Chapter 5 Isomers Constitutional Isomers Stereoisomers Cis/Trans R/S Enantiomers Diastereomers Chiral Achiral Stereocenter Meso Mirror image Superimposable/Nonsuperimposable Racemic/Racemate Stereocenter Plane of symmetry Configuration Enantioselective Enzymes/Hydrolysis/Lipase

1

Stereochemistry Chirality/Chiral/Enantiomers/Diastereomers/ Achiral Constitutional vs. Stereoisomers Biological chiralitylimonene, carvone, thalomid Stereogenic center vs chirality Historyvant Hoff, Le Belthe tetrahedral; PasteurStereochemistry Meso compoundsplane of symmetry 1 stereocenter can only be a pair of enantiomers 2 or more stereocenters is needed for diastereomers 2 stereoisomers that are mirror images of each other and nonsuperposableenantiomers 2 molecules that are mirror images of each other and superposablesame molecule 2 stereoisomers that are not mirror images of each otherdiastereomers

H

BrOH

H

BrHO

Br OH HO Br

mirror mirror

enantiomers same molecule

OH

Br H

Cl

Br H

HO Cl

not mirror images, diastereomers

1

2

3

R1

2

3S

1 2

3

S

1

2 3

R 1

23

S

12

3

S

OH OH

Constitutional isomers b/c OH is on different carbons in each molecule.Different Connectivity.

OH OH1

2 3

1

2 3

S R

Stereoisomers b/c all the connectivity is the same, it is just orientation that isdifferent. Specifically, these are enantiomers.

2

R/S nomenclatureCahn, Ingold, Prelog All 4 atoms attached to a stereocenter are assigned a priority from 1-4(a-d) based

on atomic number. The highest priority(largest atomic number) is assigned 1(a) the lowest priority is assigned 4(d).

If 2 isotopes of the same element are attached the heavier isotope gets the higher priority. If 2 identical elements are on same stereocenter then you go to the next carbon for each. You keep going out one carbon till you get to a difference. Priority is then determined based on size of different groups. Double bonds count twice. Triple bonds count three times.

Now rotate the lowest priority away from you. Follow 1 to 2 to 3(a to b to c). If

you go in a clockwise manner to go from 1 to 2 to 3(a to b to c), then the enatiomer is R(rectus). If you go counterclockwise then the enantiomer is S(sinister).

Br

OHH

OH

BrH

H BrOH

Br

HOH

Br

HO HHBr

HO

1

2

3

1

2

31

2

3

1

23

R S S R

1

2 3

R

1

2

3S

A B C D E F

Br Br

Br OCH3 HO Br

Br Br

Cl HO H3CO H

H Br H H3CO

OCH3 H Cl OH

OH Cl Br Cl

1

2

31

2

3

1

2

3

1

2 3RS

RS

1

2 3

S 1

23

R

12

3R 1

23

S

e

e

d d

d

d

3

Label the stereocenters R or S in the following

Br

HO

H HHClH

H

FBr

Cl

HOBr

CH3

Br HOH

Br

F H

Br

Br Cl

HCl

OH

OH

Br

Cl

Et

Br

HO

OCH3

OH

H

OH

F

OH

H BrCl Cl

Br

HO CCl3

HS

CH3

4

KEY

O H

H B rC l Cl

B r

HO C Cl3

H S

C H 3

1

2

3

S

1

2

3

R

1 2

3

R

C l

H O B r

C H 3

B r HO H

B r

F H

B r

B r C l

HC l

O H

O H

B r

C l

E t

B r

H O

O CH 3

O H

H

O H

F

1

2

34

1

2

3

4

1

2 3

4

14

32

1 2

3 4

1

23

1

2 3

1

23

1

23

12

3

1

2 3

1

2 3

1

2 3

1

2 3

SR

R

R

R

R

R

R

S

S

S

S S

S

B r

HO

H HHC lH

H

FB r

1

23

1

2 3

1

2 31

2

3

23

1

1 2

3

12

3R

R

S

R

S

S

S

5

Properties of enantiomers R/S have the same physical properties(bp/mp/solubility/IR/rate of reaction) because they share the same environment. Most of the physical properties are based on environment(intermolecular forces).

The have different properties with other chiral environments such as plane-polarized light. Enantiomers rotate plane polarized light in the opposite direction but by the same amount.

