Chapter 5: Stereoisomerism- three-dimensional arrangement of atoms (groups) in space

5.1 Overview of Isomerism

Isomers: different chemical compounds with the same formula

Constitutional isomers: same formula, but different connectivity of atoms (or groups)

Stereoisomers: molecules with the same connectivity but different spatial arrangement of atoms (groups)

H

H3C

H

CH3

H

H3C

CH3

H

cis-1,2-dimethylcyclopropane trans-1,2-dimethylcyclopropane

H3C

H H

CH3 H3C

H CH3

H

cis-2-butene trans-2-butene93  

different carbon skeleton different functional group different position of FG

C5H12 C4H10O

OHbutanol

O

diethyl etherNH2

NH2

C4H11N

5.2 Introduction to Stereoisomerism

Enantiomers: non-superimposable mirror image isomers.

Enantiomers are related to each other much like a right hand is related to a left hand

Enantiomers have identical physical properties, e.g., bp, mp, etc.

Chirality (derived from the Greek word for hand). Enantiomers are said to be chiral.

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Chirality Center: Chiral molecules most commonly contain a carbon with four different groups; the carbon is referred to as a chiral center, or asymmetric center, or stereogenic center, or stereocenter.

CO2H

H

HO

H3CHO2C

H

OH

CH3

CO2H

H

HO

H3CH3C

HO

H

CO2H

CO2H

H

HO

H3CH

CO2H

HO

H3C

CO2H

H

HO

H3CHO

HO2C

H

CH3

CO2H

H

HO

H3CCO2H

OH

H

H3C

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5.3 Designating Configuration Using the Cahn-Ingold-Prelog System – Assigning the Absolute Configuration

1a. Look at the four atoms directly attached to the chiral carbon atom and rank them according to decreasing atomic number.

priority of common atoms: I > Br > Cl > S > P > F > O > N > C > H

1b. If the two atoms attached to the chiral carbon are identical (designated A and B below), look at all the atoms directly attached to the identical atoms in questions (designated A-1, A-2, A-3 and B-1, B-2, B-3). Assign priorities to all these atoms based on atomic number (1 is the highest priority, 3 the lowest).

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A-1

B-1

A-2

A

B

B-2

A-3

B-3

X

Group A

Group B

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97  

1c. Compare the highest priority atoms, i.e. compare A-1 with B-1. If A-1 is a higher priority atoms than B-1, then A is higher priority than B. If A-1 and B-1 are the same atom, then compare the second highest priority atoms directly bonded to A and B (A-2 with B-2); if A-2 is a higher priority atom than B-2, then A is higher priority than B. If A-2 and B-2 are identical atoms, compare A-3 with B-3.

1d. If a difference still can not be found, move out to the next highest priority group (A-1 and B-1 in the diagram) and repeat the process.

1e. Multiple bonds are considered equivalent to the same number of single bonded

atoms.

H = C C H

CC

C C

H

O =

HO

O C

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2a. Orient the molecule so that the lowest priority atom is in the back (away from you). Look at the remaining three groups of priority 1–3. If the remaining three groups are arranged so that the priorities 1→2→3 are in a clockwise fashion, then assign the chiral center as R (“rectus” or right). If the remaining three groups are arranged 1→2→3 in a counterclockwise manner, then assign the chiral center as S (“sinister” or left).

 

CO2H

H

HO

H3C

4

12

3

OH

CO2HH3C H

1

234

orient lowest priority group away

counterclockwise = S

H3C

HO

H

CO2H

4

2

1

3CH3

CO2HHO H

3

214

orient lowest priority group away

clockwise = R

2b. Or use the “Hand Rule.” Orient the lowest priority group up. Point your thumb in the direction of the lowest priority group. If you need to use your right hand so that your fingers point in the direction of the group priorities in the order 1→2→3, then the stereogenic center is assigned R (“rectus” or right). If your left hand is required so that your fingers point in the direction of the group priorities 1→2→3, the the stereogenic center is assigned S (“sinister” or left).

