Transcript Carey Chapter 7 Stereochemistry

Bioorganic Compounds
Bioorganic Compounds
•
•
•
•
•
Amino Acids – Proteins
Lipids
Carbohydrates
Nucleic Acids
Miscellaneous
• Alkaloids
• Vitamins
• Drugs
In most cases biological activity depends on
stereochemistry
Stereochemistry
Stereochemistry
• Deals with:
• Determination of the relative positions in space
of atoms, groups of atoms
• Effects of positions of atoms on the properties
• Sterical structure:
• Constitution
• Configuration
• Conformation
Isomers
constitutional
isomers
stereoisomers
Isomers
constitutional
isomers
enantiomers
stereoisomers
diastereomers
Chirality
A molecule is chiral if its two mirror image
forms are not superposable upon one another.
ASYMMETRIC!
A molecule is achiral if its two mirror image
forms are superposable. SYMMETRIC!
Bromochlorofluoromethane is chiral
Cl
Br
H
F
It cannot be
superposed point
for point on its
mirror image.
Bromochlorofluoromethane is chiral
Cl
Cl
Br
Br
H
F
H
F
To show
nonsuperposability, rotate
this model 180° around a
vertical axis.
Another look
Chlorodifluoromethane
is achiral
The two
structures are
mirror images,
but are not
enantiomers,
because they
can be
superposed on
each other.
The Chirality Center
The Chirality Center
a carbon atom with four
different groups attached to it
w
x
C
z
y
also called:
chiral center
asymmetric center
stereocenter
stereogenic center
Chirality and chirality centers
A molecule with a single chirality center
is chiral.
Bromochlorofluoromethane is an example.
H
Cl
C
Br
F
Chirality Centers
Other Than Carbon
Silicon
b
b
a
a
Si
c
d
d
Si
c
Silicon, like carbon, forms four bonds in its stable
compounds and many chiral silicon compounds
have been resolved
Nitrogen in amines
b
b
a
a
very fast
N
c
:
:
N
c
Pyramidal geometry at nitrogen can produce a
chiral structure, but enantiomers equilibrate too
rapidly to be resolved
Sulfur in sulfoxides
b
b
a
a
slow
+S
O_
:
:
S+
O_
Pyramidal geometry at sulfur can produce a chiral
structure; pyramidal inversion is slow and
compounds of the type shown have been resolved
A molecule with a single chirality center
must be chiral.
But, a molecule with two or more
chirality centers may be chiral
or it may not.
Chiral Allenes
Allenes of the type shown are chiral
X
A
C
C
C
Y
B
A  B; X  Y
Have a stereogenic axis
Stereogenic Axis
analogous to difference between:
a screw with a right-hand thread and one
with a left-hand thread
a right-handed helix and a left-handed helix
Absolute
and
Relative Configuration
Configuration
Relative configuration compares the
arrangement of atoms in space of one compound
with those of another.
Until the 1950s, all configurations were relative
Absolute configuration is the precise
arrangement of atoms in space.
We can now determine the absolute configuration
of almost any compound
Fisher Projections
Purpose of Fischer projections is to show
configuration at chirality center without necessity
of drawing wedges and dashes or using models.
Rules for Fischer projections
H
Cl
Br
F
Arrange the molecule so that horizontal bonds at
chirality center point toward you and vertical
bonds point away from you.
Rules for Fischer projections
H
Cl
Br
F
Projection of molecule on page is a cross. When
represented this way it is understood that
horizontal bonds project outward, vertical bonds
are back.
O
C
H
O
C
H
OH
C
HO
Absolute configuration:
H
H
C
1.) D/L system
2.) R/S system
CH2OH
CH2OH
D(+)-glyceraldehyde
C
H
(ox)
C
C
L (-)-glyceraldehyde
C
X
(red)
D-configuration
X
(ox)
C
C
D = dexter = right =
R = rectus
H
(red)
L-configuration
L = levus = left = S
= sinister
Configuration of Amino Acids
The Cahn-Ingold-Prelog
R-S
Notational System
The Cahn-Ingold-Prelog Rules
1. Rank the substituents at the stereogenic
center according to decreasing atomic number.
2. Orient the molecule so that lowest-ranked
substituent points away from you.
CIP Rules
(2) When two atoms are identical, compare the
atoms attached to them on the basis of their
atomic numbers. Precedence is established
at the first point of difference.
—CH2CH3 outranks —CH3
—C(C,H,H)
—C(H,H,H)
CIP Rules
(3) Work outward from the point of attachment,
comparing all the atoms attached to a
particular atom before proceeding further
along the chain.
—CH(CH3)2 outranks —CH2CH2OH
—C(C,C,H)
—C(C,H,H)
CIP Rules
(4) Evaluate substituents one by one.
Don't add atomic numbers within groups.
—CH2OH outranks —C(CH3)3
—C(O,H,H)
—C(C,C,C)
CIP Rules
(5) An atom that is multiply bonded to another
atom is considered to be replicated as a
substituent on that atom.
—CH=O outranks —CH2OH
—C(O,O,H)
—C(O,H,H)
(A table of commonly encountered substituents ranked according to
precedence is given on the inside back cover of the text.)