Single enantiomers are considered to be optically active. R/S mixtures are racemic.

Polarimeterlight is first passed through a polarizer which allows only one band of light through. Then the light passes through the chiral environment of the enantiomer. Finally the light lands on the detector. By where it lands on the 360 degree detector the amount of deflection is calculated.

If the light is rotated clockwise, the value will be (+). This is called Dextrorotatory (dexterright).

If the light is rotated counterclockwise, the value will be (-). This is called Levorotatory (laevusleft).

The degree of rotation is given the term specific rotation, a.

[a]25D D refers to the light source. D = D line of Na(589.6 nm)

R/S has no relation to (+/-). R can be (+) in some molecules and (-) in others. Racemic mixtures give 0o reading. The R and S forms cancel each other out. Pure R will give one reading(+30 for ex.). Pure S will give opposite reading(-30). Mixtures of R/S will give readings from +30 to 30 depending on concentrations of R and S.

100% R give +30. 50% R/50% S gives 0. 100% S gives 30.

Racemic mixtures(50/50) can be referred to as R/S 2-butanol or (+/-) 2-butanol.

In most journals, scientific, medical and pharmaceutical, the %ee(enantiomeric excess) is a vital statistic when referring to a reaction. You will see entries such asThe reaction was carried out under typical conditions to give a 78 % yield an enantiomeric excess of 98%.

6

% ee = [(moles of excess enantiomer moles of other enantiomer)/total moles] x 100.

OR %ee = (observed specific rotation/specific rotation of pure enantiomer) x 100 Enantiomeric excessif ee = 50 % that means 50% is racemic and the other 50% is pure enatiomer(50 + of 50 = 75). Therefore 50 % ee means 75% of one enatiomer and 25 % of the other enantiomer. A. Given the ee If a molecule is in the R form at 90%ee, what is the % of R and S? 90%ee means 90% pure R and 10%(100-90) a mixture of R and S; therefore it is 95% R(90% + of 10%) and 5% S ( of 10%)

82%ee S means 91% S(82 + of 18) and 9% R( of 18).

71%ee R means 85.5% R(71 + of 29) and 14.5 S( of 29) B. Given the % If a molecule is 20% R and 80% S, what is the ee? ee = 80 20 = 60 % ee If a molecule is 43% R and 57% S, what is the ee? ee = 57 43 = 14 % ee C. Given the optical rotation. If the specific rotation of a molecule with R designation is + 45 and a mixture of R/S of that molecule gives an observed rotation of + 25, what is the % R, % S and the ee? ee = observed/specific x 100; ee = 25/45 x 100 = 56% ee; since it is 56% ee, that means 56% R, and 44% R/S mixture; therefore, R = 78%(56 + of 44) and S = 22%( of 44) If the specific rotation of a molecule with R designation is + 45 and a mixture of R/S of that molecule gives an observed rotation of - 25, what is the % R, % S and the ee? ee = observed/specific x 100; ee = 25/45 x 100 = 56% ee; since it is 56% ee, that means 56% S, and 44% R/S mixture; therefore, S = 78%(56 + of 44) and R = 22%( of 44) Since the observed rotation is the opposite sign of the specific rotation that means that the major isomer is the opposite of the specific rotation isomer. IE since +45 = R, then 25 is predominately S.

7

Most reactions yield a racemic form of the final product. If a reaction yields one enantiomer in excess of the other the reactions is called enantioselective. These are highly desirable. In biochemistry, you will study many enantioselective reactions driven by enzymes. Chiral Drugsmany drugs are chiral. In their chirality it is often one of the 2 enantiomers

that does all the work, while the other is inert or even toxic.

Ibuprofen, Methyldopa, Penicillamine, FDA, pharmaceuticals, Glaxo Prilosec/Nexium Diastereomerschiral molecules with more than one stereocenter. 2N = number of stereoisomers possible(where N = # of stereocenters).

A molecule with 2 stereocenters(22 = 4) would have 4 possible stereoisomers(A, B, C and D). A and B are enantiomers of each other. C and D are enantiomers of each other(because they are mirror images). A and C, A and D, B and C, B and D are diastereomers of each other because they are not mirror images. Diastereomers have different physical properties from each other. I.E. A and B melt at same temperature. C and D melt at same temperature. But the A/B temperature is different from the C/D temperature. Many times the true amount of stereoisomers is less than the maximum. This is due to meso compounds(which are achiral). Meso comopunds have a plane of symmetry which destroys chirality. If A had a plane of symmetry it would be meso. Therefore B would be meso and actually A and B would be the same thing. Therefore C and D would be enantiomers of each other and they would both be diastereomers of A/B, where A/B is the same.

