Solutions manual for Burrows et.al.

Chemistry3

10
Isomerism and stereochemistry
Answers to worked examples
WE 10.1 Structural isomers (on p. 452 in Chemistry3) For the following four compounds, AD, identify which are chain isomers, which are position isomers and which are functional group isomers. (Ph stands for phenyl, C6H5.)
O HO2C HO A Ph B Ph HO Ph C D H OH Ph O O

Strategy Determine the molecular formulae of these molecules: 1. To be structural isomers, these molecules must have the same molecular formulae. 2. To be position isomers, these molecules must have the same functional groups but at different positions. 3. To be functional group isomers, these molecules must have different functional groups. Solution 1. Molecules A, C and D are structural isomers as they have the same molecular formulae (C9H10O2). Molecule B is not a structural isomer since it has a different molecular formula (C10H12O2).

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Solutions manual for Burrows et.al. Chemistry3

2.

3.

Molecules A and C are positional isomers as they both contain the same functional groups [a carboxylic acid (-CO2H) group and a phenyl (-Ph) group] but at different positions. Molecule D is a functional group isomer of both molecules A and B, as it contains different functional groups (an alcohol and an aldehyde in D versus a carboxylic acid group in both A and B).

Answer 1. A, C and D are structural isomers all have the molecular formula, C9H10O2. A and C are position isomers (the Ph group is at different positions). C and D (and A and D) are functional group isomers (C is a carboxylic acid, D is an -hydroxyaldehyde).

WE 10.3 E/Z nomenclature (on p. 470 in Chemistry3) Draw a skeletal structure for (Z)-3-ethoxybut-2-en-1-ol. Strategy 1. Draw out the longest continuous carbon chain as a zig-zag structure and remember to number the carbon atoms. 2. Draw out its double bond at its designated position. 3. A (Z)-isomer is where both high priority substituents are on the same side of the double bond, and an (E)-isomer is where the high priority substituents are on opposite sides of the double bond. The priorities are determined using the CahnIngold-Prelog rules (See p. 480 in Chemistry3). 4. Identify the substituents from their suffix, and place them along this carbon chain at their designated positions. 5. Check that this structure is correct! Solution 1. The longest number of continuous carbon atoms is four [(Z)-3-ethoxybut-2-en-1-ol]. Draw out this carbon chain in a zig-zag arrangement.

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Solutions manual for Burrows et.al. Chemistry3

2. The suffix of this molecule is -ol [(Z)-3-ethoxybut-2-en-1-ol]; it is therefore an alcohol. This molecule also contains a double bond [(Z)-3-ethoxybut-2-en-1-ol], and this is positioned at carbon 2 (3). 3. The double bond has (Z)-stereochemistry. 4. There is an ethoxy (-OEt) group at carbon-3.
OEt HO 1 2 3 4 now consider its stereochemistry HO H C 1 H 2 3 OEt 4 CH3

suffix C4 = but-2-en-1-ol prefix 3-ethoxy 3-ethoxybut-2-en-1-ol

H on C(2) C higher priority than H on C(3) O higher priority than C both high priority groups on same side = (Z) (Z)-3-ethoxybut-2-en-1-ol

5. Check that the structure is correct by re-naming it! (Z)-3-ethoxybut-2-en-1-ol.

This structure is

Answer
higher priority higher priority HO O lower priority

H lower priority (Z)-3-ethoxybut-2-en-1-ol

WE 10.5 R/S nomenclature (on p. 482 in Chemistry3) Draw a hashedwedged line structure of (R)-butan-2-ol. Strategy 1. Draw out the longest continuous carbon chain as a zig-zag structure and remember to number the carbon atoms. 2. Identify any substituents from their suffix, and place them along this carbon chain at their designated positions. 3
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Solutions manual for Burrows et.al. Chemistry3

