1. Trans fusions determine geometry What is the geometry of the OH and CH 3 ? Trans fusions, rings must use equatorial position for fusion. Rings are locked. The H’s must both be axial Work out axial / equatorial for the OH and CH 3. A/E E/A OH is equatorial and CH 3 is axial

2. Stereoisomerism and Chirality

3. Isomerism Constitutional Isomers: Same atoms but linked (bonded) together differently. Spatial orientation not important. Are these constitutional isomers of hexane? No, different molecular formulae!! Are these constitutional isomers of cis but-2-ene? Not this one! It is 2-butene. Cis / trans does not matter.

4. Stereoisomerism Stereoisomers: Same molecular formulae, same connectivity; same constitutional isomer. Different spatial orientation of the bonds. Are these stereoisomers of cis but-2-ene? How does the connectivity differ between these two?

5. Enantiomers and Diastereomers Two kinds of Stereoisomers –Enantiomers: stereoisomers which are mirror objects of each other. Enantiomers are different objects, not superimposable. –Diastereomers: stereoisomers which are not mirror objects of each other. If a molecule has one or more tetrahedral carbons having four different substituents then enantiomers will occur. If there are two or more such carbons then diastereomers may also occur.

6. Isomers, contain same atoms, same formula Constitutional isomers, different connectivities, bonding. Stereoisomers, same connectivity, different three dimensional orientation of bonds Enantiomers, mirror objects Diastereomers, not mirror objects Summary of Isomerism Concepts

7. Mirror Objects – Carbon with 4 different substituents. We expect enantiomers (mirror objects). Reflect! These are mirror objects. Are they the same thing just viewed differently ?? Can we superimpose them? We can superimpose two atoms. but not all four atoms. The mirror plane still relates the two structures. Notice that we can characterize or name the molecules by putting the blue in the back, drawing a circle from purple, to red, to green. Clockwise on the right and counterclockwise on the left. Arbitrarily call them R and S. R S Arrange both structures with the light blue atoms towards the rear…. Notice how the reflection is done, straight through the mirror!

8. Recap: Tetrahedral Carbon with four Different Substituents. Enantiomers Simple Rotation, Same Mirror objects. Different, not superimposable. Enantiomers

9. But the reflection might have been done differently. Position the mirror differently…. Reflection can give any of the following… Can you locate the mirror which would transform the original molecule into each mirror object? In the course of each reflection, two substitutents are swapped. The other two remain unchanged. What is common to each of these reflection operations? All three of these structures are the same, just made by different mirrors. The structures are superimposable. What rotations of the whole molecules are needed to superimpose the structures? Again. all three objects on the right are the mirror object of the structure above. They are different views of the enantiomer. A swap of two substituents is seen to be equivalent to a reflection at the carbon atom.

10. Now Superimposable mirror objects: Tetrahedral Carbon with at least two identical substituents. Reflection can interchange the two red substituents. Clearly interchanging the two reds leads to the same structure, superimposable! Remember it does not make any difference where the mirror is held for the reflection. This molecule does not have an enantiomer; the mirror object is superimposable on the original, the same object.

11. Summary A reflection on a tetrahedral carbon with four different substituents produces a different, non-superimposable structure, the enantiomer. A different three dimensional arrangement of the bonds is produced, a different configuration. Such a carbon is called chiral. The carbon is a chiral center, a stereogenic center. The swapping two of the substituents on the chiral carbon is equivalent to a reflection. If a tetrahedral carbon has two or more substituents which are the same then reflection produces the same structure, the same configuration. Such a carbon is called achiral. There is only one mirror object produced by reflection, no matter where the mirror is located. It is either the same as the original structure (superimposable) or it is different (non-superimposable), the enantiomer.

12. Multiple reflections One reflection (swap of substituents) on a chiral carbon produce the enantiomer. Two reflections (swaps) yields the original back again. Even number (0, 2, 4…) of reflections (swaps) on a chiral carbon yields the original structure. An odd number (1, 3, 5…) yields the enantiomer. One swap Second swap Enantiomers Same molecule.

13. Repeating…. Reflection (in this plane) yields. Three different substitutents. Same, not enantiomers. Reflection (in this plane) yields. Four different substituents. Different, not superimposble, enantiomers.

14. Is a chiral carbon needed? No! Reflection (in this plane) yields. Different, not superimposable, enantiomers. The (distorted) tetrahedral array of the substitutents (huh??) suffices to allow for enantiomers. Recall allene:

15. Naming of configurations. A priority is assigned to each substituent on the chiral carbon Rotate the structure so that the lowest priority towards the rear. Draw an arc from the highest, to the next lower, to the next lower. If arc is clockwise it is R configuration. If arc is counterclockwise it is S. S R

16. Assigning Priorities 2 Start with first atom attached to chiral carbon C vs. F

17. When the first atom is the same… Examine what is bonded to it. Start with first atom attached to chiral carbon. No decision!! Examine atoms bonded to first atom O vs O N vs C

18. Example: assigning Priorities Substituents Assign on the basis of the atomic number of the first atom in the substituent. Highest,1 Lowest, 4 If the atoms being compared are the same examine the sets bonded to the atoms being compared. 2 3 S configuration C has priority over H!!