OH

CH 3

H

CH 3

OHH

CH 3

H O H

CH 3

H O H

CH 3

H OH

CH 3

H O H

CH 3

H O H

CH 3

H OH

A B C D Fischer projections are often used to look for meso. Fischers are also often used in carbohydrate chemistry. In Fischer projections the compound can be rotated in the plane of the paper but it can NOT be flipped. Nomenclature of diastereomers is the same as for enantiomers. Each stereocenter is given a R/S designation.

8

Cyclic compounds Cyclopentane(the 2 substituents must be the same) 1,2 disubstituted cis is meso trans is a pair of enantiomers cis and trans are diastereomers 1,3 disubstituted cis is meso trans is a pair of enantiomers cis and trans are diastereomers If the substituents are different then 1,2 cis and 1,3 cis are pairs of enantiomers instead of the same. 1,2 trans and 1,3 trans are still pairs of enantiomers and still diastereomers of the cis.

enantiomers

no plane of symmetry

cistrans

Br Cl Br ClCl ClBr Br

enantiomers

diastereomers

no plane of symmetry

Planes of symmetry

same

enantiomers

no plane of symmetry

cistransdiastereomers

diastereomers

H3C

H3C

H3C

H3C

Planes of symmetry

sameenantiomers

no plane of symmetry

cis trans

9

Cyclohexane(the 2 substituents must be the same)

1,2 disubstituted cis is a pair of rapidly intraconverting enantiomers(mimics meso) they are considered conformational isomers trans if a pair of enantiomers cis and trans are diastereomers of each other 1,3 disubstituted cis is meso trans if a pair of enantiomers cis and trans are diastereomers of each other

1,4 disubstituted cis is meso trans is meso cis and trans are diastereomers of each other

all have planes of symmetry

cis ciscis cis cis

trans

If the substituents are different then 1,2 cis, 1,3 cis, 1,4 cis and 1,4 trans are pairs of enantiomers instead of the same. 1,2 trans and 1,3 trans are still pairs of enantiomers and still diastereomers of the cis.

10

Chemical Reactions

One of the goals of organic chemist is to create enantioselective reactions so that pure chemicals can be obtained. One way to do this is to create a pure isomer and then keep it unchanged. Retention of Configurationif a chemical reactions proceeds without breaking the bonds of the stereocenter it is said to have retention of configuration When a reaction proceed through retention of configuration, the R/S designation and the optical rotation may stay the same or it may change. Inversion of Configurationif a reaction proceeds through the stereocenter it can quite often invert the stereochemistry of the stereocenter. Racemizationmost often if a reaction proceeds through the stereocenter it will racemize the mixture

Absolute/Relative Configurations Absolutethe stereochemistry is known for all stereocenters.

Relativethe stereochemistry of all stereocenters is relative to the original stereocenter which is unknown.

See the glyceraldehyde example Resolution Pasteurby crystallization of diastereomers 1848separation of (+/-) tartaric acid. Led to the field of stereochemistry. Modernby separation of diastereomers based on different physical properties which

could include mp, crystallization, solubility. Chromatography is most often used(HPLC). Enzymes are very useful also.

Stereocenters other than carbon 4-bonded atoms such as Si, Ge, N and S can be stereocenters. Chiral molecules that dont have stereocenters Allene b/c of out of plane double bonds has chirality(build a model).

11

A. Given the ee If a molecule is in the R form at 90%ee, what is the % of R and S?

90%ee means 90% pure R and 10%(100-90) a mixture of R and S;

therefore it is 95% R(90% + of 10%) and 5% S ( of 10%) Other examples:

82%ee S means 91% S(82 + of 18) and 9% R( of 18).

