Special Topics in Chemistry University of Illinois at...

University of Illinois at ChicagoUICCHEM 494

Special Topics in Chemistry

Lecture 10Stereochemistry

Duncan Wardrop

November 26, 2012

Tuesday, November 27, 12

UICUniversity of Illinois at Chicago CHEM 494, Spring 2010 Slide

Lecture 10: November 26

Historical Importance of Stereochemisty

2

Once a molecule is asymmetric, its extension proceeds also in an asymmetrical sense. This concept completely eliminates the difference between natural and artificial synthesis. The advance of science has removed the last chemical hiding place for the once so highly esteemed vis vitalis.

Emil Fischer, 1894


UICUniversity of Illinois at Chicago CHEM 494, Fall 2012 Slide


A

B

C

D

Which pair of molecules below are not stereoisomers?

Self Test Question

3

H

O

H

O

CH3Br BrCH3

O

H

O

H

F

ClBrH

F

Cl BrH




A

B

C

D


Self Test Question

3

H

O

H

O

CH3Br BrCH3

O

H

O

H

F

ClBrH

F

Cl BrH

Stereoisomers:1. same connectivity2. different arrangement

of atoms in space




A

B

C

D


Self Test Question

3

H

O

H

O

CH3Br BrCH3

O

H

O

H

F

ClBrH

F

Cl BrH

geometrical stereoisomers


of atoms in space




A

B

C

D


Self Test Question

3

H

O

H

O

CH3Br BrCH3

O

H

O

H

F

ClBrH

F

Cl BrH


conformationalstereoisomers


of atoms in space




A

B

C

D


Self Test Question

3

H

O

H

O

CH3Br BrCH3

O

H

O

H

F

ClBrH

F

Cl BrH



enantiomericstereoisomers


of atoms in space




A

B

C

D


Self Test Question

3

H

O

H

O

CH3Br BrCH3

O

H

O

H

F

ClBrH

F

Cl BrH



enantiomericstereoisomers

identicalmolecules


of atoms in space




A

B

C

D

Which structure cannot be moved in space (translation) or undergo rotation around single bonds to obtain a mirror image of the molecule (1) below?

Self Test Question

4

CH3

ClHO

CH3ClHO

Cl

H3CHO

CH3

OHCl

OH

CH3Cl

1




A

B

C

D


Self Test Question

4

CH3

ClHO

CH3

ClOH

mirror image

CH3ClHO

Cl

H3CHO

CH3

OHCl

OH

CH3Cl

1 2




A

B

C

D


Self Test Question

4

CH3

ClHO

CH3

ClOH

mirror image

CH3ClHO

Cl

H3CHO

CH3

OHCl

OH

CH3Cl

1 2

CH3

ClOH 90 º




A

B

C

D


Self Test Question

4

CH3

ClHO

CH3

ClOH

mirror image

CH3ClHO

Cl

H3CHO

CH3

OHCl

OH

CH3Cl

1 2

CH3

ClOH 90 º

180 º60º

CH3

ClOH




A

B

C

D


Self Test Question

4

CH3

ClHO

CH3

ClOH

mirror image

CH3ClHO

Cl

H3CHO

CH3

OHCl

OH

CH3Cl

1 2

CH3

ClOH 90 º

180 º60º

CH3

ClOH

60ºCH3

ClOH




A

B

C

D


Self Test Question

4

CH3

ClHO

CH3

ClOH

mirror image

CH3ClHO

Cl

H3CHO

CH3

OHCl

OH

CH3Cl

1 2

CH3

ClOH 90 º

180 º60º

CH3

ClOH

60ºCH3

ClOH

identical to 1




Chirality

5

CH3

ClHO

CH3

ClOH

mirror image1 2

A molecule is chiral if its two mirror image forms are not superimposable on one another

Superimposable molecules can be laid on top of one another so that all equivalent atoms (points) line up

180 º

2

CH3

HOCl




Chiral Objects

6

chiral: non-superimposable mirror images

snail

mirrorimage




Chiral Objects

7

milkyway mirror image

chiral: non-superimposible mirror images




Chirality

8


fingerprint mirror image




Chirality

9


DNA double helix mirror image




Chirality

10

chiral: non-superimposable mirror imagescheir (Greek) = hand

chirality is synonymous with “handedness”




Molecules can Also Be Chiral

11


HBrCl

FH

BrCl

F




Superimposibility

12

HBrCl

FH

BrCl

F

180º

to check for superimposibility, rotate mirror image 180º along a plane perpendicular to the mirror plane




Non-superimposible

13


HBrCl

FH

ClBr

F

if the images are not identical, they are non superimposible; not all points (atoms) line up




Not Everything is Chiral!