19. More… If the first atom is the same and the second shell is the same then proceed to the atoms attached to the highest priority of the second shell. Examine the first atom, directly attached to the chiral atom. Examine the atoms bonded to the first atom (the second shell). N vs N C vs C H vs H Examine atoms bonded to highest priority of second shell, N Cl vs F Cl wins!

20. Unsaturation So far have not worried about double or triple bonds. Double and triple bonds are expanded as shown below. Expanded into becomes

21. Let’s investigate what happens if low priority is positioned closer to us than chiral carbon… Now let’s swap any two substituents. We know that this produces the enantiomer, R. Swap the H and the Cl. Arc going in wrong direction because the low priority substituent is closer to us than the chiral center!!!!!! We are looking at the molecule from the wrong side. INVERT NAMING if LOW PRIORITY IS CLOSER THAN CHIRAL CENTER: Clockwise is S Counterclockwise is R H towards the rear where it belongs…

22. Physical Properties of Enantiomers Enantiomers: different compounds but have same Melting Point Boiling Point Density Enantiomers rotate plane polarized light in opposite directions. OPTICALLY ACTIVE!! The enantiomers rotate plane polarized light the same amount but in opposite directions. One clockwise; the other counterclockwise.

23. How to know if a compound is optically (in)active. Symmetry elements. The symmetry of an object is described in terms of symmetry elements. The use of a symmetry element may only interchange identical atoms. Proper Rotation. Rotation about an axis. Think of a propeller. Inversion Point. An equidistant line through the center of the molecule. Reflection plane (mirror plane). Improper Rotation. Rotation followed by reflection in plane perpendicular to axis. If a molecule has a reflection plane, inversion point, or improper rotation axis: inactive The presence of any of these symmetry elements except for proper rotation rules out enantiomers.

24. Rotational Axis

25. Reflection Plane

26. Inversion Point

27. Improper Rotational Axis

28. Allene, let’s find the symmetry elements in it. Reflection Plane Proper Rotational Axis, 180 deg Two Proper Rotational Axes, 180 deg. We recognize this molecule as being achiral because of the reflection planes or because of the improper rotational axis. Usually they go together. Can you, however, design a molecule having an improper axis but not reflection planes. Improper Rotational Axis, 90 and 270 deg

29. Polarimeter Concentration: pure liquid in g/mL; solution in g per 100 mL of solvent before after

30. Optical Activity Optically Active compounds rotate plane polarized light. Chiral compounds (compounds not superimposable on their mirror objects) are expected to be optically active. Optically Inactive compounds do not rotate plane polarized light. Achiral compounds are optically inactive.

31. Problems… If the specific rotation of pure R 2- bromobutane is 48 degrees what is the specific rotation of the pure S enantiomer? The pure S enantiomer has a specific rotation of -48 degrees. Equal but opposite!!

32. Mixtures of Enantiomers These are high school mixture problems. If you know the specific rotation of the pure enantiomers and the composition of a mixture then the specific rotation of the mixture may be predicted. And conversely the specific rotation of the mixture may be used to calculate the composition of the mixture. Specific rotation of mixture = (fraction which is R)(specific rotation of R) + (fraction which is S)(specific rotation of S)

33. Example Mixture of 30% R and 70% S enantiomer. The pure R enantiomer has a specific rotation of -40 degrees. What is the specific rotation of the mixture? Contribution from R Contribution from S

34. Using the specific rotation to obtain the composition of the mixture. For the same two enantiomers ([  of R = -40), suppose the specific rotation of a mixture is 8. degrees what is the composition? Specific rotation of mixture = (fraction which is R)( specific rotation of R) + (fraction which is S)( specific rotation of S) 8. -40. 40. + (1. – fraction which is R) Fraction which is R = 40%; fraction which is S is 60%.

35. Racemic Mixtures, Racemates The racemic mixture (racemate) is a 50:50 mixture of the two enantiomers. The specific rotation is zero. The racemic mixture may have different physical properties (m.p., b.p., etc.) than the enantiomers.

36. Optical Purity, Enantiomeric Excess Consider a mixture which is 80% R (and 20% S). Assume the specific rotation of the pure R enantiomer is 50 degrees. R R R R R R R R S S As before Specific rotation of mix = 0.80 x 50. +.20 x (-50.) = 30. Now, recall that a racemic mixture is 50% R and 50% S. Mixture is 60% R and 40% racemic. Specific rotation of mix = 0.60 x 50. +.40 x (0.) = 30. The optical purity (or enantiomeric excess) is 60%.

