Stereochemistry New L1-L3
Stereochemistry New L1-L3
Stereochemistry New L1-L3
Monday 7-30 AM
Wednesday 10-30 AM
Spring Semester
12-13 Lectures
Venue V1
Teacher:
Professor J K RAY
1780s
Organic compounds: obtained from living sources
Inorganic compounds: obtained from nonliving sources.
Friedrich Whler (1828)
Organic compounds were synthesized from inorganic sources!!
O
NH4NCO
ammonium
cyanate
H2N
NH2
Urea
origin of life
CH4, CO2, H2O, NH3, H2
electric discharges
(like lightning)
O
OH
HO
O
ASTAXANTHIN
protein chain
uncoils, liberating
astaxanthin
Cornflower
Poppy
O
O H
HO
alkalined
O
O
sugar
sugar
HO
O
O
acidic
O
sugar
sugar
N
H
H
N
Cl
OR
O
Cl
2,4-dichlorophenoxyacetic acid
O
Cl
Cl
Cl
OR
2,4,5-trichlorophenoxyacetic acid
Cl
Cl
Cl
Cl
Dioxin
(by product of Agent Orange)
Cocaine
From coca leaves was the first anaesthetic, and also blocks Na+ channels with
lower affinity and specificity than tetradotoxin.
Polio Virus
http://www.microbelibrary.org/microbelibrary/files/ccImages/Articleimages/simonson/Images/Streptococcus%20sobrinus%20fig1.jpg
Streptococcus
Bacterial Infections
Viral Infections
strep throat
the flu
gastroenteritis
colds
cholera
AIDS
tuberculosis
hepatitis
food poisoning
chicken pox
botulism
gastroenteritis
gangrene
measles
necrotizing fasciitis
mumps
boils, abscesses
E. Bola
pneumonia
pneumonia
acne
West Nile
meningitis
cervical cancer
ulcers
SOLUTION
Natural products
originally discovered as secretions of fungi or soil bacteria
Semi-synthetic products
natural products chemically modified in laboratory to improve
efficacy of natural product, reduce its side effects
Completely synthetic products
Antibiotics
first known use of antibiotics - ancient Chinese (2,500 years ago)
ancient Egyptians and Greeks used molds and plants to treat infections
Definition:
chemotherapeutic agent that inhibits or stop the growth of
micro-organisms (bacteria, fungi or protozoans)
small molecules with a molecular weight less than 2 kDa
first produced and isolated from living organisms:
- fungi Penicillium antibiotic penicillin
- bacteria Streptomyces antibiotic streptomycin
then obtained by chemical synthesis antibiotic sulfa drugs
Term "Antibiotic"
- first used for substances extracted from fungus or other microorganism
- now used also for synthetic and semi-synthetic drugs with antibacterial effects
Other informations animated:
http://www.hhmi.org/biointeractive/Antibiotics_Attack/frameset.html
Types of antibiotics
1) Based on their origin
natural (from bacteria, fungi)
Streptomyces (antibiotics: streptomycin, neomycin, vancomycin
erythromycin, rifamycin, chloramphenicol, monensin)
Pseudomonas (fosfomycin)
Bacillus sp. (mersacidin, bacitracin, polymyxin)
Penicillium (penicilin, griseofulvin)
semi-synthetic
synthetic (sulfonamids, trimethoprim, chinolons)
2) Based on their chemical composition
Penicillin
Cephalosporins
Tetracyclines
Macrolides
others
Penicillin
discovered from the fungus Penicillium notatum in 1928 by
Alexander Fleming
Alexander Fleming
6.8.1881 (Scotland) 11.3.1955 (England)
Fields: bacteriology, immunology
Nobel Prize in Physiology or Medicine in 1945
Accidental discovery
On 3 September 1928, Fleming returned to his laboratory having spent August on
vacation with his family. Before leaving he had put his cultures of staphylococci in a
corner of his laboratory. On returning, Fleming noticed that one culture was
contaminated with a fungus, and that the colonies of staphylococci that had
immediately surrounded it had been destroyed, whereas other colonies further away
were normal. Fleming identified the mould that had contaminated his culture plates as
being from the Penicillium genus, and named the substance it released penicillin on 7
March 1929.