14

achiral: not chiral; mirror images are superimposible

basketball mirror image





15






16





Symmetry Tests for Achiral Molecules

17

Any molecule with a plane of symmetry or a center of symmetry is achiral (not chiral)

A plane of symmetry bisects a molecule into two mirror image halves





18



H3C CH3plane of symmetry





19



Cl

Br plane of symmetry•

•





20



plane of symmetry

C C ClBrH H





21


center of symmetry: a line drawn from center of molecule to an element extends in opposite direction to an identical element





22


center of symmetry: a line drawn from center of molecule to an element extends in opposite direction to an identical element




A

B

C

D

Which molecule below is chiral?

Self Test Question

23

CH3H3C

Cl

Cl

H3C CH3

Br Cl

HO H

Cl

CH2

CH3




Chirality Center

24

Chirality center: an atom bonded to ligands in a spatial arrangement which is not superimposable on its mirror image

CW

ZY X

other terminologycommonly used:

• stereocenter• stereogenic center

avoid these terms; both have different meanings from chirality center

Asymmetric carbon: a carbon atom bonded to four different atoms or groups (a type of chirality center)




Chirality Center

25

A molecule with a single chirality center is chiral

CBr

ClF H bromochlorofluoromethane is chiral




Chirality Center

26


• 2-butanol is chiral• although two carbon atoms are

bonded to the chirality center, they are part of different groups

OHCH

H3C CH2CH3




Chirality Center

27


H2C CO H

CH3 • 1,2-epoxypropane: a chirality center can be part of a ring

• attached to the chirality center are:-H-CH3

-CH2O-OCH2




Chirality Center

28


CH

TD CH3

chiral as a result of isotopic substitution




1 Chirality Center = Chiral

29

A molecule with a single chirality center must be chiral.But a molecule with two or more chirality centers may be

chiral or it may not be chiral (Sections 7.10-7.13)

CBr

ClF H

OHCH

H3C CH2CH3H2C CO H

CH3

CH3

ClOH C

H

TD CH3




A. 7

B. 6

C. 5

D. 4

E. 3

How many chirality centers in a molecule of codeine?

Self Test Question

30

OH3CO

NCH3

HOH


University of Illinois at ChicagoUICCHEM 494

Special Topics in Chemistry

Cahn–Ingold–Prelog (CIP)Priority Rules

R-S Notation forChirality Centers




CIP R/S Notation

32

Step One: Locate chirality center

chirality center CH3

C

ClHO H




CIP R/S Notation

33

Step Two: Orient molecule so that lowest ranked (CIP priority) atom or group points away from you

CH3

C

ClHO H

CH3

CClHO

Hchirality center




CIP R/S Notation

34

Step Three: Number 3 highest priority groups in order of increasing priority (CIP sequence rules)

CH3

C

ClHO H

CH3

CClHO

Hchirality center

12

3




CIP R/S Notation

35

Step Four: Determine rotation direction of groups in decreasing priority

CH3

C

ClHO H

CH3

CClHO

Hchirality center

12

3

clockwise (rectus) = Rcounterclockwise (sinister) = S(R)-1-chloroethanol




A

B

C

D

Which molecule has a chirality center with an absolute con!guration of R?

Self Test Question

36

F HBr

Cl

HO H

OHH

CH3

OHO

H CH3




A

B

C

D


Self Test Question

36

F HBr

Cl

HO H

OHH

CH3

OHO

H CH3

1

2 3




A

B

C

D


Self Test Question

36

F HBr

Cl

HO H

OHH

CH3

OHO

H CH3

1

2 3clockwise = R




Enantiomers

37

molecules which are non-superimposible mirror images are called enantiomers;

enantiomer describes a relationship between two molecules (enantiomer: opposite handedness)

(S)-2-butanol (R)-2-butanol

enantiomers have opposite configurations (R/S) at every chirality center

OH OHenantiomers OH180 º




Enantiomers

38

molecules which are non-superimposible mirror images are called enantiomers;

enantiomer describes a relationship between two molecules (enantiomer: opposite handedness)

(S)-2-chloro-2-butanol (R)-2-chloro-2-butanol

enantiomers have opposite configurations (R/S) at every chirality center




Isomers

39

stereoisomers

Can the molecules be interconverted by rotation

around single bonds?

noyes

conformational configurational

isomers

Do the molecules have the same connectivity?

no yesconstitutional(structural)




Stereoisomers

40

configurational stereoisomers

Is the isomerism at a doulbe bond?

yes

geometrical optical

no

enantiomers diastereomers

Are the compounds non-superimposible mirror

images?

yesno




A

B

C

D

Which pair of molecules are enantiomers?

