Stereochemistry

3-dimensional Aspects ofTetrahedral Atoms

Chiral• Entire molecules or simply atoms that do not possess a

plane of symmetry are called “chiral”.

• Conversely, the term “achiral” is applied to molecules oratoms that possess a plane of symmetry.

Chiral?

• Is methane, CH4, a chiralmolecule?

• What makes a moleculechiral?

• The molecule cannot havea plane of symmetry

H

HH

H

Answer:

• No, methane has aplane of symmetry andtherefore cannot bechiral.

H

H

H H

H

HH

H

rotation

Chiral?

• Consider CH3X andask yourself if thismolecule is chiral…?

X

HH

H

Answer:

• No, CH3X has a planeof symmetry andtherefore cannot bechiral

X

H

H H

X

HH

H

rotation

Chiral?

• Consider CH2XY andask yourself if thismolecule is chiral…?

X

HY

H

Answer:

• No, CH2XY has aplane of symmetry andtherefore cannot bechiral

X

Y

H H

X

HY

H

rotation

Chiral?

• Consider CHXYZ andask yourself if thismolecule contains achiral center.

• The carbon atom inthis molecule has fourdifferent groupsattached to it.

X

HY

Z

Answer:

• CHXYZ does not havea plane of symmetryand therefore IS chiral

X

Y

H Z

X

HY

Z

rotation

The Chiral Carbon Atom• Carbon atoms that are bonded to four different groups

cannot contain a plane of symmetry.

• These carbons are CHIRAL and may be called “chiralcarbons”, “chiral centers”, “asymmetric centers”,“stereogenic centers” or simply “stereocenters”.

• This leads to a “handedness” and we can consider bothpossible “hands”, or mirror images.

Check this one out…

• How many chiralcenters do you see?

• None, this moleculehas a plane ofsymmetry.

Br

What about this one?

• How many chiralcenters do you see?

• One chiral center –and this molecule ischiral overall becauseit does not have aplane of symmetry.

BrH

One more time…

• How many chiralcenters do you see?

• Two chiral centers, butthis molecule has aplane of symmetry sothe molecule, overall,is not chiral.

BrH

BrH

Mirror Images of a Chiral Carbon

These two molecules have the same numberand kinds of atoms, and even the same orderof connectivity, but their three-dimensionalarrangement is that of mirror images.

Br

HOCH3

H

Br

OHH3C

H

"S" "R"

Non-Superimposable?

• Notice that when you attempt to lay oneisomer on top of the other one, all fourgroups will not match up…

• Non-superimposable!!

Br

HOCH3

H

Br

OHH3C

H

"S" "R"

rotation

Br

OHH

H3C

"S"

Stereoisomers

• What is the definition of a stereoisomer?

• Molecules that have the same number andkinds of atoms, and the same connectivityof these atoms, but have a different three-dimensional arrangement.

Enantiomers

• A specific type of stereoisomer

• Enantiomers are stereoisomers that aremirror images that cannot be superimposedupon each other.

Assignment of Configurations

• We use the convention “R” or “S” todifferentiate between the two possibleenantiomers.

Br

HOCH3

H

Br

OHH3C

H

"S" "R"

To Assign R or S to the Configuration:

Apply the Cahn-Ingold-Prelog Rules:

Step 1: Determine what four atoms areattached to the chiral carbon in question.

Step 2: Assign priorities to the four atomsbased on their Atomic Numbers (the highestpriority is #1, the lowest, #4).

An Example of Priority Assignment:

• The highest atomic number corresponds tobromine (atomic number 35, #1), then oxygen(atomic number 8, #2), then carbon (atomicnumber 6, #3) and finally hydrogen (atomicnumber 1, #4).

Br

HOCH3

H

1

2

3

4

Position the Molecule:

Step 3: Rotate the molecule so the lowest priorityfaces away from you.

Step 4: Determination of “R” or “S”…

1

32

4

1

3 2

4rotate

The “R” Configuration:

• If 1 → 2 → 3 is aclockwise rotation,you are viewing theR configuration.

"R"

1

3 2

4

The “S” Configuration:

• If 1→ 2 → 3 is acounterclockwiserotation, you areviewing the Sconfiguration."S"

1

32

4

What if two of the groups arevery similar?

• If a priority difference cannot be determinedbecause two of the atoms on the chiralcenter are the same, then utilize the atomsconnected to each of these, until adifferentiation may be made.

