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Home , Absolute configuration, Chirality, Stereocenter, Stereoisomerism

Chapter 5: - three-dimensional arrangement of (groups) in space 5.1 Overview of Isomerism

Isomers: different chemical compounds with the same formula

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

C5H12 C4H10O C4H11N NH O 2 OH NH2 butanol diethyl ether different skeleton different functional group different position of FG

Stereoisomers: with the same connectivity but different spatial arrangement of atoms (groups) H C CH 3 3 H3C H

H H H CH3

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

H H H CH3

H C CH H C H 3 3 3 93 cis-2-butene trans-2-butene

5.2 Introduction to Stereoisomerism

Enantiomers: non-superimposable 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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47 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 . H H

HO OH CO2H HO2C H3C CH3

H H

H CO2H HO HO CO2H CO2H H3C H3C H3C HO CO2H H HO H3C

H H

H OH HO HO CO2H CO2H H3C H3C HO H CH3 CO2H HO2C H3C

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

1a. Look at the four atoms directly attached to the chiral carbon 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).

A-2 Group A

A-3 A A-1

X

B-3 B B-1

Group B B-2

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48 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.

C C H = C C H C C

O C O = O H H

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2a. Orient the 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). 4 4 4 H 4 3 1 H 2 H H 2 H C orient lowest priority HO CO2H orient lowest priority 3 CO2H 3 2 1 group away HO 2 group away H3C CO2H CH OH 3 CO2H HO 3 H3C 1 1 3 clockwise = R counterclockwise = S 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).

4 4 4 H4 H H 1 1 2 1 2 OH HOHO 2 HO3 2C 2 CO2H CH H3C H3C 3 CO2H 3 CO2H H3C 3 HO 3 1 (R)-(-)-Lactic acid (S)-(+)-Lactic acid 98 (Right Hand) (Left Hand)

49 You must be able to draw tetrahedral properly!! In the plane of the paper Dash: projecting behind and in the same plane the plane of the paper Dash and Wedge are on as the tetrahedral carbon away from you adjacent position off the (adjacent position off the tetrahedral carbon tetrahedral carbon) H Wedge: projecting out C OH HO2C of the plane of the paper CH3 toward you

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

H H H Br C HO C C OH Br OH CO H HO C HO2C 2 2 CH CH3 H3C 3

Cl Br Cl OH OH

Cl OH OH Cl Br

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

3 CH3 CO2H CO2H switch the clockwise = R CH and CO H H C C switch the H and OH C 3 2 OH 1 HO H HO C H OH 2 2 H3C H3C inverts the inverts the stereochemistry stereochemistry

switch the CH3 H H switch the H and CH3 OH and CO2H 2 left hand = S C OH C OH C CO2H HO2C HO2C HO H CH3 1 CH3 inverts the 3 stereochemistry inverts the stereochemistry

5.4 Optical Activity – samples enriched in one will rotate plane polarized and are said to be optically active. The optical is dependent upon the substance, the sample concentration, the path length through the sample, temperature, and the wavelength of light. 100

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589 nm - D-line of a sodium lamp

Plane polarized light: light that oscillates in only one plane

0 ° CHOH 0 ° + α - α H CHO HO C HO C C C 2 C H CH3 CH3 HO2CCH2OH HO H HOH2C HO OH

dextrorotatory (d): rotates light levororotatory (l): rotates light to the right (clockwise) to the left (counterclockwise) 101

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

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 α = optical rotation in degrees l = path length in dm T α [α]λ = c = concentration of sample in g/mL l • c T = temperature in °C λ = wavelength of light, usually D for the D-line of a sodium lamp (589 nm) 102

51 The is a physical constant of a chiral molecule

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

H NH2

for : HO2C

[α]D = +14.5° (c 10, 6N HCl) An optically pure substance consists exclusively of a single enantiomer.

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

ee = ______(observed α) • 100 (α of the pure enanomer)

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5.5 Stereoisomeric Relationships: Enantiomers and

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 C CH 3 3 H3C H H H H CH3

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

H H H CH3

H3C CH3 H3C H 104 cis-2-butene trans-2-butene

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

OH OH OH OH

CH3 CH3 CH3 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.

