Stereochemsitry Flashcards
Isomerism
Relates to structural differences between different molecules
Conformation
Different arrangements of the atoms of a SINGLE MOLECULE
- Happen as a result of rotation around single bonds
Configuration and Conformation
Configuration: rearrangment of bond/atoms in a molecule
Conformation: change of postiton of atom (they rotate or something)
- Taka a cat for example, it can strike poses and look cute all day by changing it’s conformation but if you swape a limb or something then you changed it’s configuration
Isomers
Have the same molecular formula but different structures
- Constitutional Isomers
- Stereoisomers
Constitutional Isomers
Two or more compounds that have the some constitution but differ in bond connectivity (differ in order of attachment of atoms)
Steroisomer
Same constitution (formula) and connectivity but differ in spatial arrangement
Olefin Isomer Nomenclature
Designated as Z (zusammen-together) when
- The double bond geometry in which the groups at each end of the bond have higher priority on the same side
Designated as E (entgegen-apart) when
- The double bond geometry in which the groups at each end of the bond have higher priority on the opposite side
Use E/Z only if there 3 or more unique substituents, other wise use cis (same side)/trans (opposite sides)
Cahn-Ingold Prelog (CIP) system
Priorities are assigned based on atomic numbers using
- The atom directly attached to the sterocenter that has the higher atomic number is assigned the higher priority
- For two identical atoms, the atomic number of the atoms attached to each determine priority
– If one is attached to ANY atom that has a higher atomic number than ANY of the atoms attached to the other one then it has higher priority
– Move away from sterochemisty in the direction that will first give a difference in priorities
Carbonyl (C=O) is higher priority than phenyl
- Because it is next to two oxygen which got higher atomic numbers than the 3 carbons
Phenyl (Ph) is higher priority thatn C=C bond
- The Ph is 3 carbon while the double bond is only 2 carbons
CIP System
Additional rules
When moving to find an atom that gives rise to difference in priorities
- Double bonds count as two single bonds
- Triple bonds count as three single bonds
A phenyl group is counted as if the C is attached to C,C and C (this is because the C is attached to a double bond (sp2) site and a single bond on the other side)
- Sp2 (aromatic)>Sp2 (alkene)
- for substituted phenyl rings ortho>meta>para (first point of difference, ortho is closer, followed by meta, and para)
CIP System
Isotopes, lone pair
Higher isotopes (more e-) have priority over lower isotope (stick to atomic mass order)
- T>D>H or (3)H>(2)H>H; (13)C>(12)C
A lone pair is the only group with a priority lower than H (almost no atomic mass)
- Do not assign E/Z to double bonds in aromatic rings smaller than 8-membered
I>Br>Cl
Enantiomer
Chirality
Two steroisomers that result from the reflection of the compound on the left in a missor
- Not superimposed on one another
- Becomes possible when compound contain a center of asymmetry; chiral center
– Chiral center has a central atom that is attached to 4 different group (thus lacking symmetry)
- Have identical chemical and physical properties as long as they remain in achiral environement
- They will be indentical with respect to:
– Melting point, Boiling point
– UV/vis, IR, NMR, mass spectra
– Chromatographic retention time
– Rate of reaction with achiral reagent
Why is Enantimoers optically active?
They are distinguished from one another by their ability to rotate the plane of polarized light when it passed through a solution of an enantiomer
- Optical rotation is measured in a POLARIMETER and is expressed as [alpha] which is called specific rotation
- Two enantiomers will rotate polarized light with equal magnitude but with opposite signs (ie, if one has [alpha] =+14.5 the other one got an [alpha] = -14.5°)
What is the optic rotation of a mixture of Equal amount of two enantimoer?
The [alpha] =0°, because their rotation will cancel each other out
- Such a mixture is called Racemic Mixture and is indicated using (±)- or (dl)- in the name
-
Non-racemic mixture
A non equal mixture of two enantiomers will have a non zero value for [alpha]
- It will be less than that of a pure enantiomer
Chiral Centers
May occur at atoms other than C
- Any configurationally stable tetrahedral atom can be a chiral center if attached to four different groups
– An example is seen with sulfur in the form of sulfoxides (Esomeprazole, Prilosec; for acid-reflux disease)
— If S is bonded with two different groups, the O and lone pair make up the four groups
- Omeprazole is the racemate
Chiral Center: Amines
Amine are NOT chrial center because they are NOT configurationally stable (otherwise an amine that has three different R goups and a lone pair attached to N would be a chiral center)
- At room temp they undergo rapid inversion of configuration that equilibrates the isomer => NOT optically active (Nitrogen never is)
What is the importance of steroisomerism to drugs?