An example with two similargroups:

• Consider the chiral carbon atom shown.• Note how it has a methyl group (C with three

H’s) and an ethyl group (C with two H’s and aC). The presence of the C atom determines thepriority.

CH2CH3

HOCH3

H

2

13

4

How does one assign priorities tofunctional groups that containmultiple bonds?• Consider the functional group with the multiple

bond to be equivalent to the same number ofsingle-bonded atoms.

• An example would be the C=O bond. In this case,the carbon-oxygen double bond is equivalent tothe carbon atom being bonded TWICE to theoxygen atom, and vice versa.

An example containing amultiple bond:

Br

CH3C

HN

Br

CH3C

HN

N

N

equates to:

R or S?

• Is the molecule shownthe “R” or the “S”enantiomer?

• Determine the priorityassignments andassign the correctconfiguration

H

COH

CH3

O

H

Answer:• After rotation of the molecule so the lowest

priority is in the back, rotation of 1→ 2 → 3shows that this chiral center is the “S”configuration.

H

COH

CH3

O

H

OH

CCH3

H

O

H4

2

3

1

4 1

2

3

The Relationship of Enantiomers

• Enantiomers are non-superimposable mirrorimages.

• For every “R” stereocenter in one isomer,the mirror image has an “S”, and vice versa.

• A molecule with 5 stereocenters (ex. R, S,S, S, R) has an enantiomer whosestereocenters are the opposite (i.e. S, R, R,R, S).

Racemic Mixture:

• A racemic mixture is a 50:50 mixture ofboth enantiomers.

• The process of physically separating theenantiomers of a racemic mixture is called“resolution”.

Characteristics of Enantiomers

• Enantiomers have the same physicalproperties (ex. melting point, boiling point,density, solubility, refractive index, etc.).

• The only way to differentiate between twoenantiomers is to measure the OpticalActivity of each.

Optical Activity

• Chiral molecules possess the ability torotate “plane-polarized” light.

• A solution of each enantiomer of a moleculewill rotate the light the same magnitude butin opposite directions. This is the only wayto physically differentiate between twoenantiomers.

Determination of Specific Rotation:

• Every solution concentration is different and so isevery polarimeter, so we compare optical activityusing the Specific Rotation.

• The Specific Rotation, [α]D, is the observed rotation,α, caused by a solution of chiral molecules whoseconcentration (C) is 1 g/mL with a cell path length(l) of 1 dm, which is the distance the light travelsthrough the solution.

• The observed rotation, α, has both amagnitude and a direction for rotation.

• The magnitude is directly dependent uponthe concentration and the cell path length.– Double the concentration, and you will double

the magnitude.– Halve the cell path length and you will halve

the magnitude.

• Direction of Rotation:– Rotation of light in a clockwise fashion is a

dextrorotatory rotation, or rotation to the right,symbolized by “d” or (+).

– Rotation of light in a counterclockwise fashionis a levorotatory rotation, or rotation to the left,symbolized by “l” or (-).

To Calculate the Specific Rotation:α = observed rotation in degreesC = concentration in grams per milliliterl = cell path length in decimeters

[!]D = !/C l

Problem:• Calculate the specific rotation for a solution

of Compound X, whose concentration (C) is500 mg/mL, in a polarimeter whose cellpath length (l) is 10 cm, if the observedrotation (α) is (+) 6.50 º.

• Answer: (+) 13.0 º. Be sure to convert allunits (g/mL and dm) before calculating.You must include the direction of rotation.

Fischer Projections

• A Fischer Projection is a two-dimensionalrepresentation of a three-dimensionalcarbon atom.

C

D

BA

C

D

BAequates to

Conversion of 3-D to 2-D:

• By convention, a Fischer Projection is alwaysdrawn in the same manner: the horizontal linesrepresent bonds coming towards you and thevertical lines are bonds going away from you.

• Everyone views structures in 3-dimensions slightlydifferently and very often from a differentperspective. There are several correct FischerProjections for any single chiral center.

“Flatten” the Chiral Center:• Try “flattening” your chiral centers the same way

each time, to prevent careless errors. The exampleshown here positions the view point between Aand B. Note where C and D wind up as a result.