(S)-(+)-Lactic acid(Left Hand)

(R)-(-)-Lactic acid(Right Hand)

H

HO2C CH3OH

4

2

3

1H

CO2HH3CHO

4

2

3

1

H3C

HO

H

CO2H

4

2

1

3CO2H

H

HO

H3C

4

12

3

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You must be able to draw tetrahedral carbons properly!!

LINEAR ALKANES: You should draw the carbon backbone in the plane of the paper, and draw substituents either coming towards you (with wedges) or going away from you (with dashes). Note that each carbon should look like a tetrahedron.

Correct Incorrect • •• •

HC

HO2C CH3OH

In the plane of the paperand in the same plane as the tetrahedral carbon (adjacent position off the tetrahedral carbon)

Wedge: projecting outof the plane of the papertoward you

Dash: projecting behind the plane of the paperaway from you

Dash and Wedge are onadjacent position off the tetrahedral carbon

HC

HO2C CH3OH

HC

CO2HH3CHO

HC

HO2C CH3OH

Cl

Cl

Cl

ClOH OH

Br

Br

OH OH

BrBr

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Interchanging any two groups inverts the stereochemistry. Switch the lowest priority group to the desired position. Then switch the other two groups. The “double-switch” does not change the stereochemistry.

CH3C

HO2C HOH

CO2HC

HH3CHO switch the H and OH

CO2HC

OHH3CH

inverts the stereochemistry

switch the CH3 and CO2H

CH3C

OHHO2CH

inverts the stereochemistry

12

3clockwise = R

switch the H and CH3HC

HO2C CH3OH

switch the OH and CO2H H

CHO CH3

CO2H1

2

3

left hand = S

inverts the stereochemistry inverts the

stereochemistry

5.4 Optical Activity – samples enriched in one enantiomer will rotate plane polarized light and are said to be optically active. The optical rotation is dependent upon the substance, the sample concentration, the path length through the sample, temperature, and the wavelength of light.

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101  

589 nm - D-line of a sodium lamp

Plane polarized light: light that oscillates in only one plane

Polarimeter

0 ° + α 0 °- α

dextrorotatory (d): rotates lightto the right (clockwise)

levororotatory (l): rotates lightto the left (counterclockwise)

CH3CH

HOHO2C CH3

CH

HO2CHO

C

CHO

CH2OHHOH C

CHO

HOH2C OHH

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α : angle (# of degrees) plane polarized light is rotated by an optically active sample. Expressed in degrees.

Enantiomers will rotate plane polarized light the same magnitude (α) but in opposite directions (+ or -)

90% (+) + 10% (-) will rotate light 80% of pure (+) 75% (+) + 25% (-) will rotate light 50% of pure (+) 50% (+) + 50% (-) will be optically inactive

50:50 mixture of enantiomers (+/-): racemate or racemic mixture

Each individual molecule may be chiral; however, the bulk property of the substance is achiral (if it is in an achiral environment). Specific Rotation [α]D: a standardized value for the optical rotation

[α]λ = T α  l • c

α  = optical rotation in degrees l = path length in dm c = concentration of sample in g/mL T = temperature in °C λ  = wavelength of light, usually D for the

D-line of a sodium lamp (589 nm)

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103  

[α]D = +14.5° (c 10, 6N HCl)

for alanine:

The specific rotation is a physical constant of a chiral molecule

The [α]D may also depend upon solvent, therefore the solvent is usually specified.

HO2C

NH2H

An optically pure substance consists exclusively of a single enantiomer.

Optical purity of a optically active substance is expressed as the enantiomeric excess = % one enantiomer – % other enantiomer

ee = ______________________________ • 100

 (observed  α)    

(α  of  the  pure  enan;omer)  

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5.5 Stereoisomeric Relationships: Enantiomers and Diastereomers

Isomers: different chemical compounds with the same formula

Constitutional isomers: same formula, but different connectivity of atoms (or groups)

Stereoisomers: same connectivity but different spatial arrangement of atoms (groups)

enantiomers: non-superimposable, mirror image isomers

diastereomers: non-superimposable, non-mirror image isomers

H

H3C

H

CH3

H

H3C

CH3

H

cis-1,2-dimethylcyclopropane trans-1,2-dimethylcyclopropane

H3C

H H

CH3 H3C

H CH3

H

cis-2-butene trans-2-butene

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105  

Diastereomeric relationships occur when more than one chiral center is present in a molecule.