* CH3 Cholesterol: eight chiral centers H 8 CH3 H * * 2 = 256 possible stereoisomers * * * H *H (only one of which is naturally occurring) HO * H

H H OH H3C H OH

H3C trans (S) H cis (S) OH H H H3C C C C CH3 H H H H HO H H3C HO H

H C 3 trans (R) H cis (R) H H

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53 5.6 Symmetry and Chirality

Monarch butterfly: bilateral symmetry= Mirror symmetry & mirror symmetry axis (6 fold) of symmetry Mirror symmetry

Whenever winds blow butterflies find a new place on the willow tree -Basho (~1644 - 1694)

Point (center) of symmetry 107

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. CH3 CH3 CH3 CH3 H CO H H H H 2 CO2H HO2C H H H CO2H H

achiral chiral Not a symmetry symmetry plane plane O OH O H H H H H C O CH3 H C O C C H C C H H H O H H O

Chiral center (stereogenic, asymmetric) 108

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

Br Br Br Br Br H H Br

H H H H H Br Br H meso (achiral) chiral

OH OH H CO2H HO2C CO2H CO2H HO2C HO H HO2C H OH H OH OH no mirror plane

OH HO H CO H 2 HO2C CO2H CO H 2 H HO2C H H HO2C OH OH HO OH mirror plane

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

horizontal line is coming vertical line is going back out of the plane of the behind the plane of the page (toward you) paper (away from you)

carbon

(R)-(+)-

CHO CHO CHO H OH H OH H C CH2OH HO CH2OH CH2OH

(S)-(-)-glyceraldehyde

CHO CHO CHO HO H HO H HO C CH2OH H CH2OH CH2OH

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55 Manipulation of Fischer Projections 1. Fischer projections can be rotated by 180° (in the plane of the page) only!

CHO CH2OH CHO CH2OH 180 ° H OH HO H 180 ° HO H H OH

CH2OH CHO CH2OH CHO (R) (R) (S) (S)

180° 180°

Valid Valid Fischer Fischer projection projection

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a 90° rotation inverts the stereochemistry and is illegal!

90 ° CHO OH H OH ≠ OHC CH2OH

CH2OH H (R) (S)

90 °

This is not the correct convenon 90° for Fischer projecons

Should be projecng toward you Should be projecng away you

This is the correct convenon for Fischer projecons and is the enanomer

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

H OH HO CH2OH

CH2OH H (R) (R)

CHO H HO H OHC OH hold steady CH2OH CH2OH (S) (S)

120° 120°

hold hold steady steady hold steady

120° 120°

hold hold hold steady steady 113 steady

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.

2 place at the top 4 CO2H H 1 H2N H 4 2 HO2C NH2 1 hold steady CH3 CH3 rotate other 3 3 three groups counterclockwise 1-2-3 counterclockwise = S

2 4 2 CO2H H CO2H 4 1 2 H NH2 1 H2N CO2H H2N CH3 CH3 1 3 CH3 H 3 3 4

1-2-3 clockwise = R 114

57 Fischer projections with more than one chiral center:

CO2H CO2H CO2H CO2H

H2N H H NH2 H NH2 H2N H

H OH HO H H OH HO H

CH3 CH3 CH3 CH3

mirror images mirror images (enantiomers) (enantiomers)

non-mirror image (diastereomers)

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

CH3 CH3 (R) (S) H H CH3 H3C (S) (R) H H The chair-chair interconversion not really a plane of symmetry enantiomers coverts one enantiomer to the other. H H (R) H C (S) 3 CH H3C 3 CH3 H H (S) H H (R) CH CH3 plane of symmetry 3

The gauche conformation of butane is chiral H CH H C 3 3 H H C C 3 H C C C H 3 C H H H H H Rotation about the C2-C3 bond coverts one chiral conformation H C 3 H3C H CH into its enantiomer. 3 H3C H

H H H H H H 116

58 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.

H H (R) + H NH H NH2 N H3O 2 H (R) C • (S) (S) C H NH2 N H C CO H H3C (R) CO2 N 3 2 C (S) (S) (R) H (R)-(–) H3C (R) CO2H N (R) H + (-)-sparteine H2N H H C H (R) H N H N + 2 H3C (S) CO2H H2N H H3O (S) (S) C C • H C CO H N 3 2 H3C (S) CO2 (R) H (S)-(+)

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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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