Antibiotic resistance
Definition: ability of microorganism to resist the antibiotic effects
antibiotic resistance evolved via natural selection through
random mutation, or by applying stress on a population
once such a gene is generated, bacteria can transfer genetic
information by horizontal transfer (between individuals) of
plasmid by bacterial conjugation
if bacterium carries several resistance genes = multiresistant
Antibiotic
Discovered
Introduction
Resistance
into clinical use first identified
Penicillin
1928
1943
1946
Streptomycin
1943
1947
1959
Tetracycline
1948
1952
1953
Vancomycin
1956
1972
1988
Dangers of antibiotics
1) allergic reactions - most often with penicillin
2) destruction of helpful microbes
3) damage to organs and tissues
Penicillins: Mechanism of
Action
Penicillins inhibit the bacterial transpeptidase enzyme by
mimicking its natural substrate, the terminal D-alaD-ala
Transpeptidase attacks the -lactam ring of penicillin, forms a
covalent bond; enzyme is now out of business
Topics
Stereochemistry
Nucleophilic substitution at
saturated carbon and Elimination
reaction
Conformational Analysis
Pericyclic Reactions
Drawing Molecules
H
HH
HH
HH
HH
H3C
OH
HH
or
H H
HH
H H
linoleic acid
CH3CH2CH2CH2CH2CH=CHCH2CH=CHCH2CH2CH2CH2CH2CH2CH2CO2H
linoleic acid
or
H
HH
HH
H H
C C
H H H H
linoleic acid
H H
H
C
OH
linoleic acid
CO2H
Stereochemistry
Stereochemistry of Reactions
Stereoisomers
Yes
Yes
No
Not Isomers
Constitutional
No
O
OH
H3C
H
H
H
H
CH3
H
H
H
H
H3C
CH3
Configurational
Optical
No
H3CH2C
Diastereomer
Cl
H
CH3
H
H3C
H3C
H3C
CH2CH3
Yes
Cl
Br
H
H
Geometric
H3C
H3C
Br
Cl
H
Stereochemistry
Stereochemistry:
The study of the three-dimensional structure of
molecules
Stereoisomers:
same molecular formula, same bonding sequence,
different spatial orientation
Types of Stereoisomers
Two types of stereoisomers:
enantiomers
two compounds that are nonsuperimposable mirror
images of each other
diastereomers
Two stereoisomers that are not mirror images of
each other
Geometric isomers (cis-trans isomers) are one
type of diastereomer.
Stereochemistry
CH
3
H3C
H
CH2
Caraway seed
CH3
H
H2C
spearmint
CH3
Stereochemistry
The properties of many drugs depends on
HN
HN
their stereochemistry:
O
O
CH
CH3
NH3NH
O
NHCH3
Cl
Cl
Cl
O
CH3NH
Cl
(S)-ketamine
(R)-ketamine
anesthetic
hallucinogen
Stereochemistry
Chiral and Achiral Molecules:
Some molecules are like hands. Left and right hands are mirror images, but they
are not identical, or superimposable.
CHIRALITY is a property of an object which is nonsuperimposable with its mirror image. Most objects in the
environment are chiral. In chemistry this term applies to molecules,
specific conformations of molecules, as well as to macroscopic objects
such as crystals.
Chirality is removed if an object /molecule acquires a plane of
symmetry, or a center of symmetry.
Achiral
Many molecules and objects are achiral:
identical to its mirror image
not chiral
H
Cl Cl
Cl Cl
Stereochemistry
Identifying of Stereogenic Centers:
Stereogenic centers may also occur at carbon atoms that are part of a ring.
To find stereogenic centers on ring carbons, always draw the rings as flat
polygons, and look for tetrahedral carbons that are bonded to four different
groups.
43
Stereochemistry
Drawing Stereogenic Centers - the wedge diagram:
In 3-methylcyclohexene, the CH3 and H substituents that are above and below the
plane of the ring are drawn with wedges and dashes as usual.
44
HO2C
HO
H
CO2H
OH
H
H Br
CH2CH3
C
H3CH2C
CO2H
H
OH
HO
H
Br
O
C OHF
C H
CH3
H
H 3C
H
C
F
Cl
H
Chiral vs.BrAchiral
CH3following molecules as chiral
Example: Identify the
or achiral.