BA

D C

Flatten

C

D

BA

Consider this Molecule:

• Draw the 3-dimensionchiral center as aFischer Projection. Br

OHH3C

H

• Remember that everyone sees objects in 3-dimensions differently. If your answer looksdifferent, it may just be a different perspective.

Br

OHH3C

H

H

CH3

BrHO

BrHO

H3C H

rotate

flatten

Compare two Fischer Projections:

• Fischer Projectionscan be manipulated toto determine if themolecules you areviewing are the sameor enantiomers.

C

D

BA CD

B

A

“Legal” Movements?

• Fischer Projections must maintain the conventionthat horizontal lines are bonds coming AT youand the vertical lines are bonds going AWAYfrom you.– Fischer Projections may be rotated 180 degrees in

either direction, but never 90 nor 270 degrees.– Fischer Projections may also be turned by holding one

group constant and rotating the remaining threegroups, in either direction.

Examples:C

D

BArotate 180º

C

D

B A

never 90º or 270º

but

C

D

BA

D

B

CA

hold one

constant,

rotate the

others

Same or Enantiomers?• When comparing Fischer

Projections, the goal is tomatch two of the groupsand see what happens withthe remaining two.

• If the remaining twomatch, they are the samemolecule.

• If the remaining two donot match, they are mirrorimages (enantiomers).

C

D

BA

C

D

BA

same!

B

D

CA

C

D

BA

enantiomers!

Manipulate and Match?

• Always leaveone moleculeuntouched andmanipulate theother.

• You can see,after rotation,these are thesame molecule.

rotate 180º

C

D

B A

C

D

BA

C

D

BA

vs.

Same!

Determination of R or S using aFischer Projection:• Assign Priorities as before.• Rotate so the lowest priority is at top or bottom.• Determine direction of rotation 1→ 2 → 3

(clockwise is R, counterclockwise is S).4

1

23

"S"

Multiple-Centered Fischer Projections?

• Fischer Projectionswere developed todeal with systems withmultiple chiral centers.

• Remember the samemolecules will alwaysmatch completely andenantiomers willalways be mirrorimages.

OH

H CH3

BrH3C

H

OH

H3C H

CH3Br

H

Molecules with more than one chiralcenter:• For a molecule with “n” chiral centers, there are a

total of 2n possible stereoisomers that one candraw.

• Consider a molecule with 4 chiral centers. Howmany possible stereoisomers are there?

• 24 = 16 possible stereoisomers

Consider a Molecule with TwoStereocenters:• Shown below are the four possible stereoisomers

for 2-bromo-3-chlorobutane.

CH3H3C

H HBr Cl

CH3H3C

Br HH Cl

RR RS

CH3H3C

Br ClH H

CH3H3C

H ClBr H

SS SR

What’s the Relationship?

• The stereoisomersshown here are a set ofenantiomers, the S, Rand the R, S isomers.

• The other set ofstereoisomers, the S, Sand the R, R isomers,are also enantiomers.

CH3H3C

H HBr Cl

RS

CH3H3C

Br ClH H

SR

But, What About…??

• What’s the relationshipbetween the S, R isomer andthe R, R isomer?

• Part of the molecule is amirror image and the otherpart is the same.

• These stereoisomers arecalled “diastereomers”

CH3H3C

H HBr Cl

CH3H3C

Br HH Cl

R

R

R

S

Diastereomers

• Another specific type of stereoisomer• Diastereomers are stereoisomers with two

or more chiral centeres that are not entirelymirror images nor entirely the same.

• The physical properties vary widely fromone diastereomer to another. There is nopredictable physical relationship betweendiastereomers, not even optical activity.

Meso Compound

• A specific type of diastereomer• Meso compounds are stereoisomers with

two or more chiral centers that also containa plane of symmetry.

An Example of a Meso Compound

• 2,3-butanediol is an example of a meso compound.• These two are exactly the same!!• Because meso compounds have a plane of

symmetry, they cannot be optically active.

CH3H3C

H HOH OH

RS

CH3H3C

HO OHH H

• This ends your review of stereochemistry andthe major subjects that you should understand:– This list includes the concepts of: chiral,

stereocenter, enantiomer, racemic mixture, opticalactivity, specific rotation, diastereomers, and mesocompounds.

– Assignment for R or S can be made for either achiral carbon atom or a Fischer Projection.

– Fischer Projections can be manipulated to comparerelationships of molecules (same, enantiomers ordiastereomers).

– Calculations for Specific Rotation