71%ee R means 85.5% R(71 + of 29) and 14.5 S( of 29)

B. Given the % If a molecule is 20% R and 80% S, what is the ee? ee = 80 20 = 60 % ee If a molecule is 43% R and 57% S, what is the ee? ee = 57 43 = 14 % ee

C. Given the optical rotation. If the specific rotation of a molecule with R designation is + 45 and a mixture of R/S of that molecule gives an observed rotation of + 25, what is the % R, % S and the ee?

ee = observed/specific x 100; ee = 25/45 x 100 = 56% ee; since it is 56% ee, that means 56% R, and 44% R/S mixture; therefore, R = 78%(56 + of 44) and S = 22%( of 44)

If the specific rotation of a molecule with R designation is + 45 and a mixture of R/S of that molecule gives an observed rotation of - 25, what is the % R, % S and the ee?

ee = observed/specific x 100; ee = 25/45 x 100 = 56% ee; since it is 56% ee, that means 56% S, and 44% R/S mixture; therefore, S = 78%(56 + of 44) and R = 22%( of 44)

Since the observed rotation is the opposite sign of the specific rotation that means that the major isomer is the opposite of the specific rotation isomer. IE since +45 = R, then 25 is predominately S.

12

1. What is the % R and S of the following? 88 %ee R 25 % ee S 42 % ee R 91 % ee R 68 % ee S 2. What is the % ee for the following? 90 % R 10 % S 40 % R 60 % S 70 % R 30 % S 85 % R 15 % S 74 % R 26 % S 3. If the observed rotation is +35 and the pure R rotates at +43, what is the % ee, % R and % S? 4. If the % ee = 50%R and pure S rotates at 20, what is the observed rotation? 5. (2S, 3R, 4R, 5S)-2,3,4,5-tetrachlorononane is made in the lab using stereospecific reactions. What is the stereochemistry of the enantiomer of that molecule? What is the stereochemistry of one of the diastereomers? How many possible stereoisomers are there for this molecule? 6. Four stereoisomers of dibromopentane are isolated. RR RS SR SS RR has the same bp as SS has the same solubility as RS has a different bp from 7. In the following pairs, label them as the same molecule, enantiomers or diastereomers.

H 3C H 2 C C H 3

HB r

H 3 C C H 2 C H 3

HB r

H O

H

C H 2O H C H 2 O H

H O

H

d . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

f . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

( 2 R ,3 R ) - 2 ,3 - d ic h lo r o p e n t a n e a n d

( 2 S ,3 R ) - 2 ,3 - d ic h l o r o p e n ta n ee . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

a . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

H

H 3C B rO H

H O C H 3

HB r

b . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

H

H O C l

B r

C l

H

H 3C B r

H O

H

c . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

13

1. What is the % R and S of the following? 88 %ee Rthis means 88% R and 12%(R/S mix) therefore 88% R and (6% R/6%S) or 94% R and 6% S 25 % ee Sthis means 25% S and 75%(R/S mix) therefore 25% S and (37.5% R/37.5%S) or 62.5% S and 37.5% R 42 % ee Rthis means 42% R and 58%(R/S mix) therefore 42% R and (29% R/29%S) or 71% R and 29% S 91 % ee Rthis means 91% R and 9%(R/S mix) therefore 91% R and (4.5% R/4.5%S) or 95.5% R and 4.5% S 68 % ee Sthis means 68% S and 32%(R/S mix) therefore 68% S and (16% R/16%S) or 84% R and 16% S 2. What is the % ee for the following?

90 % R 10 % S90-10 = 80% ee R 40 % R 60 % S60-40 = 20% ee S

70 % R 3 % S70-30 = 40% ee R 85 % R 15 % S85-15 = 70% ee R

74 % R 26 % S74-26 = 48% ee R 3. If the observed rotation is +35 and the pure R rotates at +43, what is the % ee, % R and % S? % ee = obs/sp x 100 = 35/43 x 100 = 81% ee R 81 % ee Rthis means 81% R and 19%(R/S mix) therefore 81% R and (9.5% R/9.5%S) or

90.5% R and 9.5% S 4. If the % ee = 50%R and pure S rotates at 20, what is the observed rotation? Pure S = -20 then R = +20 % ee = obs/sp x 100; 50 = x/+20 x 100; 50 = 100x/20; (50)(20) = 100 x; 1000 = 100 x; x = 10, therefore the observed rotation is +10 5. (2S, 3R, 4R, 5S)-2,3,4,5-tetrachlorononane is made in the lab using stereospecific reactions. What is the stereochemistry of the enantiomer of that molecule? What is the stereochemistry of one of the diastereomers? How many possible stereoisomers are there for this molecule? Enantiomer 2R, 3S, 4S, 5R Possible isomers 2N = 24 = 16 Diastereomer 2R, 3R, 4R, 5S 2S, 3S, 4R, 5S 2S, 3R, 4S, 5S 2S, 3R, 4R, 5R 2S, 3S, 4S, 5R 2R, 3R, 4S, 5R 2R, 3S, 4R, 5R 2R, 3S, 4S, 5S 2R, 3S, 4R, 5S 2R, 3R, 4S, 5S 2R, 3R, 4R, 5R 2S, 3R, 4S, 5R 2S, 3S, 4R, 5R 2S, 3S, 4S, 5S