CH3 C CH2CH3
Cl
CH3CHCH2CH2CH3
CH3
Br
Br
Br
Cl
CH3
CH3CCH2CH3
Cl
Br
H
trans-1,3-dibromocyclohexane
ethylcyclohexane
CH2CH3
CH3CH2
Br
H
H
Br
H
C
Br
CH2CH3
Asymmetric Carbons
Example: Identify all asymmetric carbons
present in the following compounds.
H
Br
OH H
H
H3C
CH3
CH2CH3
H
H
Br
Br
Br
H CH
3
Cl
Cl
H3CH2C
H
CH3
Cl=D?
H
H3C
CH2CH3
CN
HO
CN
NC
HO
OH
R
R
H
R
H
A
CN
CN
H
B
CN
OH
HO
CN
R
H
A
H
B
(Mirror images)
Stereogenic centres
If a molecule contains one carbon atom carrying four different groups, generally do not possess
a plane of symmetry or inversion center and must therefore be chiral.
A carbon atom carrying four different groups is a stereogenic or chiral centre
Constitutional and Stereo Isomers
OH
R
R *
HO
OH
CN
CN
CN
H
HO
R
CN
H
Enontiomers
Constitutional Isomers
NC
R
CN
Trans-cis isomers
-bond should be broken
Stereo isomers
HO
R
CN
H
NC
R
H
OH
H
R
OH
CN
Racemic mixture
A racemic mixture is a mixture of two enantiomers
in equal proportion
MeMgCl
CHO
:
OH
50
OH
HO
50
HO
CHO
OH
OH
HO
50
H
O
50
Cahn-Ingold-Prelog rules :
HO
Absolute configuration :
The R & S notation
CH3
CH3
H
OH
CH2
CH2
CH3
CH3
Sequence rules:
1.
H (4)
CH2
CH3
(3)
CH3
(1) HO
(2)
CH3
H
CH2
CH3
OH 1
CH2CH3
2
H, H, H
H (4)
CH2
H, H
CH3
(Y) (C)
(Y) (C)
C
(Y) (C)
CH2CH3
CH CH2
(C) (C)
H, H, C
H, C, C
Vinyl>Ethyl
CH2CH2Br
C
CH3CH2
H4
CH(CH3)2
1
C Y C
(R) and (S) Nomenclature
C
C
H
OH
C Y
CH2OH
C
Y
O 2 H
Y C
1
C C OH
4 H CH2OH
3
Y
C
C O
Y
C Y2
O C H
Y
C4 H
C
OH
CH2OH
Y
C
Y
Y
C
C
Y
C
Y
Cl
Cl
Et
nPr
H
(R)-3-chlorohexane
nPr
Et
H
(S)-3-chlorrohexane
Me
H
OH
HO
Et
Et
(S)
(R)
Stereochemistry
Labeling Stereogenic Centers with R or S:
Since enantiomers are two different compounds, they need to be distinguished by
name. This is done by adding the prefix R or S to the IUPAC name of the
enantiomer.
Naming enantiomers with the prefixes R or S is called the Cahn-Ingold-Prelog
system.
To designate enantiomers as R or S, priorities must be assigned to each group
bonded to the stereogenic center, in order of decreasing atomic number. The
atom of highest atomic number gets the highest priority (1).
60
H3C
CO2H
CO2H
H
NH2
Natural alanine
(S)-alanine
H
H2N
CH3
Unnatural alanine
(R)-alanine
Stereochemistry
Labeling Stereogenic Centers with R or S:
If two isotopes are bonded to the stereogenic center, assign priorities in order of
decreasing mass number. Thus, in comparing the three isotopes of hydrogen, the
order of priorities is:
62
Stereochemistry
Labeling Stereogenic Centers with R or S:
63
In the case of large linear molecule the molecule backbone has to be laid on the
plane of the paper such that the substituents pointed towards and/or away from
the viewer
HOCH2CH(OH)CH(OH)CH(OH)CHO
RRR
Ribose, carbohydrate
C5(H2O)5
OH
OH
OH
HO
CHO
HO
OH
OH
OH
HO
OH
OH
OH
OH
OH
OH
OH
OH
CHO
HO
OH
CHO
OH
CHO
HO
OH
OH
CHO
HO
OH
HO
RSR RSS
SRS SRR
SSS
OH
CHO
RRS
SSR
CHO
HO
OH
OH
CHO
OH
OH
Stereochemistry
Stereogenic Centers
Many
biologically
active
molecules
contain
stereogenic
centers on
ring carbons.