- For some drugs one enantiomer contain most or all of the activity
- Administration of a racemic mixture of such drug only provide patients with 50% of an effective dose
- In other instance two enantiomers can have entirely different medicicnal activities
Detromethorphan:Levomethorphan (enantiomers)
Non-addicting, antitussive, no analgestic potency, sold as OTC: Addicting, poten analgesic, Schedule I drug
Thalidomide
- (S) - toxic
- (R) - active, calming
R or S for Enantiomer
1) Assign priorities to all groups
2) Redraw so the lowest priority point back into the paper
- It is (R) if the other three groups decrease in priority in a clockwise direction
- It is (S) if the other three groups decrease in priority in a counterclockwise direction
What happens when the lowest priority group is oriented between you and the chiral center?
If it is between you and the chiral center (not dashed)
- Make use of opposite assignment
– R if group decrease counterclock wise
– S if group decrease clock wise
What happens if the lowest priority group lie IN the plane of the paper
In this case you have two choices
- Imagine that you are in the plane of the paper and apply either of the first two methods above
- Alternatively, assigning priortities => mentally switch the lowest priority group with whatever group lies behind the plane (dashed), => make opposite assignment that you would normally make
Fisher Projection
- Groups on the horizontal line come out of the plane (bolded lines)
- Groups on the vertical line go behind the plane (dashed lines)
- Where the line cross is a carbon
Used extensively in carbohydrate and amino acid chemistry
How to apply R- and S- designation to Fisher Projection?
Assign Priorities
- If the lowest priority group lies on the vertical line (top or bottom; behind the plane; dashed lines); observe the decreasing order of the 3 other groups and make NORMAL (CW=R, CCW=S) assignment
- If the lowest priority group lies on the horizontal line (right or left; come out of the plane; bolded lines); observe the decresing order of the 3 other group and make opposite assignment
What do Fisher projection make easy?
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It makes it easy to make comparison between two identically substituted chiral centers
- If the projection is rotated in either direction by 90° then the two structure are enantiomers
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What is the older method for specifying the absolute configuration?
It relies on the comparison with a reference compound
- The reference chosen is glyceraldehyde as it has only one chrial center
– The enantiomer that has a (+) optical rotation is designated as D (last of OH on the right)
– The enatiomer that has a (-) optical rotation is designated as L (last of OH on the left)
Carbohydrates; Fisher Projection
Carbon at the highest oxidation state is at the top
- The H and OH are located on the horizontal line
– L-enantiomer has the OH group to the LEFT
– D-enantiomer has the OH group to the right
Amino Acids: Fisher
Use the same system but the H and NH2 groups are on the horizontal line
Fisher Projetion: Multiple Chiral Centers
It is drawn so that the highest oxidation sate carbon is as close as possible to the top position
- Again the orientation of OH on the furthest below determines whether it is D- or L-
Why is D- and L- system not wide spread?
Mainly used in carbohydrate and amino acids
- It becomes less useful as the structures deviate significantly from that of glyceraldehyde
– Only for D-glyceraldehyde do the rotation have to be (+) while L-glyceraldehyde be (-)
— For other compounds D-enantiomer may have [alpha] = positive or negative value
Opposite Configuration in Fisher Projection
When two compounds have many chiral center; if each chiral center has opposite configuration as the corresponding one as in the other compound => Enantimoers
- Assign S; R not D and L
Diastereomers
Stereoisomers that are not enantiomers are disastereomer (not mirror images).