Self Test Question

41

H HCl Br

HHClBr

HO H H OH

HO H

OH

H H

CH3OH

OHCH3




A

B

C

D

Which pair of molecules are enantiomers?

Self Test Question

41

H HCl Br

HHClBr

HO H H OH

HO H

OH

H H

CH3OH

OHCH3

Remember: if a molecule has a plane or center of symmetry, it is not chiral

and therefore has no enantiomers.




A

B

C

D

E

Which molecule is (R)-1-hexen-3-ol?

Self Test Question

42

OH

OH

HO H

OHH

HHO




A

B

C

D

E


Self Test Question

42

OH

OH

HO H

OHH

HHO

1

23




A

B

C

D

E


Self Test Question

42

OH

OH

HO H

OHH

HHO

1

23

clockwise = R




A. R,R,S

B. S,S,R

C. R,S,R

D. S,R,S

E. S,R,R

The three asymmetric carbon atoms in penicillin G are labeled a-c. List the R/S con!guration of each in order of a,b,c.

Self Test Question

43

a b

c

NO

HN

O

S

OOH

H





Self Test Question

44

N(CCH)

C(OON)

S(SC)

a

NO

HN

O

S

OOH

H

A. R,R,S

B. S,S,R

C. R,S,R

D. S,R,S

E. S,R,R





Self Test Question

45

b

NO

HN

O

S

OOH

H

A. R,R,S

B. S,S,R

C. R,S,R

D. S,R,S

E. S,R,R





Self Test Question

46

C(SCC)

C(OOO)c

NO

HN

O

S

OOH

H

A. R,R,S

B. S,S,R

C. R,S,R

D. S,R,S

E. S,R,R





Self Test Question

47

a b

c

NO

HN

O

S

OOH

H

A. R,R,S

B. S,S,R

C. R,S,R

D. S,R,S

E. S,R,R




List the R/S con!guration of each asymmetric carbon in the enantiomer of penicillin G in the order a,b,c.

Self Test Question

48

A. R,R,S

B. S,S,R

C. R,S,R

D. S,R,S

E. S,R,R

ab

c

ab

c

(R)

(R)

(S)N

O

HN

O

S

OOH

H NO

HN

O

S

OHO

H

penicillin G enantiomer of penicillin G




List the R/S con!guration of each asymmetric carbon in the enantiomer of penicillin G in the order a,b,c.

Self Test Question

48

A. R,R,S

B. S,S,R

C. R,S,R

D. S,R,S

E. S,R,R

ab

c

ab

c

(R)

(R)

(S)

Remember: enantiomers have opposite configurations at every chirality center.

NO

HN

O

S

OOH

H NO

HN

O

S

OHO

H

penicillin G enantiomer of penicillin G




Steps:

Conventions/Rules:

(2S,3R)-3-chloro-2-hexanol or (2S,3R)-3-chlorohexan-2-ol

• R & S are italicized when typed• a comma separates each steredescriptor (no spaces)• stereodescriptors are not considered when alphabetizing subgroups• asymmetric locants are not written if their exclusion is unambiguous

1. Number longest chain so that highest priority group has lowest locant.2. List locants of asymmetric carbons in increasing order within parentheses at the beginning of name.3. List stereodescriptor (R/S) after each asymmetric locant.

parentchirallocant

Stereoisomers with >1 Chirality Center

49

HO H

Cl H12345

R/S , chirallocant R/S( ) class suffix-




Drawing Fisher Projections

50

Step One: Draw (imagine) totally eclipsed conformation

HOBr

H

H

HH

HO H

H Br HBr

H OH Br H

OHH

bond-line Newman Projection Sawhorse Projection

CH3HO HBr H

Fisher Projection





51

Step Two: Imagine that the carbon skeleton atoms form a “C” and you are looking at the back of the C.

HOBr

H

H

HH

HO H

H Br HBr

H OH Br H

OHH


CH3HO HBr H

Fisher Projection

HO H

Br H

H H





52

Step Three: Flatten out the “C” so vertical bonds point away from you and horizontal toward you.

HO HCH3

Br HH H

CH3

HOBr

H

H

HH

HO H

H Br HBr

H OH Br H

OHH


CH3HO HBr H

Fisher Projection

HO H

Br H

H H




Which Fisher project is (2R,3R)-2,3-pentandiol?

Self Test Question

53

H OHCH3

H OHH H

CH3

HO HCH3

H OHH H

CH3

HO HCH3

HO HH H

CH3

H OHCH3

HO HH H

CH3

A

B

C

D




Which Fisher project is (2R,3R)-2,3-pentandiol?

