Chm 222
Spring 2015, Exercise Set 5
The Stereochemistry Pillar
Mr. Linck
c
Boniface
Beebe Productions
January 19, 2016
Version 3.0.
NOTE: An asterisk in the problem title indicates that it is a continuing problem from
the previous one. Two asterisk tells you the problem depends on the last two, etc.
5.1. Learning Organic Chemistry
Review your notes from the last lecture. Summarize the subjects that were covered.
Present that summary to another student in the class.
5.2. Ring Structure and Chemical Thinking
If cyclopropane is “strained”, that is, has weaker than normal C-C bonds, and cyclohexane is not strained, which should have the most negative energy change for the
reaction with Cl2 to form a straight chain compounds with chlorine atoms on the
ends?
Cn H2n
+
Cl2
=
ClCH2 (CH2 )n−2 CH2 Cl
HINTS: (1) Think through a series of reactions–use Hess’s law–that starts with rupturing a C-C bond into two radicals, and proceed from there such that the sum of
your reactions equals the desired overall result. (2) Be sure you understand your
conclusion.
5.3. Ring Instability
What hybridization would you have a carbon atom in cyclopropane use? Is anything wrong with the bonding given your choice of hybridization and the structure of
cyclopropane? HINT: Think angles.
5.4. Another Ring Instability Issue*
Draw a cyclopropane ring looking down a C-C bond and comment on any obvious
instability.
5.11
2
Figure 1: Newman projection of a cyclohexane ring.
5.5. Ring Instability**
State the two issue that affect ring instability.
5.6. Potential Ring Instability
Draw a planar cyclohexane ring and then make a Newman projection looking down
a C-C bond. Comment on any obvious instability.
5.7. The Cyclohexane Structure
In Figure 1 is a Newman projection of a cyclohexane ring where each carbon is
tetrahedrally coordinated. What is the relationship (gauche or antiperiplanar) of X
and Y?
5.8. The Cyclohexane Structure*
In Figure 1 is a Newman projection of a cyclohexane ring. What is the relationship
(gauche or antiperiplanar) of X and the -CH2 at the lower center (blue lines for those
looking in color)?
5.9. The Cyclohexane Structure**
In Figure 1 is a Newman projection of a cyclohexane ring. What is the relationship
(gauche or antiperiplanar) of Y and the -CH2 at the upper center (black lines for
those looking in color)?
5.10. The Cyclohexane Structure***
Again referencing Figure 1, if you were to put a large group at position X or Y, which
would you choose for maximum stability? Why?
Chm 222
Exercise Set 5
5.20
3
Figure 2: The flip of a cyclohexane ring within a Newman projection.
5.11. Stability in Cyclohexane Structures****
Imagine a motion where the front -CH2 in Figure 1 is pulled down, causing X to
rotate up, and, simultaneously, the rear -CH2 is pulled up, causing Y to rotate down.
The process is shown in Figure 2. Is X axial or equatorial in the starting material.
Is X axial or equatorial in the product? What about Y? What can you say about a
“flip” of the cyclohexane structure?
5.12. Stability in Cyclohexane Structures
If X is larger than Y (Figures 1 and 2), which of the two structures in Figure 2 is
most stable?
5.13. Three-Dimensional Ring Structure
Draw a line structure representation of the cyclohexane ring in the chair form without
any hydrogen atoms present.
5.14. Three-Dimensional Ring Structure*
Draw a cyclohexane ring in the chair form with axial hydrogen atoms.
5.15. Three-Dimensional Ring Structure**
Draw a cyclohexane ring in the chair form with equatorial hydrogen atoms.
5.16. Flipping the Chair Form
Draw a “flipped” cyclohexane ring. This means, if the right hand carbon of your
original drawing was “up,” make the right hand carbon now “down.”
5.17. Flipping the Chair Form*
Convince yourself with your diagrams of the last problem that upon “flipping” all the
axial hydrogen atoms becomes equatorial and all the equatorial ones become axial.
5.18. Top and Bottom of a Cyclohexane Ring
Draw a cyclohexane ring with both the axial and equatorial hydrogen atoms on one
of the carbons shown. Is one of those hydrogen atoms “on top”?
Chm 222
Exercise Set 5
5.28
4
5.19. Isomers in Cyclohexane
What is the fundamental reason why a cyclohexane ring has cis and trans isomers
whereas hexane does not?