- May have completely different chemical and physical properties
- In achiral environment, if they are optically active, their [alpha] may vary in both sign and magnitude
When comparing two identically substituted compounds that have multiple chiral center
- If even one retain the same configuration when the other changes then it is not enantiomer
This means E- and Z- as well as cis- and trans- isomer are calssified as being diastereomer
Meso-compound
Diastereomer
A plance of symmetry exist in the molecule
- Not optically active because they are no asymmetric
- If meso isomers are possible then for n-chiral centers, there will be fewer than 2^n steroisomers possible
Prochirality
A Molecule that possesses enantiotopic groups is called prochiral
Ethanol has no chiral centers because the centeral C is attached to two equivalent H
- As long as it stays in an achiral environment, then they will be equivalent
- If it’s placed into a chiral environmen, then they may be differentiated from one another (enzyme react with ethanol; they react with the H that is less sterically hindered)
– These type of groups are called enantiotopic (they may be distinguishable in chiral environment)
— They react in a different way or a different rate in a chiral environment
Saturated Rings
Cyclic compounds that have two or more substituents on the ring(s) may also exist as stereosisomers
- If substituents lie on the same face (both dashed or both bolded), then it is cis-
- If substituent lie on opposite faces, the trans
Ring Junctions of saturated rings can be cis- or trans-
- Cis- if both on the same side
- Trans- if on opposite sides
Conformation
Acyclic Compounds
Conformation: different 3-dimensional arrangement of the atoms of a molecule as a result of rotation (without bond cleavage)
Conformation
Eclipse
When H eclipsed each other there are non-bonding interactions (torsion strain) that increase the E of th emolecule
- Each H-H eclipsing interaction add 1 kcal/mol to total E (unfavorable interactions) Me-H add 1.3; Me-Me add 4
– The E difference between staggered (preferred) and eclipsed ethane conformers is 2.9 kcal/mol
— Staggered (antiperiplanar-60° away from each other) is most preferred, followed by gauche (only Me-Me add energy 0.9 kcal/mol), then partially eclipsed, and finally fully eclipsed
Cyclohexane Two Conformation
Boat Conformation:
- Four pairs of eclipsing H that raise the E of the conformation
Chair Conformation:
- No eclipsing H and so is lower in E
Molecules prefer to exist in their lowest E conformation
Cyclohexane; Hydrogen Sets
Two distinct sets:
- Equatorial: Each carbon has one H that is in the average plane of the ring
- Axial: Each carbon has one H that is perpendicular to the ring
Every other carbon has an axial H on the top face of the ring; while the axial H of the other C are on the bottom face
Chair Conformation Inversion
Form a different chair
- When this happen, what ever occupied an Axial position in one chair form => Equatorial upon inversion
Substituent when occupies the axial position
Chair Conformation
When that happens; it experiences steric interactions with the Axial H that reside at the 3- and 5- position
- These 1,3-diaxial interactions raise the E of that particular conformation
– The effect is more severe as the size increase
An Example is
- Axial Methyl got the CH3 on Axial at 1-position => 1,3 Diaxial interactions
– Gonna want to change the conformation
— Equatorial Methyl got the CH3 on (E) => No interaction => more favorable
Diaxial conformations are much higher in E and will be inverted into diequatorial conformation
Equatorial Vs. Axial
Subtituent that is (E) is lower in energy than the same substituent that is (A)
- Two substituent on a ring can be cis- or trans-
Conformation have one axial and one equatorial substituent even when inverted
- The bulky (larger) group will get to be in th e (E) postition => lower in E
Cyclohexenes (6-membered) and Conformations
Cyclohexenes have one double bond
- The two sp2 hybridized carbons => they and the two carbons adjacent to them reside in the same plane
– Only the furthest two carbons from the double bond are not in the same plane
Cyclopentanes (5-membered ring) and conformation
Got Two Major Conformation:
- Envelope: four carbons in one plane with the fifth carbon out of the plane (like the flap of an envelope)
- Half-Chair: lower in energy; like the envelope but twisted to minimize eclipsing
Cyclobutanes (4-membered rings) and Conformation
Not flat but are puckered with a torsion angle of about 35°
- The puckering help minimize eclipsing
Cyclopropanes (3-membered rings) and Conformation
They are planar ( flat; a lot of drugs are in this form because they are strong) and they are high in energy:
- The C-C-C bond angles are small (60° as opposed to the normal tetrahedral bond angle of 109.5°)
- All of the hydrogens eclipse one another on each face
Steroids
All got three 6-membered rings and one 5-membered ring (envelop)
- Trans- low E
- Series of chairs; Flat
