stereochemistry arrangements of atoms in 3-d space
TRANSCRIPT
Stereochemistry
Arrangements of Atoms in 3-d Space
Stereochemistry
• Stereochemistry:The study of the three-dimensional structures of
molecules, particularly stereoisomers
• Structural isomers:Have the same molecular formula, same types of
bonds, but different bonding sequences, “connectivity”
• Stereoisomers:Have the same molecular formula, same bonding
sequences, but different spatial arrangements & relative orientations
Stereochemistry
CHIRALITY: If an object’s mirror image (i.e. a molecule’s 3-d reflected shape) … “cannot be brought to coincide with itself” (i.e. It is non-superimposable), it is chiral.
• To maintain orbital overlap in the pi bond, C=C double bonds cannot freely rotate.
• Although the two molecules below have the same connectivity, they are NOT identical.
Stereochemical cis-transIsomers
Naming Alkene Stereoisomers : the E-Z Notational System
vs. “cis-trans”
Triglycerides & Unsaturated Fatty AcidsSaturated & Unsaturated: cis- vs. trans-
Stereochemical Notation
cis and trans are useful when substituents are identical or analogous
Oleic acid, an unsaturated fatty acid, has a cis double bond; (Hs are identical.)
cis and trans references are ambiguous when analogies are not obvious
C C
CH3(CH2)6CH2 CH2(CH2)6CO2H
H H
Oleic acid
Example
A systematic body of rules for ranking substituents must be used, which is related to, but different from the cis and trans references.
C C
H F
Cl Br
When there are four different substituents, cis and trans does not work.
C C
E : higher ranked substituents on opposite sides
Z :higher ranked substituents on same side higher
lower
The E-Z Notational System
Consider each sp2 carbon of the double bond
separately.
Rank the pair of substituents relative to
each other.
C C
E : higher ranked substituents on opposite sides
Z : higher ranked substituents on same side
higher
lower
The E-Z Notational System
Consider each sp2 carbon of the double bond
separately.
Rank the pair of substituents relative to
each other.
C C
E : higher ranked substituents on opposite sides
Z : higher ranked substituents on same side
(E) Entgegen
higher
higherlower
lower
C C
(Z) Zusammen
lower
higher
lower
higher
The E-Z Notational SystemCompare the pairs
C CC C
The substituents are ranked in order of
decreasing atomic number on each carbon.
(E) Entgegen (Z) Zusammen
higher
higherlower
lower
lower
higher
lower
higher
The E-Z Notational SystemRanking
The Cahn-Ingold-Prelog (CIP) System
The system used was devised byR. S. CahnSir Christopher IngoldVladimir Prelog
Their rules for ranking groups were devised for another kind of stereochemistry, chirality, but have been adapted to alkene stereochemistry.
Higher atomic number outranks lower atomic number
Br > F Cl > H
higher
lower
Br
F
Cl
H
higher
lower
C C
Example
Higher atomic number outranks lower atomic number
Br > F Cl > H
higher
lower
Br
F
Cl
H
higher
lower
C C
Example
(Z )-1-Bromo-2-chloro-1-fluoroethene
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)
CIP Rules
—C(H,H,H)
higher lower
Work outward from the point of attachment,
comparing all the atoms attached to a particular atom before proceeding furtheralong the chain.
—CH(CH3)2 outranks —CH2CH2CH3
—C(C,C,H) —C(C,H,H)
CIP Rules
higher lower
CIP Rules
higher
lower—CH(CH3)2 outranks —CH2CH2CH3
—C(C,C,H) —C(C,H,H)
higher lower
CIP Rules
higher
lower—CH2CH(CH3)2 outranks —CH2CH2CH(CH3)2
higher
lower
lowerhigher
(Z)- configuration
Evaluate substituents one by one. The ranking is not cumulative:Do not add atomic numbers within groups.
—CH2OH outranks —C(CH3)3
—C(O,H,H) —C(C,C,C)
CIP Rules
higher lower
An atom that has double or triple bonds to another atom is considered to be replicated as a substituent on that atom. See oxygen:
—CH=O outranks —CH2OH
—C(O,O,H) —C(O,H,H)
CIP Rules
lowerhigher
The molecules above are (E) configurations.