3. Draw out the stereochemistry. This can be worked out using the Cahn-Ingold-Prelog rules (See p. 480 in Chemistry3). 4. Check that this structure is correct! 5. Draw out the hashed-wedged line structure of this molecule. Solution 1. The longest number of continuous carbon atoms is four [(R)-butan-2-ol]. Draw out this carbon chain in a zig-zag arrangement. 2. The suffix of this molecule is -ol [(R)-butan-2-ol]; it is therefore an alcohol. 3. The chiral centre at carbon-2- has (R)-stereochemistry. A (R)-configuration is where the three highest priority groups (1, 2 and 3) on a particular conformation can be rotated clockwise (123), whilst the lowest priority group, 4, is at the rear of this conformer.
OH 1 2 3 4 now consider the group priority H 3 C H H H 4 H 1 OH 2 C H CH3

suffix C4 = butan-2-ol butan-2-ol

CIP group priorities 1 = O (-OH) 2 = C (-CH2CH3) 3 = C (-CH3) 4 = H (-H)

1 OH Et 2 now redraw in a "hashed-wedged" structure H3C

now consider its stereochemistry

4 H H3C 3

OH Et

(R)-butan-2-ol

4. Check that the structure is correct by re-naming it! (Z)-3-ethoxybut-2-en-1-ol. 5. The hashed-wedged line structure of this molecule is:

This structure is

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Solutions manual for Burrows et.al. Chemistry3

OH

(R)-butan-2-ol

Answer
Draw in hashed-wedged notation and then rank the groups (14) directly attached to the chiral centre and apply the CIP rule: OH * 3 first draw butan-2-ol and identify the chiral centre (R)2 (R)-butan-2-ol 4 H 1 OH

OH

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Solutions manual for Burrows et.al. Chemistry3

Answers to end of chapter questions (on p. 493 in Chemistry3)

1. The synclinal conformation of 1,2-dichloroethane is 4.8 kJ mol1 higher in energy than the anti-periplanar conformation. The two energy barriers for rotation about the CC bond in 1,2-dichloroethane are 21.5 kJ mol1 and 38.9 kJ mol1 higher than the energy of the anti-periplanar conformation (a) Sketch a graph of energy versus angle of rotation about the CC bond (dihedral angle) for 1,2-dichloroethane.

Strategy 1. Draw out the most stable Newman projection of 1,2-dichloroethane. 2. Rotate clockwise the proximal (front) carbon atom of this projection (from part 1) by 60o and consider its relative energy. 3. Repeat this 60o clockwise rotation until a full revolution (180o) has been achieved. 4. Sketch the change in energy versus the relative angle of rotation. For ease, set the most stable projection has having 180o; this is its dihedral angle. 5. Label each anti-periplanar, anticlinal, syn-periplanar and synclinal projections. Solution

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Solutions manual for Burrows et.al. Chemistry3

H H HH

Cl Cl H H Cl H Cl H Cl H

H H

Cl Cl

syn-periplanar Cl H anticlinal energy 21.5 kJ mol1 4.8 kJ mol1 H H H Cl H Cl H Cl H H Cl HH anticlinal

HH syn-periplanar

38.9 kJ mol1

Cl

Cl H synclinal

H H anti-periplanar

H H synclinal

60

120

180

240

300

360

angle of rotation (dihedral angle) ()

(b)

What conformation of 1,2-dichloroethane has the highest energy?

Strategy Eclipsed conformers are higher in energy than staggered conformers. Draw out the three possible eclipsed projections of 1,2-dichloroethane, and consider which projection has the greatest eclipsing interactions. Solution Of the three eclipsing interactions, there are two identical synclinal projections and a single syn-periplanar projection. These synclinal projections contain two C-Cl/C-H and one C-H/C-H eclipsing interactions. The remaining syn-periplanar projection contains two C-H/C-H and one C-Cl/C-Cl eclipsing interactions; this C-Cl/C-Cl eclipsing interaction is by far the most unfavoured. Therefore, the syn-periplanar conformer of 1,2-dichloroethane has the highest energy.

