Stereochemistry 3-dimensional Aspects of Tetrahedral Atoms

Stereochemistry

3-dimensional Aspects of Tetrahedral 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 or atoms that possess a plane of symmetry.

Chiral?

• Is methane, CH4, a chiral

molecule?• What makes a molecule

chiral?• The molecule cannot have

a plane of symmetry

H

H HH

Answer:

• No, methane has a plane of symmetry and therefore cannot be chiral.

H

H

H H

H

H HH

rotation

Chiral?

• Consider CH3X and

ask yourself if this molecule is chiral…?

X

H HH

Answer:

• No, CH3X has a plane

of symmetry and therefore cannot be chiral

X

H

H H

X

H HH

rotation

Chiral?

• Consider CH2XY and

ask yourself if this molecule is chiral…?

X

H YH

Answer:

• No, CH2XY has a

plane of symmetry and therefore cannot be chiral

X

Y

H H

X

H YH

rotation

Chiral?

• Consider CHXYZ and ask yourself if this molecule contains a chiral center.

• The carbon atom in this molecule has four different groups attached to it.

X

H YZ

Answer:

• CHXYZ does not have a plane of symmetry and therefore IS chiral

X

Y

H Z

X

H YZ

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 “chiral carbons”, “chiral centers”, “asymmetric centers”, “stereogenic centers” or simply “stereocenters”.

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

Check this one out…

• How many chiral centers do you see?

• None, this molecule has a plane of symmetry.

Br

What about this one?

• How many chiral centers do you see?

• One chiral center – and this molecule is chiral overall because it does not have a plane of symmetry.

BrH

One more time…

• How many chiral centers do you see?

• Two chiral centers, but this molecule has a plane of symmetry so the molecule, overall, is not chiral.

BrH

BrH

Mirror Images of a Chiral Carbon

These two molecules have the same number and kinds of atoms, and even the same order of connectivity, but their three-dimensional arrangement is that of mirror images.

Br

HO CH3

H

Br

OHH3CH

"S" "R"

Non-Superimposable?

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

• Non-superimposable!!

Br

HO CH3

H

Br

OHH3CH

"S" "R"

rotation

Br

OHHH3C

"S"

Stereoisomers

• What is the definition of a stereoisomer?

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

Enantiomers

• A specific type of stereoisomer

• Enantiomers are stereoisomers that are mirror images that cannot be superimposed upon each other.

Assignment of Configurations

• We use the convention “R” or “S” to differentiate between the two possible enantiomers.

Br

HO CH3

H

Br

OHH3CH

"S" "R"

To Assign R or S to the Configuration:

Apply the Cahn-Ingold-Prelog Rules:

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

Step 2: Assign priorities to the four atoms based on their Atomic Numbers (the highest priority is #1, the lowest, #4).

An Example of Priority Assignment:

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

Br

HO CH3

H

1

2

3

4

Position the Molecule:

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

Step 4: Determination of “R” or “S”…

1

3 24

1

3 2

4rotate

The “R” Configuration:

• If 1 2 3 is a clockwise rotation, you are viewing the R configuration."R"

1

3 2

4

The “S” Configuration:

• If 1 2 3 is a counterclockwise rotation, you are viewing the S configuration."S"

1

32

4

What if two of the groups are very similar?

• If a priority difference cannot be determined because two of the atoms on the chiral center are the same, then utilize the atoms connected to each of these, until a differentiation may be made.

An example with two similar groups:

• 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 a C). The presence of the C atom determines the priority.

CH2CH3

HO CH3

H

2

1 34

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

bond to be equivalent to the same number of single-bonded atoms.

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

An example containing a multiple bond:

Br

CH3CH

N

Br

CH3CH

N

NN

equates to:

R or S?

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

• Determine the priority assignments and assign the correct configuration

H

C OHCH3

O

H

Answer:• After rotation of the molecule so the lowest

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

H

C OHCH3

O

H

OH

C CH3

H

O

H4

23

1

4 1

2

3

The Relationship of Enantiomers

• Enantiomers are non-superimposable mirror images.

• 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 whose stereocenters are the opposite (i.e. S, R, R, R, S).