14

6. Four stereoisomers of dibromopentane are isolated. Fill in the blanks using the 4 isomers below. RR RS SR SS RR has the same bp as SS SS has the same solubility as RR RS has a different bp from SR 7. In the following pairs, label them as the same molecule, enantiomers or diastereomers.

H 3CH 2C CH3

HBr

H3C CH 2CH 3

HBr

HO

H

CH2OH CH2OH

HO

H

d. EN AN TIO M ERS

f. ENA NTIO M ERS

(2R ,3R )-2,3-dichloropentane a nd

(2S,3R )-2,3-dichloropentanee. DIASTER EOM ER S

a. ENA NTIO M ERS

H

H 3C BrOH

HO CH3

HBr

b. SAM E

H

HO Cl

Br

Cl

H

H 3C Br

HO

H

c. D IA STER EO M ERS

1,2 trans 1,2 tra ns

1

23

R1

2

3

R

1

23R

S

12

3 S

1

2

3S

1

2

3

1

2 3

R1

23

S

1

2

3

R

12

3

S

15

d. ____________________

f. ____________________

e. ____________________

a. ___________________

b. ___________________

c. ___________________

ClBr

BrCl

C2H5C2H5

Br H3C H3C HH OH OH Br

H

CH3HO

Br

Br

HHOH3C

g. ____________________

2R, 3R, 4S 2S, 3S, 4S

2R, 3R, 4S, 5R, 6S 2S, 3S, 4R, 5S, 6R

16

d. Diastereomers

f. Diastereomers

e. SAME

a. Diastereomers

b. Same

c. EnantiomersCl

Br

BrCl

C2H5C2H5

Br H3C H3C HH OH OH Br

H

CH3HO

Br

Br

HHOH3C

g. Enantiomers

2R, 3R, 4S 2S, 3S, 4S

2R, 3R, 4S, 5R, 6S 2S, 3S, 4R, 5S, 6R

1

2 32

1

3

17

HBr I

Br H

Br H3C

Cl

I I

H

Br

Br Cl

F ClF I

H

Cl Cl

H

Cl Cl

Cl

BrH

H Br

F F

HH Br

(2R, 3R, 4S, 5R) (2S, 3S, 4R, 5S)

18

HBr I

Br H

Br H3C

Cl

I I

H

Br

Br Cl

F ClF I

H

Cl Cl

H

Cl Cl

Cl

BrH

H Br

F F

HH Br

(2R, 3R, 4S, 5R) (2S, 3S, 4R, 5S)

SAME

ENANTIOMERS

SAME

DIASTEREOMERS

ENANTIOMERS

ENANTIOMERS

DIFFERENT CMPDS

DIASTEREOMERS

19

OH OH

Br HOH CH2CH3

Br

H3C H3CH OH

O H OH

E N AN T IOM ER S

D IA ST E R E OM E R S

Br HOH CH2CH3

Br

H3C H3CH OH

SAME MOLECULE

SAME MOLECULE

DIASTEREOMERS

20

Homework, Chapter 5 Name:

Label the priority of the four groups connected to the stereocenter and then determine if the stereochemistry is R or S.

Cl

Br

HO

F

Br

SCH3

OH

Cl HBr

H

H3CO SH

Br

Cl

OH

O

H

Br

21

Homework, Chapter 5 KEY

Label the priority of the four groups connected to the stereocenter and then determine if the stereochemistry is R or S.

Cl

OH

H

Br Cl

Br

HO

F

H

H3CO SH

Br

O

Cl

Br

H

Br

OHH3CS

2,3,3-trimethylpentane

12

3

4

S

R

S

R

S S

S

R

S

1

2

3

4

1

2

3

2

1

3

4

4

1 2

3

1

2

3

1

2

3

1

2

3

A

B C

22

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