Stereochemistry
Labeling Stereogenic Centers with R or S
If two isotopes are bonded to the stereogenic center,
assign priorities in order of decreasing mass number.
Thus, in comparing the three isotopes of hydrogen, the
order of priorities is:
Stereochemistry
Labeling Stereogenic Centers with R or S
H3 C
H
OCH2CH3
CH3
C H4
F 2NH2
Example priorities:
I > Br > Cl > S > F > O > N > 13C > 12C > 3H > 2H > 1H
Cl
HO
OH
Br
Cl
OH
NH2
HS
R = Me; CF3
CO2H
CHO
Z (zusammen, together)
H
1
H3C
Br 1
1
Cl
CH3
(Z)-2-butene
Or cis-2-butene
E (entgegen, opposite)
(E)-2-bromo-1-chloro-1-fluoroethene
Br
CH2CH3
CH3
H3C
CH3
Cl
(Z)-1-bromo-1-chloro-1-butene
Et
H3C
CH3
(Z,4S)-3,4-dimethyl-2-hexene
CH2CH2CH3
CH2CH2CH2CH3
(E)-3-methyl-4-propyl-3-octene
(2E),(4E)-2-chloro-2,4-hexadiene
I. Stereoisomers
H3C OH
Projections: 3D
H
H3C
Newman
CH3
H
Fischer
Br
HO
Br
H
H
HO
Br
CH3
CH3
CH3
(2R,3R)-3-bromo-2-butanol
72
I. Stereoisomers
H3C OH
Projections: 3D
H
H3C
Newman
CH3
H
Fischer
Br
HO
Br
H
H
HO
Br
CH3
CH3
CH3
(2R,3R)-3-bromo-2-butanol
Cl
Me
Me
Cl
N
Me
N
H3C
Me
Trgers base
Nitrogen at bridgehead position,
Pyramidal inversion prevented, chiral
C(CH3)3
CH3
P
H3 C
H2C=HCH2C
[]D = 16.80
S-enantiomer
CH3
C(CH3)3
CH3
Br
H3CH2CH2C
CH2CH3
H3CH2C
Br
CH2CH2CH3
a pair of enantiomers
O
O
P
H3CH2CO
16 O
O18
H
OCH3
H
H3CH2CO
P
OCH2CH3
a pair of enantiomers
a pair of enantiomers
H3C
Diastereomers
Diastereomers are stereoisomers that are not mirror images.
Two diastereomers are different compounds and have different
relative stereochemistry.
Diastereomers may be chiral (have no plane of symmetry):
Ar
CO2Me
Ar
CO2Me
O
Diastereomers may be
achiral
OH
OH
plane of symmetry
CH3
H3C
*
CH
*
CH
Cl
OH
3-Chloro-2-butanol
CH3
OH
HO
Cl
Cl
CH3
OH
HO
Cl
CH3
B
erythro enantiomers
CH3
CH3
H
Cl
CH3
CH3
threo enantiomers
diastereomers
A&C
A&D
B&C
B&D
Tartaric acid
stereoisomers ?
22 = 4
HOOC-CH(OH)-CH(OH)-COOH
OH
OH
HO2C
HO2C
OH
diastereomers
enantiomers
HO2C
S
CO2H
R
COOH
HO
HO
COOH
CO2H
CO2H
HO2C
OH
OH
OH
OH
OH
COOH
CO2H
CO2H
OH
HO2C
H
OH
COOH
pair of enantiomers
HO
OH
COOH
H
OH
OH
COOH
meso compound
H3C
Me
C
H
Me
C
Me
Me
achiral
O
H
N
H
N
PPh2
PPh2
N
H
N
H
O
nonsuperimposable enantiomers
Allenes:
compounds containing a C=C=C unit
central carbon is sp hybridized
linear
substitutedallenes
biphenyls
hasbeenresolved
halflifeforracemization
is78minat118oC
Conformational enantiomers:
Hexahelicene
Cl
Cl
Cl
Cl
Propellor
Cl
Cl
Cl
Cl
Cl
Rotation restricted
Cl
Cl Cl
Cl
Cl
Cl
perchlorotriphenylamine
Optical Activity
Polarimetry is a laboratory technique that
measures the interaction between a
compound and plane polarized light.