5.20. Isomers in Cyclohexane
Draw trans-1,3-dichlorocyclohexane where the cyclohexane ring is drawn flat.
5.21. Isomers in Cyclohexane
Draw trans-1,3-dichlorocyclohexane in it stable conformation (3D drawing required).
5.22. Isomers in Cyclohexane
Draw the planar and 3D structures for cis-1,3-dichlorocyclohexane.
5.23. Stable Conformers in Rings
Sketch the stable conformation of each of the following.
5.24. Conformers in Cyclohexane
Can you show axial and equatorial substituents in a planar cyclohexane structure?
Why or why not?
5.25. Cyclohexane Conformations
Draw the most stable conformer of cis-1-t-butyl-3-methylcyclohexane.
5.26. Cyclohexane Conformations
A monosubstituted cyclohexane ring is more stable with the substituent in what
position? Does that mean there is none of the other conformer? Explain.
5.27. Energy Difference in Cyclohexane Conformations
The free energy difference, G(axial C6 H11 X) - G(eq C6 H11 X) is 7.3 kJ/mole for X
= CH3 . Calculate the ratio of equatorial species to axial. HINT: ∆G = - R T
ln([eq]/[ax]) where R is the universal gas constant, 8.314 J/(K mole).
Chm 222
Exercise Set 5
5.40
5
5.28. Energy Difference in Cyclohexane Conformations
The ratio of the conformer of C6 H11 X, [eq]/[ax], when X is a phenyl group, is 110.
What is the free energy difference between the two conformers. Which is more stable?
HINT: See that of the last problem.
5.29. Cyclohexane Conformations
Consider the two monosubstituted cyclohexane rings, C6 H11 X, where X is -CF3 in one
and -CCl3 in the other. Which would you predict has the largest fraction of material
with the X group axial? Explain.
5.30. Conformers in Cyclohexane
Can you show the stable conformer of a substituted cyclohexane in a planar diagram?
Why or why not?
5.31. Isomers in Cyclohexane
Can you show a cis isomer in a 3D structure of cyclohexane? Why or why not?
5.32. Stable Isomers
Is cis- or trans-1,2-dimethylcyclopropane more stable? Why?
5.33. Isomers in Ring Structures
Draw all of the isomers of dimethylcyclobutane.
5.34. Isomers in Ring Structures
Draw the isomer cis-1-isopropyl-cis-5-methyl-cyclohexanol in the planar representation. HINT: The stereochemistry designation is relative to the position of the hydroxy
group.
5.35. Isomers in Ring Structures*
Draw the isomer cis-1-isopropyl-trans-5-methyl-cyclohexanol in the planar representation. HINT: The stereochemistry designation is relative to the position of the
hydroxy group.
5.36. Conformers in Ring Structures**
Draw the stable conformer of the compounds in the last two problems.
5.37. Stable Conformers
Use the table of cyclohexane stabilities to guess (and draw) the stable conformation
of trans-1- chloro-3-ethyl-cyclohexane.
5.38. Ring Stability and Reactions
It is possible to imagine both 1 and 2 closing to make a lactones. Which is likely to
occur most readily? Why? HINT: A lactone is a cyclic ester.
5.39. Ring Stability and Reactions
Use epwa to describe any reaction that 3 might undergo in dilute aqueous acid. Why
does your reaction occur?
Chm 222
Exercise Set 5
5.40
6
X
F
Cl
Br
CN
SH
A (kcal/mole)
0.15
0.43
0.38
0.17
0.9
X
CH3
CF3
C2 H5
CCH
SCH3
A (kcal/mole)
1.7
2.1
1.75
0.41
0.7
Table 1: The A values (∆Go value) for the change from equatorial to axial conformer
in kcal/mole for some X groups in C6 H11 X.
Chm 222
Exercise Set 5
5.48
7
5.40. Stable Conformation
Draw the stable conformation of cis-1-ethyl-2-isopropylcyclohexane.
5.41. Reactions and Stability
Use 1,2-ethandiol to make the ketal of 4 and 5. Which is most stable? Why?
HINT: Stability in ring compounds should make you think of (1) ring size and (2)
conformation.
5.42. Isomer Drawing
Lindane, an insecticide, is cis-(1,2,4,5)-trans-(3,6)-hexachlorocyclohexane. Draw the
structure in the planar representation.
5.43. Stable Conformation*
Draw the stable conformation of lindane.