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Solutions manual for Burrows et.al. Chemistry3

Eclipsing interactions for 1,2-dichloroethane

eclipsed interactions;
H Cl Cl Cl H Cl

for H,H = for H,Cl = for Cl,Cl = increasing steric strain

H H Cl H H H H H H Cl H H

synclinal

syn-periplanar

synclinal

Answer The syn-periplanar conformation of 1,2-dichloroethane has the highest energy.

3.

The citric acid cycle (Krebs cycle) is a series of reactions in the body involved in the oxidation of fats, proteins, and carbohydrates to form carbon dioxide and water (p.956 in Chemistry3). One step in the citric acid cycle is the addition of water to fumaric acid to make malic acid. (a) Does the alkene double bond in fumaric acid have the (E)- or (Z)-configuration?

Strategy 1. Draw out the condensed structure of fumaric acid to include all H-atoms. 2. For molecules containing a single stereoisomeric double (C=C) bond. Its (Z)-isomer is where both high priority substituents are on the same side of the double bond, whereas, its (E)-isomer is when these high priority substituents are on opposite sides of the double bond. These priorities are determined using the Cahn-Ingold-Prelog rules (see p. 480 in Chemistry3).

Solution 1. The condensed structure of fumaric acid is shown below: 8

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Solutions manual for Burrows et.al. Chemistry3

O HO condensed structure of fumaric acid H O C C C C OH H

2.

For this double bond, assign the priority of its substituents using the Cahn-IngoldPrelog rules (See p. 480 in Chemistry3); the carbon atom (C) of the carboxylic acid group has higher priority than the H-atom. This alkene has (E)-configuration as both high priority substituents are on opposite sides of this double bond.
O HO assigning the configuration of fumaric acid H O (E)C C C C OH H C = high priority H = low priority

Answer
C has a higher atomic number than H HO2C H H CO2H C has a higher atomic number than H

(E)-configuration

(b)

Maleic acid is a configurational isomer of fumaric acid. Draw the structure of maleic acid.

Strategy The only configuration in fumaric acid is its (E)-double (C=C) bond. As maleic acid is a configurational isomer, it must be the same condensed structure as fumaric acid (butenedioic acid) but a different alkene configuration. Fumaric acid is the (E)-isomer of butenedioic acid.

Solution Maleic acid is the (Z)-isomer of butenedioic acid. 9

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Solutions manual for Burrows et.al. Chemistry3

O condensed structure and configuration of maleic acid HO C C H

O C C H OH C = high priority H = low priority

(Z)-

Answer
HO2C H CO2H H

(Z)-configuration

(c)

Explain why the conversion of fumaric acid to ()-malic acid is an example of an enantioselective reaction.
OH HO2C H2O CO2H Enzyme (fumarase) HO2C CO2H (-)-malic acid

fumaric acid

Strategy For a reaction to be enantioselective, an unequal mixture of enantiomers must be formed. A common example involves the conversion of an achiral starting material to an enantiomerically enriched product. Solution This reaction involves the selective formation of one enantiomer (-)-(S)-malic acid; its mirror image, (+)-(R)-malic acid, is not preferred. As there are two potential products {(-)-(S)- and (+)-(R)-malic acids} which can be formed; this reaction is selective as only one of these two products are formed. This reaction is not specific. A specific reaction is where only one product can be formed. Answer This is an enantioselective reaction because ()-malic acid is formed in preference to (+)malic acid. 10
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Solutions manual for Burrows et.al. Chemistry3

(d)

Assign the (R)- or (S)-configuration to the chiral centre in ()-malic acid.