Racemic Mixture:

• A racemic mixture is a 50:50 mixture of both enantiomers.

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

Characteristics of Enantiomers

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

• The only way to differentiate between two enantiomers is to measure the Optical Activity of each.

Optical Activity

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

• A solution of each enantiomer of a molecule will rotate the light the same magnitude but in opposite directions. This is the only way to physically differentiate between two enantiomers.

Determination of Specific Rotation:

• Every solution concentration is different and so is every polarimeter, so we compare optical activity using the Specific Rotation.

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

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

• The magnitude is directly dependent upon the 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 fashion is a levorotatory rotation, or rotation to the left, symbolized by “l” or (-).

To Calculate the Specific Rotation: = observed rotation in degrees

C = concentration in grams per milliliter

l = cell path length in decimeters

[]D = /C l

Problem:• Calculate the specific rotation for a solution

of Compound X, whose concentration (C) is 500 mg/mL, in a polarimeter whose cell path length (l) is 10 cm, if the observed rotation () is (+) 6.50 º.

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

Fischer Projections

• A Fischer Projection is a two-dimensional representation of a three-dimensional carbon atom.

C

D

BA

C

D

BAequates to

Conversion of 3-D to 2-D:

• By convention, a Fischer Projection is always drawn in the same manner: the horizontal lines represent bonds coming towards you and the vertical lines are bonds going away from you.

• Everyone views structures in 3-dimensions slightly differently and very often from a different perspective. There are several correct Fischer Projections for any single chiral center.

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

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

BA

D C

Flatten

C

D

BA

Consider this Molecule:

• Draw the 3-dimension chiral center as a Fischer Projection. Br

OHH3CH

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

Br

OHH3CH

H

CH3

BrHO

BrHO

H3C H

rotate

flatten

Compare two Fischer Projections:

• Fischer Projections can be manipulated to to determine if the molecules you are viewing are the same or enantiomers.

C

D

BA CD

B

A

“Legal” Movements?

• Fischer Projections must maintain the convention that horizontal lines are bonds coming AT you and the vertical lines are bonds going AWAY from 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 three groups, in either direction.

Examples:C

D

BArotate 180º

C

D

B A

never 90º or 270º

but

C

D

BA

D

B

CA

hold oneconstant,rotate theothers

Same or Enantiomers?

• When comparing Fischer Projections, the goal is to match two of the groups and see what happens with the remaining two.

• If the remaining two match, they are the same molecule.

• If the remaining two do not match, they are mirror images (enantiomers).

C

D

BA

C

D

BA

same!

B

D

CA

C

D

BA

enantiomers!

Manipulate and Match?

• Always leave one molecule untouched and manipulate the other.

• You can see, after rotation, these are the same molecule.

rotate 180º

C

D

B A

C

D

BA

C

D

BA

vs.

Same!

Determination of R or S using a Fischer 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 Projections were developed to deal with systems with multiple chiral centers.

• Remember the same molecules will always match completely and enantiomers will always be mirror images.

OH

H CH3

BrH3C

H

OH

H3C H

CH3Br

H

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

total of 2n possible stereoisomers that one can draw.

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

• 24 = 16 possible stereoisomers

Consider a Molecule with Two Stereocenters:• 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 stereoisomers shown here are a set of enantiomers, the S, R and the R, S isomers.

• The other set of stereoisomers, the S, S and the R, R isomers, are also enantiomers.

CH3H3C

H HBr Cl

RS

CH3H3C

Br ClH H

SR

But, What About…??

• What’s the relationship between the S, R isomer and the R, R isomer?

• Part of the molecule is a mirror image and the other part is the same.

• These stereoisomers are called “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 entirely mirror images nor entirely the same.

• The physical properties vary widely from one diastereomer to another. There is no predictable physical relationship between diastereomers, not even optical activity.

Meso Compound

• A specific type of diastereomer

• Meso compounds are stereoisomers with two or more chiral centers that also contain a 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

RSCH3H3C

HO OHH H

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

stereocenter, enantiomer, racemic mixture, optical activity, specific rotation, diastereomers, and meso compounds.

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

– Fischer Projections can be manipulated to compare relationships of molecules (same, enantiomers or diastereomers).

– Calculations for Specific Rotation