37. Look from this point of view. Fischer Projection H,low priority substituent, is closer so CCW is R. Reposition to Standard Fischer projection orientation: vertical bonds recede horizontal bonds come forward Standard short notation: R and S designations may be assigned in Fischer Projection diagrams. Frequently there is an H horizontal making R CCW and S CW. Cl to Ethyl to Methyl

38. Manipulating Fischer Projections Even number of swaps yields same structure; odd number yields enantiomer. 1 swap or Etc. All of these represent the same structure, the enantiomer (different views)!! R S

39. Manipulating Fischer Projections Even number of swaps yields same structure; odd number yields enantiomer. 2 swaps or Etc. All of these represent the same structure, the original (different views)!! R R

40. Rotation of Entire Fischer Diagrams Rotate diagram by 180 deg Same Structure simply rotated: H & Br still forward; CH 3 & C 2 H 5 in back. Rotation by 90 (or 270) degrees. Enantiomers. Non superimposable structures! Not only has rotation taken place but reflection as well (back to front). For example, the H is now towards the rear and ethyl is brought forward. This simple rotation is an example of “proper rotation”. This combination of a simple rotation and reflection is called an “improper rotation”.

41. Multiple Chiral Centers S S R R Do a single swap on each chiral center to get the enantiomeric molecule. Each S configuration has changed to R. Now do a single swap on only one chiral center to get a diastereomeric molecule (stereoisomers but not mirror objects). R S S R

42. Multiple Chiral Centers S S R R R S S R Enantiomers

43. Multiple Chiral Centers S S R R R S S R Diastereomers

44. Everyday example: shaking hands. Right and Left hands are “mirror objects” R --- R is enantiomer of L --- L and have equivalent “fit” to each other. R --- L and L --- R are enantiomeric, have equivalent “fit”, but “fit” differently than R -- - R or L – L.

45. Diastereomers Require the presence of two or more chiral centers. Have different physical and chemical properties. May be separated by physical and chemical techniques.

46. Meso Compounds S S R R R S S R Must have same set of substituents on corresponding chiral carbons. As we had before here are the four structures produced by systematically varying the configuration at each chiral carbon.

47. Meso Compounds S S R R R S S R Mirror images! But superimposable via a 180 degree rotation. Same compound. Enantiomers Mirror images, not superimposable. Diastereomers. Meso What are the stereochemical relationships?

48. Meso Compounds: Characteristics R S Meso Can be superimposed on mirror object, optically inactive. R Has at least two chiral carbons. Corresponding carbons are of opposite configuration. S Can demonstrate mirror plane of symmetry Molecule is achiral. Optically inactive. Specific rotation is zero. Can be superimposed by 180 deg rotation.

49. Meso Compounds: Recognizing R S Meso R S What of this structure? It has chiral carbons. Is it optically active? Is it meso instead? Assign configurations. Looks meso. But no mirror plane. Rearrange by doing even number of swaps on upper carbon. Now have mirror plane. Original structure was meso compound. In checking to see if meso you must attempt to establish the plane of symmetry.

50. Cycloalkanes Based on these planar ring diagrams we observe reflection plane and expect optical inactivity…. But the actual molecule is not planar!! Examine cyclohexane. Look for reflection planes! This plane of symmetry (and two similar ones) are still present. Achiral. Optically inactive. The planar diagrams predicted correctly. There are other reflection planes as well. Do you see them? Horizontal reflection plane. Vertical reflection plane.

51. Substituted cyclohexanes cis The planar diagram predicts achiral and optically inactive. But again we know the structure is not planar. This is a chiral structure and would be expected to be optically active!! But recall the chair interconversion…. Earlier we showed that the two structures have the same energy. Rapid interconversion. 50:50 mixture. Racemic mixture. Optically Inactive. Planar structure predicted correctly Mirror objects!!

52. More… trans 1,2 dimethylcyclohexane No mirror planes. Predicted to be chiral, optically active. Ring Flips?????? Each structure is chiral. Not mirror images! Not the same! Present in different amounts. Optically active! Other isomers for you… 1,3 cis and trans, 1,4 cis and trans. R,R trans Enantiomer.

53. Resolution of mixture into separate enantiomers. Mixtures of enantiomers are difficult to separate because the enantiomers have the same boiling point, etc. The technique is to convert the pair of enantiomers into a pair of diastereomers and to utilize the different physical characteristics of diastereomers. Formation of diastereomeric salts. Racemic mixture of anions allowed to form salts with pure cation enantiomer. Racemic mixture reacted with chiral enzyme. One enantiomer is selectively reacted. Racemic mixture is put through column packed with chiral material. One enantiomer passes through more quickly.

55. Chirality in the Biological World –A schematic diagram of an enzyme surface capable of binding with (R)-glyceraldehyde but not with (S)-glyceraldehyde. All three substituents match up with sites on the enzyme. If two are matched up then the third will fai!