Self Test Question

53

HO H

HO H

HOH

H

OH

HH

HO H

HOH

HH

H OHCH3

H OHH H

CH3

HO HCH3

H OHH H

CH3

HO HCH3

HO HH H

CH3

H OHCH3

HO HH H

CH3

A

B

C

D




Properties of Enantiomers

54

CH3O

H

(R)-(-)-carvone

(S)-(+)-carvone

CH3O

H

boiling point = 231 ºCdensity = 0.961H-NMR δs = same as (S)13C-NMR δs = same as (S)IR spectrum ῡs = same as (S)optical rotation = –61ºsmell = earthy

boiling point = 231 ºCdensity = 0.961H-NMR δs = same as (R)13C-NMR δs = same as (R)IR spectrum ῡs = same as (R)optical rotation = +61ºsmell = spearmint




Properties of Enantiomers

55

(S)-(+)-Carvone

(R)-(-)-Carvone

(S)-carvone is the enantiomer of (R)-carvone

Enantiomers have the same physical properities including IR vibrational

frequencies, mp, bp, Rf, etc.

IR spectra for both enantiomers of carvone--

and for any two enantiomeric

compounds--are identical.




Optical Rotation

56

enantiomers rotate plane polarized light an equal magnitude, but in opposite directions

(–) = counterclockwise = levorotary(+) = clockwise = dextrorotary




Optical Rotation

57

• degree of optical rotation depends on concentration of a solution containing the chiral compound

• [α]: specific optical rotation; determined in specified concenetration and path length units for universal comparison

[α] =(c)(l)

(100)(α)25D

α = degree of rotation determined by polarimeterc = concentration (g/dL); 10 dL = 1 L

l = path length (cm)




Optical Rotation

58

• racemic mixture = contains equal quantities of both enantiomers (1:1, 50/50, etc); [α] = 0º

• enantiomeric excess (ee) = |% A enantiomer - % B enantiomer|

% A enantiomer % B enantiomerenantiomeric excess (ee)

100 0 100

75 25 50

50 50 0

25 75 50

0 100 100




Optical Rotation

58

• racemic mixture = contains equal quantities of both enantiomers (1:1, 50/50, etc); [α] = 0º

• enantiomeric excess (ee) = |% A enantiomer - % B enantiomer|

% A enantiomer % B enantiomerenantiomeric excess (ee)

100 0 100

75 25 50

50 50 0

25 75 50

0 100 100

race

mic

mix

ture




R/S versus (+)/(-)

59

• Enantiomers have equal magnitudes, but opposite signs of specific rotation

• Caution: the sign of rotation (+/-) cannot be determined from R/S configuration!

CH3O

H

CH3O

H

N

O

ON

HN

O

ON

HO

O

O

O

HH

(S)-(+)-carvone[α] = +61º

(R)-(–)-carvone[α] = –61º

(S)-(–)-thalidomide[α] = –64º

(R)-(+)-thalidomide[α] = +64º




Diastereomers:Chiral Molecules with >1 Chirality Center

60

diastereomers:

• stereoisomers that are not mirror images

• stereoisomers with ≥ 2 chirality centers that are not all opposite

• diastereomers may have different physical properties!




Meso Forms

61

meso forms = achiral molecules with chirality centersmeso forms are optically inactive (0º optical rotation)

HO H

HHO

H OH

OHH

HO H

OHH

H OH

HHOS R R S R R S S




Meso Forms

61


HO H

HHO

H OH

OHH

HO H

OHH

H OH

HHO

HH

OHOH

HOOH

HH

S R R S R R S S




Meso Forms

61


HO H

HHO

H OH

OHH

HO H

OHH

H OH

HHO

HH

OHOH

HOOH

HH

meso meso

S R R S R R S S

Two tests for meso:

1. plane or center of symmetry

2. two chirality centers with same groups, but opposite configurations




Determining the Number of Stereoisomers

62

2n = maximum number of stereoisomersn = chirality centers

HOOH

H

O

OH

OH

OH

2n = 24 = 16 stereoisomers





63



HO Halkenes that have geometrical isomers are also

a type of chirality center!





64



O

OHOH

OH




A. 2B. 4C. 8D. 16E. 32

Thyrotropin releasing hormone (TRH) stimulates the anterior pituitary to release thyroid stimulating hormone (TSH); the thyroid gland regulates metabolism. How many stereoisomers are possible in TRH?

Self-Test Question

65

NH

OHN

O

NHN

O

N

O NH2TRH


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