Since enantiomers interact with plane
polarized light differently, polarimetry can
be used to distinquish between
enantiomers.
Optical Activity
Regular (unpolarized) light vibrates in all
directions.
Plane-polarized light:
light composed of waves that vibrate in only a
single plane
obtained by passing unpolarized light through
a polarizing filter
Optical Activity
When plane polarized light passes
through a solution containing a single
chiral compound, the chiral compound
causes the plane of vibration to rotate.
Polarimeter
Optical Activity
Chiral compounds are optically active:
capable of rotating the plane of polarized light
H
CH2CH3
HO
(S)-2-butanol
+13.5o rotation
C
CH3CH2
H
OH
(R)-2-butanol
CH3
o
-13.5 rotation
Optical Activity
Compounds that rotate the plane of polarized light
to the right (clockwise) are called dextrorotatory.
d
(+)
IUPAC convention
IUPAC convention
Optical Activity
(observed )
[ ]
c l
where a = specific rotation
c = concentration in g/mL
l = path length in dm
a (observed) = rotation
observed for a specific
sample
Optical Activity
Example: A solution of 2.0 g of (+)-glyceraldehyde
in 10.0 mL of water was placed in a 100. mm
polarimeter tube. Using the sodium D line, a
rotation of 1.74o was observed at 25oC. Calculate
the specific rotation of (+)-glyceraldehyde.
(observed )
[ ]
c l
Optical Activity
Given: (obs) = 1.74o
1m
10 dm
l 100. mm
1.00 dm
1000 mm 1 m
2.0 g
c
0.20 g mL
10.0 ml
Find: []
1.74
o
[ ]
8.7
0.20 1.00
Optical Activity
H
HO
CH3
CH3
CH2CH3
CH3CH2
H
OH
+13.5o rotation
-13.5o rotation
(S)-(+)-2-butanol
CH3
(R)-(-)-2-butanol
R- (+)-limonene
smell of orange
S- (-)-limonene
smell of lemons
Jasmone
S
R
CO2Me
strong odour
(+)-Z-methyl epijasmonate
CO2Me
odourless
(-)-Z-methyl epijasmonate
Me
*
COOH
Ibuprofen
500 mg of one tablet contains only half of its as active drug
Me
Me
COOH
S is active
COOH
R is inactive
Stereochemistry
Physical Properties of Stereoisomers
Enantiomeric excess (optical purity) is a measurement of
how much one enantiomer is present in excess of the
racemic mixture. It is denoted by the symbol ee.
ee = % of one enantiomer - % of the other enantiomer.
Consider the following exampleIf a mixture contains
75% of one enantiomer and 25% of the other, the
enantiomeric excess is 75% - 25% = 50%. Thus, there is a
50% excess of one enantiomer over the racemic mixture.
The enantiomeric excess can also be calculated if the
specific rotation [] of a mixture and the specific rotation
[] of a pure enantiomer are known.
ee = ([] mixture/[] pure enantiomer) x 100.
Enantiomeric Excess
When a mixture of enantiomers is neither
enantiomerically pure (all one enantiomer) nor
racemic (equal amounts of two enantiomers), the
relative amounts of the enantiomers in the mixture
can be expressed as the enantiomeric excess (optical
purity).
e.e. = d - l x 100
d + l
(excess of one over the other) x100
=
(entire mixture)
Resolution of Enantiomers
Enantiomers have the same physical properties so they can not be separated directly.
A possible technique for separation is chemical modification into diastereomers, which
possess different physical properties. Once in hand, diastereomers can be separated
by physical means, such as boiling point or recrystallization and then converted back
into enantiomers.
Two key requirements:
1. The reaction must be reversible so that the enantiomers can be released.
2. The reagent that reacts with the enantiomers must be stereochemically pure.
Example: The resolution of (S) and (R)-2-butanol via esterification with
enantiomerically pure (R,R)-tartaric acid.
Key reaction: Esterification
O
R-C-O-H
acid
H-O-R'
alcohol
O
R-C-O-R'
ester
H2O