True (A) False (B)
Question
The molecules above are (Z) configurations.
True (A) False (B)
Question
Disubstituted Cyclohexanescis-trans Isomerism
In cyclic structures (rings) cis and trans notation is used to distinguish between stereoisomers just as in C=C double bonds, Cis— identical groups are positioned on the SAME side
of a ring -drawn as being planar. Trans— identical groups are positioned on OPPOSITE
sides of a ring -drawn as being planar.
Cyclic Stereoisomers
Cycloalkane Stereochemistrycis -trans Isomers
Cyclohexane StereochemistryDrawings: cis isomers & the need for perspective
Are the methyl groups axial or equatorial?What is the actual conformational shape of the cyclohexane ring?
H
CH3H
CH3 cis-1,4-dimethylcyclohexane
H
H3C
CH3
Hring-flip
Chair Conformers cis-1,4-dimethylcyclohexane
Cyclohexane StereochemistryTrans isomers
H
CH3H3C
Htrans-1,4-dimethylcyclohexane
CH3
H
CH3
Hring-flip
Chair Conformers trans-1,4-dimethylcyclohexane
Stereochemistrycis-1,2-disubstituted-cyclohexane
axial
equatorial
Stereochemistrytrans-1-tert-Butyl-3-Methylcyclohexane
Cyclohexane StereochemistryCis -Trans Isomers
Position cis trans
1,2 e,a or a,e e,e or a,a
1,3
1,4
a = axial; e = equatorial
e,a or a,e e,e or a,a
e,e or a,a a,e or e,a
Indicate the relationship of the pair of molecules shown.
A. same molecules B. mirror images C. different molecules D. constitutional isomers E. cis and trans isomers
Question
Consider the molecule below. What is the maximum number of methyl groups that can be in the equatorial position at the same time?
A. 0B. 1C. 2D. 3E. 4
Question
Conformations of Fused Rings
Stability of Fused Rings
Trans-fused cyclohexane rings are more stable than cis-fused
Conformations of Fused Rings
Worksheet 7 (Part 2): Ambrox
• There are many important structures that result when one ring is fused to another.
.
• Camphor, which you smelled the first day of class, and camphene are fragrant natural products isolated from evergreens.
Many Bicyclic Systems
Representing compounds with two fused rings.
To name a bicyclic compound, include the prefix “bicyclo” in front of the total carbon alkane name. For example, the compounds below could both be
named, bicycloheptane.
Bicyclic CompoundsNomenclature
The two molecules are not identical, therefore they cannot have the same name.
Count the number of carbons connecting the bridgeheads.
Bicyclic CompoundsNomenclature
1. Start numbering at a bridgehead carbon and number the longest carbon chain connecters first.
2. Then give the substituents the lowest numbers possible.
• Practice with SKILLBUILDER 4.5.
Bicyclic CompoundsNomenclature
Bicyclic CompoundsNomenclature
Decalin = Bicyclo[4.4.0]decane
Structure of Steroids
• Fundamental framework of steroids is a tetracyclic carbon framework.
A B
C D
Decalin-like
Steroids
Structure of Cholesterol
HO
CH3
H
H
H
CH3
CH3 CH3
CH3
Cholesterol is an important steroid endogenously produced in all plants and
animals.
Cholesterol
• Cholesterol is essential to life. It is the biosynthetic precursor of a large number of important molecules: Sex hormones, Vitamin D, Bile acids, Corticosteroids
HO
CH3
H
H
H
CH3
CH3 CH3
CH3
• There are many biologically important steroids, two related to primary sex traits are:
Hormonal Steroids
Vitamin D3
HO
H
CH3
CH3 CH3
CH3
• Insufficient sunlight can lead to a deficiency of vitamin D3, interfering with Ca2+ transport and bone development. Rickets may result; as well as very bad moods.