Example
1
1
17
1
35
4
2
9
2
Order of decreasing rank
4  of 3  2
9
anticlockwise
S
clockwise
R
H=1
35
1
3
3
4
17
F=9
Cl=17
Br=35
Application of C. I. P. rules for
Geometric Isomers
CH3
CH3
C
C
H
E/Z system
H
C
2
1
Br
Br
1
CH3 C
CH3
trans
1
Cl
C
H
cis
2
H
CH3 C
CH2 CH3
(Z)-1-Bromo-1-chloro-2-methyl-1-butene
Zusammen = together
2
C
Cl
2
CH3 C
1
CH2 CH3
(E)-1-Bromo-1-chloro-2-methyl-1-butene
Entgegen = opposit
CIP Rules
(1) Higher atomic number outranks lower
atomic number
Br > F
Cl > H
higher Br
C
lower
F
Cl
higher
H
lower
C
(Z )-1-Bromo-2-chloro-1-fluoroethene
The E-Z Notational System
E : higher ranked substituents on opposite sides
Z : higher ranked substituents on same side
higher
C
lower
lower
C
higher
Entgegen
higher
C
lower
higher
C
lower
Zusammen
Physical properties of enantiomers
Same:
melting point, boiling point, density, etc
Different:
properties that depend on shape of molecule
(biological-physiological properties) can be
different
Properties of Chiral Molecules:
Optical Activity
Optical Activity
A substance is optically active if it rotates
the plane of polarized light.
In order for a substance to exhibit optical
activity, it must be chiral and one enantiomer
must be present in excess of the other.
Light
has wave properties
periodic increase and decrease in amplitude of
wave
Light
optical activity is usually measured using light
having a wavelength of 589 nm
this is the wavelength of the yellow light from a
sodium lamp and is called the D line of sodium
Polarized light
ordinary
(nonpolarized)
light consists of
many beams
vibrating in
different planes
plane-polarized
light consists of
only those beams
that vibrate in the
same plane
Polarization of light
Nicol prism
Rotation of plane-polarized light

Specific rotation
observed rotation () depends on the number
of molecules encountered and is proportional to:
path length (l), and concentration (c)
therefore, define specific rotation [] as:
[] =
100 
cl
concentration = g/100 mL
length in decimeters
Racemic mixture
a mixture containing equal quantities
of enantiomers is called a racemic mixture
a racemic mixture is optically inactive
( = 0)
a sample that is optically inactive can be
either an achiral substance or a racemic
mixture
Optical purity
an optically pure substance consists exclusively
of a single enantiomer
enantiomeric excess =
% one enantiomer – % other enantiomer
% optical purity = enantiomeric excess
e.g. 75% (-) – 25% (+) = 50% opt. pure (-)
Resolution of Enantiomers
Separation of a racemic mixture into its two
enantiomeric forms
Resolution of a racemic modification
1. Physical methods:
- Spontaneous resolution
- Inclusion compounds
- Chromatography
2. Chemical methods:
- Diastereomeric salt formation
3. Biochemical methods:
- Enzymatic decomposition
Strategy
enantiomers
C(+)
C(-)
Strategy
enantiomers
C(+)
C(-)
2P(+)
C(+)P(+)
C(-)P(+)
diastereomers
Strategy
enantiomers
C(+)
C(-)
2P(+)
C(+)P(+)
C(-)P(+)
C(+)P(+)
C(-)P(+)
diastereomers
Strategy
enantiomers
C(+)
C(+)
P(+)
C(-)
2P(+)
C(+)P(+)
C(-)P(+)
C(+)P(+)
C(-)P(+)
diastereomers
P(+)
C(-)
Resolution of a Racemic Mixture
(S)-base
(R)-acid
(S)-acid
enantiomers
(R,S)-salt (S,S)-salt
diastereomers
(R,S)-salt (S,S)-salt
HCl
HCl
(S)-baseH+ (S)-baseH+
+
+
(S)-acid
(R)-acid
Lock and Key Model
CHO
CH2OH
H
H
C
OH
H
CHO OH
H
CHO
C
OH
CH2OH
CHO
OH
Discrimination of Enantiomers by
Biological Molecules
Chiral Molecules
with
Two Chirality Centers
How many stereoisomers when a particular
molecule contains two chiral centers?
2,3-Dihydroxybutanoic acid
O
3
2
CH3CHCHCOH
HO OH
4 Combinations = 4 Stereoisomers
Carbon-2 R
Carbon-3 R
R
S
S
R
S
S
CO2H
[] = -9.5°
CO2H
[] = +9.5°
R
S
HO
H
OH
H
OH
H
enantiomers
HO
R
H
S
CH3
CH3
diastereomers
CO2H
CO2H
S
R
HO
HO
H
OH
H
H
enantiomers
OH
H
R
S
CH3
[] = +17.8°
[] = -17.8°
CH3
Three stereoisomers of 2,3-butanediol
CH3
CH3
H
HO
OH
H
H
HO
CH3
OH
H
OH
H
H
OH
CH3
CH3
CH3
2R,3R
2S,3S
2R,3S
chiral
chiral
achiral
How many stereoisomers?
maximum number of stereoisomers = 2n
where n = number of structural units capable of
stereochemical variation
structural units include chirality centers and cis
and/or trans double bonds
number is reduced to less than 2n if meso forms
are possible
Cholic acid
HO H
CH3
H
H
CH2CH2COOH
H
H3C
HO
CH3
H
OH
11 chirality centers
211 = 2048 stereoisomers
one is "natural" cholic acid
a second is the enantiomer of
natural cholic acid
2046 are diastereomers of cholic
acid