Strategy Assign the configuration of this molecule using the Cahn-Ingold-Prelog rules (See p. 480 in Chemistry3). For ease, use a conformer in which the lowest priority group on the chiral centre is facing away from you. Solution Rotate the projection in 2(c), by 180o using a vertical axis, gives the more user-friendly sawhorse projection for determining this configuration.
rotate 180o around a vertical axis CO2H (-)-malic acid

OH HO2C

OH H HO2C CO2H

Assigning the configuration for this chiral centre using the Cahn-Ingold-Prelog rules:
1 OH H C 4H C H 3 assign configuration OH 1 OH 3 CH2CO2H

O HO C 2

O C

H4 HO2C 2

CIP group priorities 1 = O (-OH) 2 = C (-C(=O)OH) 3 = C (-CH2CO2H) 4 = H (-H)

anti-clockwise rotation = (S)OH H HO2C CO2H

(-)-(S)-malic acid

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The configuration for ()-malic acid is (S)- as shown below:

OH H HO2C CO2H

(-)-(S)-malic acid

Answer
Rotate molecule so that the lowest priority group (H) is facing away from you
4 H HO2C 3 1 OH CO2H 2 1 HO HO2C 2 (S)-

4 CO2H

5.

Lamivudine (Epivir) is used for the treatment of HIV (Aids) and is an example of a class of drugs called nucleoside reverse transcriptase inhibitors. These inhibitors stop HIV from infecting cells in the body. Only the ()-enantiomer of lamivudine is registered for the treatment of HIV because it is more active and less toxic than either the (+)-enantiomer or the racemate. In the ()-enantiomer, the chiral centre at position-2 has the (R)-configuration and the chiral centre at position-5 has the (S)-configuration. Draw the structure of ()-lamivudine using hashedwedged line notation.
H2N N O N 5 S ()-lamivudine 1 O 2 OH

Strategy 12
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Solutions manual for Burrows et.al. Chemistry3

1. 2.

3. 4.

Redraw this molecule in a condensed form. Arbitrarily assign both chiral centres in ()-lamivudine using the Cahn-IngoldPrelog rules (See p. 480 in Chemistry3). It will be easier if you consider one chiral centre at time. Pick out the correct diastereoisomer (2R,5S)-. Draw out this diastereoisomer using hashed-wedged line notation.

Solution 1. The condensed structure of lamivudine is shown below:

H2N condensed structure of lamivudine H N O N C5 H C H O H 2C S H C H OH

2.

Arbitrarily assign the configurations of this molecule using the Cahn-Ingold-Prelog rules. For ease, use a conformer in which the lowest priority groups on both chiral centres are facing away from you. Assign the configuration for the chiral centre at carbon-2 using the Cahn-IngoldPrelog rules: the chiral centre at carbon-2 has (R)-stereochemistry. A (R)configuration is where the three highest priority groups (1, 2 and 3) on a particular conformation can be rotated clockwise (123), whilst the lowest priority group, 4, is at the rear of this conformer.

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Assigning the configuration at C(2) H2N N O N H

4 2 H O C C H C S 1

H C H 3 OH

assign configuration

4 2 H RO C RS 1

3 CH2OH

H CIP group priorities 1 = S (-SR) 2 = O (-OR) 3 = C (-CH2OH) 4 = H (-H)

clockwise rotation = (R)-

Assign the configuration for the chiral centre at carbon-5 using the Cahn-IngoldPrelog rules: the chiral centre at carbon-2 has (S)-stereochemistry. A (S)configuration is where the three highest priority groups (1, 2 and 3) on a particular conformation can be rotated anticlockwise (123), whilst the lowest priority group, 4, is at the rear of this conformer.
Assigning the configuration at C(5) H2N N O

4 H 1 H O N C 2 C 3 H C S

H C H OH

assign configuration

R2N 2

4 H C

OH

CH2SR 3 anti-clockwise rotation = (S)-

H CIP group priorities 1 = O (-OR) 2 = N (-NR2) 3 = C (-CH2S-) 4 = H (-H)

3. The required (2R,5S)-diastereoisomer is shown below.

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Solutions manual for Burrows et.al. Chemistry3

H2N N O H H O N 2 (R)(S)- 5 S

OH

(2R,5S)-lamivudine

4. The hashed-wedged structure of (2R,5S)-lamivudine is shown below.

H2N N O H H O N 2 (R)(S)- 5 S hashed = wedged =

OH

(2R,5S)-lamivudine

Answer
H2N N O N H S O OH H

()-lamivudine

Solutions provided by J. Eames ([email protected])

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