Cholesterol: Biochemical Reactions
HO
CH3
H
H
H
CH3
CH3 CH3
CH3
+ H2
H2
H2
H
H
Cholic Acid
Cholic Acid
HO
CH3
H
H
H
CH3
CH3
HOH
HO
O
OH
• Oxidation in the liver degrades cholesterol to produce Cholic acid which is the most abundant of the bile acids.
• Is the A/B ring system cis or trans?
• What functions are present?
|H
Cortisone
•Corticosteroids are involved in maintaining electrolyte levels, in the metabolism of carbohydrates, and in mediating allergic reactions by suppressing the immune system.
O
CH3
H
H
H
CH3OH
O
O
OH
• What principal functions are present?
Progesterone
• Supresses ovulation during pregnancy.
O
H
H
H
H3C
H3CO• What
principal functions are present?
Conformations of Multi-fused Rings
• Trans-fused cyclohexane ring is more stable than cis-fused cyclohexane ring. DIAMOND:
Molecular Chirality: Enantiomers
Chirality
Chirality
“I call any geometrical figure, or group of points, chiral, andsay that it has chirality, if its image in a plane mirror … cannot be brought to coincide with itself. Two equal and similar righthands are homochirally similar.”
Sir William Thomson (Lord Kelvin)The Baltimore Lectures, 1904
A molecule is chiral if its two mirror image forms are not superimposable upon one another.
A molecule is achiral if its two mirror image forms are superimposable.
Chirality
Tetrahedral Atoms
Achiral:
Chirality in Three Dimensions
BrCl
H
F
Bromochlorofluoromethane is chiral
It cannot be superimposed point for point on its mirror image.
BrCl
H
F
Bromochlorofluoromethane is chiral
H
ClBr
FTo show nonimsuperposability, rotate this model 180° around a vertical axis.
Chirality & nonsuperimposable mirror images
Enantiomers
Isomers
stereoisomersconstitutionalisomers
Isomers
stereoisomersconstitutionalisomers
diastereomersenantiomers
Stereochemistry
• Two types of stereoisomers:enantiomers
• pairs of compounds that are nonsuperimposable mirror images of each other
diastereomers• stereoisomers that are not mirror images of each
other– Eg. geometric isomers (cis-trans, E-Z isomers)
Stereochemistry
• Many molecules and objects are achiral:– identical to its mirror image– not chiral
Stereochemistry
• Cis-1,2-dichlorocyclopentane is achiral even though it contains 2 chiral carbon atoms:– It contains an internal mirror plane of symmetry
• Any molecule that has an internal mirror plane of symmetry is achiral even if it contains chiral carbon atoms.
Both cis- and trans-1,2-dimethylcyclohexane are chiral.
True (A) False (B)
Question
Question How many of the following compounds contain an internal mirror plane of symmetry?
A) 1 B) 2 C) 3 D) 4
QuestionWhich of the following molecules is chiral?
A B
C D
a carbon atom with fourdifferent groups attached to it
also called:chiral center; chiral carbonasymmetric centerasymmetric carbonstereocenterstereogenic center
The chiral carbon atom
w
x y
z
C
• There are 8 chiral carbon atoms in chlolesterol, which can have a total of 28 stereoisomers.
• SEE: SKILLBUILDER 5.7.
Stereoisomers
• Molecules with an even number of chiral centers that have a plane of symmetry are achiral and called MESO compounds.
• Another way to test if a compound is a MESO compound is to see if it is identical to its mirror image. If identical, it is NOT chiral. It is achiral.
• Meso compounds have less than the predicted number of stereoisomers based on the 2n formula.
• SEE: SKILLBUILDER 5.8.
Symmetry and Chirality
Enantiomers
Stereochemistry• Enantiomers are different stereochemical
compounds:They have the same boiling point, melting
point, density. Their physical/chemical properties are identical.
They differ in rotation of plane polarized light, doing so in equal but opposite directions. (polarimetry)
They behave differently with other chiral molecules • Enzymes• Receptors: eg. taste and scent
Importance of Stereochemistry
• Enzymes are capable of distinguishing between stereoisomers:
Red Wine / StereochemistryAbsolute Configuration
In 1847, Louis Pasteur performed the first resolution of enantiomers from a racemic mixture of tartaric acid salts.