OH

CH3

OH

CH3

OH

CH3

OH

CH3(1R, 2S) (1S, 2R) (1R, 2R) (1S, 2S)

enantiomers enantiomers

diastereomers (non-superimposable, non-mirror image)

Enantiomers must have the opposite stereochemistry (configuration) at all chiral centers.

In general, enantiomers have identical physical properties except optical rotation (which is equal in magnitude but opposite in sign). Diastereomers may have completely different physical properties.

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Maximum number of stereoisomers = 2n. where n = number of structural units capable of stereochemical variation. Structural units include chiral centers and cis and/or trans double bonds.  

HO

CH3 H

CH3

H H

H

H****

****

Cholesterol: eight chiral centers 28 = 256 possible stereoisomers (only one of which is naturally occurring)

OH

C

H

CH3CH

CH

H3C

H3C

H

H

OHH

H

H3C

H

OHH

H3C

H

H

HHO

H

H3C

H

HHO

(S) (S)

(R) (R)

trans

trans

cis

cis

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5.6 Symmetry and Chirality

Monarch butterfly: bilateral symmetry=

mirror symmetry

Whenever winds blow butterflies find a new place on the willow tree

-Basho (~1644 - 1694)

Point (center) of symmetry

Mirror symmetry

Mirror symmetry & axis (6 fold) of symmetry

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Molecules are not chiral if they contain a plane of symmetry: a plane that cuts the molecule in half so that one half is the mirror image of the other half. Molecules (or objects) that possess a mirror plane of symmetry are superimposable on their mirror image and are termed achiral.

CO2H

CH3

H

H HO2C

CH3

H

H

CO2H

CH3

H

HH

H

CH3

CO2H

achiral chiral

Chiral center (stereogenic, asymmetric)

C CC

HOH

HH

H H

O

O

symmetryplane

C CC

HOH

HH

H OH

O

OCH3

H

Not asymmetry

plane

108  

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109  

Meso Compounds: molecules that contain chiral atoms but are achiral because they also possess a plane of symmetry.

Br

H

Br

H

Br

H

Br

H

Br

H

H

Br

H

Br

Br

H

meso (achiral) chiral

HO2CCO2H

OH

OH

HO2CCO2H

OH

OHHO2C

CO2HHO

OH

H

HCO2H

OHH

HO2C

HOH

HO2C

CO2HH

OH

OH

H

CO2H

OHH

HO2C

HHO

mirror plane

no mirror plane

5.7 Fischer Projections - representation of a three-dimensional molecule as a flat structure. A tetrahedral carbon is represented by two crossed lines:

vertical line is going back behind the plane of the paper (away from you)

horizontal line is coming out of the plane of the page (toward you)

carbon substituent

(R)-(+)-glyceraldehyde (S)-(-)-glyceraldehyde

OHHCHO

CH2OHCH2OHCCHO

HOH

CHO

CH2OHH OH

HHOCHO

CH2OHCH2OHCCHO

HHO

CHO

CH2OHHO H

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Manipulation of Fischer Projections 1.  Fischer projections can be rotated by 180° (in the plane of the

page) only!

180° 180°

CHO

CH2OHH OH

CHO

CH2OHHHO

(R) (R)CHO

CH2OHOHH

CHO

CH2OHHO H

(S) (S)

180 ° 180 °

Valid Fischer

projection

Valid Fischer

projection

111  

a 90° rotation inverts the stereochemistry and is illegal!

