 isomers below.
RR
RS
SR
RR has the same bp as
SS
SS has the same solubility as
RR
RS has a different bp from
SR
SS
7. In the following pairs, label them as the same molecule, enantiomers or diastereomers.
a. E NA NT IO M E RS
1,2 tra ns
1,2 trans
H
1
R
OH
Br
H 3C
3
2
Br
H
R
2
HO
1
3
2
1 Br
S
HO
H
3
H
S
1
2
3
b. SAM E
C H3
2
R
S
HO
2
1 Br
H 3C
Cl
1
1
Br
1
H
R
d. EN AN T IO M E RS
S
H 3 CH 2 C
C H3
2
H3 C
CH 2 CH 3
2
3
3
c. D IA ST E R EO M E RS
Br
3
H
H
3
Cl
(2R ,3R )-2,3- dichlor opentane a nd
e. DI AST ER E OM ER S
(2S,3R )- 2,3-dichloropentane
1
HO
3
S
H
C H 2 OH
H
2
C H 2 OH
3
HO
1
R
2
f. E NA NT IO M E RS
16
a. ___________________
b. ___________________
Cl
Br
c. ___________________
Cl
Br
Br
H3C
H
H3C
OH
OH
H
Br
d. ____________________
C2H5
C2H5
H
Br
e. ____________________
HO
Br
CH3
HO
H3C
H
f. ____________________
2R, 3R, 4S
2S, 3S, 4S
2R, 3R, 4S, 5R, 6S
2S, 3S, 4R, 5S, 6R
g. ____________________
17
a.
Diastereomers
b.
Same
c.
Enantiomers
Cl
Br
Cl
Br
Br
H3C
H
H3C
OH
C2H5
OH
H
Br
C2H5
1
H
Br
e. SAME
2
2
3
HO
Br
d. Diastereomers
CH3
1
HO
H3C
H
3
f. Diastereomers
2R, 3R, 4S
2S, 3S, 4S
2R, 3R, 4S, 5R, 6S
2S, 3S, 4R, 5S, 6R
g. Enantiomers
18
H
Br
Br
H
H
H
Br
Cl
H
Cl
Cl
I
Br
Cl
H
I
Cl
Cl
F
F
F
H
Br
H
Br
Br
H3C
Cl
I
F
Br
(2R, 3R, 4S, 5R)
(2S, 3S, 4R, 5S)
Cl
H
I
19
SAME
ENANTIOMERS
H
Br
Br
H
SAME
H
H
Br
Cl
H
Cl
Cl
I
Br
Br
H3C
Cl
H
DIASTEREOMERS
I
H
Br
H
DIFFERENT CMPDS
Cl
Cl
F
F
ENANTIOMERS
Br
F
Cl
I
F
Br
(2R, 3R, 4S, 5R)
(2S, 3S, 4R, 5S)
Cl
DIASTEREOMERS
H
I
ENANTIOMERS
20
OH
Br
H
OH
HO CH2 CH3
H 3C H
H3C OH
Br
OH
OH
E N AN T IO M ER S
D IA S T E R E O M E R S
Br
H
HO CH2CH3
H 3C H
H3C OH
DIASTEREOMERS
Br
SAME MOLECULE
SAME MOLECULE