The different enantiomers formed different shaped crystals, which he microscopically separated with tweezers.
O O
CH3 CH3
H3C H3CCH2 CH2
Smells
(–)-Carvonespearmint oil
(+)-Carvonecaraway seed oil
Ibuprofen is chiral, but normally sold asa racemic mixture, which is 50% of each
enantiomer
Chiral drugs
CH2CH(CH3)2
HH3C
CO
C
HO
The enantiomer above is responsible for its analgesic and anti-inflammatory properties.
Stereochemistry
• The pharmacological activity of many drugs depends on their stereochemistry:
(S)-(+)-ketamine (R)-(-)-ketamine
anesthetic hallucinogen
A Sedative or a Potent Teratogen?
Stereochemistry
A molecule with a single stereogenic center is chiral. A carbon atom with four different substituents is a stereogenic center and chiral.2-Butanol is an example.
Chirality and Chiral Carbon Atoms
CH3
OH
H
C CH2CH3
Examples of molecules with 1 chiral carbon
CH3
C
CH2CH3
CH2CH2CH2CH3CH3CH2CH2
a chiral alkane
Examples of molecules with 1 chiral carbon
Linalool, a naturally occurring chiral alcohol
OH
Examples of molecules with 1 chiral carbon
1,2-Epoxypropane: a chiral carboncan be part of a ring
O
H2C CHCH3
attached to the chiral carbon are:
—H
—CH3
—OCH2
—CH2O
Examples of molecules with 1 chiral carbon
Limonene: a chiral carbon can be part of a ring
CH3
H C
CH3
CH2
attached to thechiral carbon are:
—H
—CH2CH2
—CH2CH=
—C=
Examples of molecules with 1 chiral carbon
Chiral as a result of isotopic substitution
CH3CD
T
H
Optical Rotation
Relative Configuration and
Absolute Configuration
Optical Activity• Chiral compounds are optically active:
– capable of rotating the plane of polarized light
• Enantiomers rotate the plane of polarized light by exactly the same amount but in opposite directions.
(S)-(+)-d-2-butanol (R)-(-)-l-2butanol
+13.5o rotation -13.5o rotation
Optical Activity
• Compounds that rotate the plane of polarized light to the right (clockwise) are called dextrorotary.
• d• (+) IUPAC convention
• Compounds that rotate the plane of polarized light to the left (counterclockwise) are called levorotary.
• l• (-) IUPAC convention
Optical Activity
Relative configuration compares the arrangement of atoms in space of one compound with those of another.
Absolute configuration is the precise arrangement of atoms in space.
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.
Now, the absolute configuration of almost any compound can be determined
Configuration
No bonds are made or broken at the chiral carbon
in this experiment. Therefore, when (+) d-3-buten-2-ol
and (+) d -2-butanol have the same sign of rotation, the
arrangement of atoms in space at the chiral carbon
atom
is analogous. The two have the same relative
configuration.
CH3CHCH2CH3
OH
Pd
[a] + 33.2° [a] + 13.5°
Relative configuration: Optical Rotation
CH3CHCH
OH
CH2
HHO
H OH H2, Pd
HHOH2, Pd
H OH
Two possibilities
But in the absence of additional information, we can't tell which structure corresponds to(+) d -3-buten-2-ol, and which one to (–) l-3-buten-2-ol.
HHO
H OH H2, Pd
HHOH2, Pd
H OH
Two possibilities
Nor can we tell which structure corresponds to(+)-2-butanol, and which one to (–)-2-butanol.
HHO
H OH H2, Pd
HHOH2, Pd
H OH
Absolute configurations
[a] +33.2°[a] +13.5°
[a] –13.5° [a] –33.2°
Not all compounds that have the same relative
configuration have the same sign of rotation. No bonds
are made or broken at the chiral carbon in the
reaction shown, so the relative positions of the atoms
are the same. Yet the sign of rotation can change.