90°  

90 °

CHO

CH2OHH OH

(R)

90 °

H

OHCH2OHOHC

(S)

≠

This  is  not  the  correct  conven;on  for  Fischer    projec;ons  

Should  be  projec;ng  toward  you  Should  be  projec;ng  away  you  

This  is  the  correct  conven;on  for  Fischer    projec;ons  and  is  the  enan;omer  

112  

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2.  If one group of a Fischer projection is held steady, the other three groups can be rotated clockwise or counterclockwise.

holdsteady

120°   120°  

holdsteady hold

steady

holdsteady

120°  

holdsteady

120°  

holdsteady

CHO

CH2OHH OH

holdsteady

CHO

HHO CH2OH

CHO

CH2OH

HO H

holdsteady

H

CH2OH

OHC OH

(R) (R)

(S) (S)

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Assigning R and S Configuration to Fischer Projections 1. Assign priorities to the four substituents according to the Cahn-Ingold-Prelog rules 2. Perform the two allowed manipulations of the Fischer projection to place the lowest priority group at the top or bottom. 3. If the priority of the other groups 1→2→3 is clockwise then assign the carbon as R, if the priority of the other groups 1→2→3 is counterclockwise then assign the center as S.

CH3

HCO2HH2N

3

2

4

1

1-2-3 clockwise = R

CO2H

CH3

H NH2

2

1

3

4CO2H

HH2N CH3

2

3

4

1

CO2H

CH3

H2N H1

2

3

4

place at the top

hold steadyrotate otherthree groupscounterclockwise

H

CH3

HO2C NH2 12

3

4

1-2-3 counterclockwise = S

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Fischer projections with more than one chiral center: CO2H

NH2H

CH3

H OH

CO2H

HH2N

CH3

HO H

CO2H

HH2N

CH3

H OH

CO2H

NH2H

CH3

HO H

mirror images(enantiomers)

non-mirror image(diastereomers)

mirror images(enantiomers)

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5.8 Conformationally Mobile Systems

not really a plane of symmetry

(S)(S)

(R)(R)

H

H

CH3

CH3 H3C

CH3

H

H

(S)(S)

(R)(R)

enantiomers

(S)(S)

(R)(R)CH3

H

H

CH3(S)(S)

(R)(R)

CH3

H3C

H

HH

H3C

H

CH3

plane of symmetry

CC

HH3C

HH

H CH3

CC

HH3C

HH

H3C H

H

H3C HH3C

HHH

CH3HH3C

H H

The gauche conformation of butane is chiral

1,2-dimethylcycloheane and the gauche conformation of butane are chiral; however, . . . .

The chair-chair interconversion coverts one enantiomer to the other.

Rotation about the C2-C3 bond coverts one chiral conformation into its enantiomer.

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117  

5.9 Resolution of Enantiomers - a process of separating a racemate into pure enantiomers.

Crystallization

Chiral resolving agents. The enantiomers of the racemate must be temporarily converted into diastereomers.

N(S)(S)

(R)(R)

(R)(R)

(S)(S)N

H

H

H3C CO2HC(R)(R)

NH2H

H3C CO2HC(S)(S)

HH2N

+

H3C CO2C(R)(R)

NH2H

N(S)(S)

(R)(R)

(R)(R)

(S)(S)N

H

H

N(S)(S)

(R)(R)

(R)(R)

(S)(S)N

H

H

H

H

•

•

(-)-sparteine

H3O+

H3O+

H3C CO2C(S)(S)

HH2N

H3C CO2HCNH2H

H3C CO2HCHH2N

(S)-(+)

(R)-(–)

118  

Chapter 6 Chemical Reactivity and Mechanisms 6.1 Enthalpy (ΔH) - the heat (energy) exchange between the reaction and its environment at constant pressure

Bond breaking processes require heat from the environment. Homolytic: symmetrical bond breaking process

Heterolytic: unsymmetrical bond breaking processes Bond dissociation energy (ΔH°) – energy required for homolytic cleavage of a covalent bond. Table 6.1 (p. 238)

Heat of reaction (ΔH°) - total enthalpy change bond during a reaction. ΔH°products – ΔH°reactant = ΔH°reaction

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