Stereochemistry

1. Stereochemistry 3-dimensional Aspects of Tetrahedral Atoms

2. 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.

3. Chiral? • Is methane, CH4, a chiral molecule? • What makes a molecule chiral? • The molecule cannot have a plane of symmetry

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

5. Chiral? • Consider CH3X and ask yourself if this molecule is chiral…?

6. Answer: • No, CH3X has a plane of symmetry and therefore cannot be chiral

7. Chiral? • Consider CH2XY and ask yourself if this molecule is chiral…?

8. Answer: • No, CH2XY has a plane of symmetry and therefore cannot be chiral

9. 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.

10. Answer: • CHXYZ does not have a plane of symmetry and therefore IS chiral

11. 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.

12. Check this one out… • How many chiral centers do you see? • None, this molecule has a plane of symmetry.

13. 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.

14. 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.

15. 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 ofmirror images.

16. 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!!

17. 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.

18. Enantiomers • A specific type of stereoisomer • Enantiomers are stereoisomers that are mirror images that cannot be superimposed upon each other.

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

20. 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).

21. 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).

22. Position the Molecule: Step 3: Rotate the molecule so the lowest priority faces away from you. Step 4: Determination of “R” or “S”…

23. The “R” Configuration: • If 1  2  3 is a clockwise rotation, you are viewing the R configuration.

24. The “S” Configuration: • If 1 2  3 is a counterclockwise rotation, you are viewing the S configuration.

25. 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.

26. 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.

27. 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.

28. An example containing a multiple bond:

29. R or S? • Is the molecule shown the “R” or the “S” enantiomer? • Determine the priority assignments and assign the correct configuration

30. 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.

31. 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).

32. 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”.

33. 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.

34. 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.

35. 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.

36. 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.

37. 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 (-).

38. To Calculate the Specific Rotation:  = observed rotation in degrees C = concentration in grams per milliliter l = cell path length in decimeters

39. 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: (+) 13.0º. Be sure to convert all units (g/mL and dm) before calculating. You must include the direction of rotation.

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

41. 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.

42. “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.

43. Consider this Molecule: • Draw the 3-dimension chiral center as a Fischer Projection.

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

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

46. “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.

47. Examples:

48. 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).

49. Manipulate and Match? • Always leave one molecule untouched and manipulate the other. • You can see, after rotation, these are the same molecule.

50. 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).