CH3CH2CHCH2Br
CH3
HBr
[a] -5.8° [a] + 4.0°
Relative configuration
CH3CH2CHCH2OH
CH3
Absolute Configuration
Rank the 4 groups (atoms) bonded to the chirality center
The R,S system of nomenclature
There is NO DIRECT CORRELATION between (R) and (S) configurations, and the relative configuration / the optical rotation: (+)/(-)
Treat the single carbon atom as a double bond, but
taking into account the tetrahedral geometry
1. Rank the substituents at the stereogenic carbon center according to their atomic
number.
2. Orient the molecule so that lowest-ranked substituent points away from you.
3. If the order of decreasing precedence traces a clockwise path, the absolute configuration
is R. If the path is anticlockwise, the configuration is S.
The Cahn-Ingold-Prelog (CIP) Rules
Orient the lowest priority (4) away from you: [Highest is (1)]
Clockwise = R configuration
Counterclockwise = S configuration
Switch any 2 substituents and the new configuration is opposite R S; S R
• The groups attached to the chiral center are the same (-CH2-) below.
• Analyze the atomic numbers of the next atoms in the bonding sequence.
Designating Configurations
14
2 3
TieAdjacent atoms:
Next atoms::
• Double bonds count as two single bonds.
• Is the following molecule is R or S?
Designating Configurations
Cl
A = R- B = S-
Question
Naming from the Perspective Formula
1
23
4
1. Rank the groups bonded to the asymmetric carbon
2. If the group (or atom) with the lowest priority is bonded by hatched wedge,
3. If necessary, rotate the molecule so that the lowest priority group (or atom) is bonded by a hatched wedge
4.
C OH
H3C
HCH3CH2
Enantiomers of 2-butanol
CHO
CH3
HCH2CH3
(S)-2-Butanol (R)-2-Butanol
What is the stereochemical designation of the following molecule?
Question
A. (R)
B. (S)
C. non-chiral (achiral)
Indicate the relationship of the pair of molecules shown.
A. same moleculesB. enantiomersC. diastereomersD. different moleculesE. constitutional isomers
Question
Indicate the relationship of the pair of molecules shown.
A. same moleculesB. enantiomersC. diastereomersD. different moleculesE. constitutional isomers
Question
Indicate the relationship of the pair of molecules shown.
A. same moleculesB. enantiomersC. diastereomersD. different moleculesE. constitutional isomers
Question
Indicate the relationship of the pair of molecules shown.
A. same moleculesB. enantiomersC. diastereomersD. different moleculesE. constitutional isomers
Question
Indicate the relationship of the pair of molecules shown.
A. same moleculesB. enantiomersC. diastereomersD. different moleculesE. constitutional isomers
Question
HH3C
H
H
chiral carbon in a ring
R
—CH2C=C > —CH2CH2 > —CH3 > —H
Question
The S-isomer is an effective sedative. The R- is a
teratogen in humans, but not rats.
In the structures above, which is the R-isomer, A or B?
H
A B
What is the stereochemical designation of the following molecule?
Question
A. (R)
B. (S)
C. non-chiral (achiral)
Fischer Structures“The Horizontal Bonds Point Towards You!”
Emil Fischer, 1815-1919(the second) Nobel Prize in Chemistry, 1902
Rules for Fischer projections
Arrange the molecule so that horizontal bonds at chiral carbon point toward you and vertical bonds point away from you.
Br Cl
F
H
Rules for Fischer projections
Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.
Br Cl
F
H
Rules for Fischer projections
Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back.
Br Cl
F
H
What is the stereochemical designation of the indicated chirality center?
A. (R)
B. (S)
C. non-chiral (achiral)
Question
Disubstituted CyclohexanesStereoisomerism
A. same moleculesB. enantiomersC. diastereomersD. different moleculesE. constitutional isomers
Indicate the relationship of the pair of molecules shown.
Question
Indicate the relationship of the pair of molecules shown.
Question
A. same moleculesB. enantiomersC. diastereomersD. different moleculesE. constitutional isomers