5.44. Stable Conformation and Predictive Thinking
The compound 5-hydroxy-1,3-dioxane (that nomenclature means a six membered ring
with two oxygens replacing CH2 groups in the 1 the 3 positions) is more stable in the
axial conformation than in the equatorial, in contrast to hydroxycyclohexane. Why?
HINT: Think about hydrogen bonding.
5.45. Conformers, Isomers, or the Same Thing
How do you define each of the following terms: conformers, identical molecules, isomers?
5.46. Conformers, Isomers, or the Same Thing
Look at each of the following and indicate whether the relationship is: conformer,
identical molecule, or isomer?
5.47. Free Energy Difference and Equilibrium Constant
The free energy change, ∆Go , for conversion of the axial form of a monosubstituted
cyclohexane to the equatorial form is -1.92 kcal/mole when the substituent is COOH.
What is the equilibrium constant for this conversion? HINT: See discussion in problem 27.
Chm 222
Exercise Set 5
5.56
8
5.48. Free Energy Difference and Stability
The value of ∆Go (for a process such as described in the last problem) for a phenyl substituent is -2.9 kcal/mole. What is the stable conformation of cis-4-phenylcyclohexanoic
acid? HINT: You need data from problem 47.
5.49. Ring Instability
Chemists have been able to synthesize (with difficulty) cubane, C8 H8 , 6. Why is this
compound so unstable?
5.50. 3D Drawing of Rings
Here on the left is a planar perspective of a steroid ring. Put the substituents onto
the proper positions with the proper geometric orientations in the chair form of that
molecule, sketched without substituents on the right hand side.
5.51. Conformer Stability
Draw the conformers (with respect to the cyclohexane ring) of menthol, 7, and indicate which is the most stable.
5.52. 3D Structure and NMR
How many kinds of hydrogen atoms are present in bornane, 8? How would each be
split in 1 H nmr?
5.53. Conformational Energy and Explanations
The difference in energy between the axial and equatorial conformers of the cyclohexylhalides (Eaxial - Eequatorial ) is F, 0.15; Cl, 0.43; Br, 0.38;, I, 0.43, all in kcal/mole.
Which of these data make sense to you on an initial look? Which don’t? Is there any
way you can account for the similarity of the last three?
5.54. Reactions and Stereochemistry Review
Progesterone, 9, is reacted with dimethylcuprate(I). Where will attack occur and
what will be the stereochemistry of the product. Why?
5.55. Isomeric Stability
Which is more stable, cis- or trans-1,3-dimethylcyclohexane? Why?
Chm 222
Exercise Set 5
5.61
9
5.56. Isomeric Stability
Which is more stable, cis-(1,5)-trans-(2,4)- or cis-(1,4)-trans-(2,5)- tetramethylcyclohexane? HINT: The nomenclature here means, in the first case, for instance, that
the methyl groups on atoms 1 and 5 are on the same side, and opposite that of the
methyl groups on atoms 2 and 4.
5.57. Chirality
How do you rigorously define a chiral molecule? HINT: There are two ways to state
this, one of which involves mirror images. In my view, that is the hard way, especially
in practice. Think i and σ.
5.58. Chirality*
What works reasonably well (most of the time) to define a chiral molecule centered
on a carbon atom?
5.59. Chirality
Which of the following are chiral molecules? HINT: Remember, in cases where there
are two (or more) chiral centers, you have to have 3D drawing to assess stereochemistry. When you don’t have it, you must generate it, even if you make assumptions
in building your drawing.
5.60. Chirality
Which of the following have a “chiral” (or stereogenic) center?
Chm 222
Exercise Set 5
5.66
10
5.61. Superposition of Two Molecules
If it is possible, show how you would rotate 9A to yield 9B. Specify the amount and
your axes of rotation (i.e., 30o about the C-Cl bond).
5.62. Superposition of Two Molecules
If it is possible, show how you would rotate 9C to yield 9D. Specify the amount and
your axes of rotation (i.e., 30o about the C-Cl bond).
5.63. Reactions and Chirality
Consider three reactions: Ethyl Grignard reacts with 2-pentanone, 3 hexanone, and
10, then with dilute acid, each separately. Which of these has a chiral center in the
product?
5.64. Review, Functional Groups
What functional groups are in captopril, 11, a drug used to treat high blood pressure:
5.65. Chirality*
Identify the chiral centers in captopril, 11.
Chm 222
Exercise Set 5
5.72
11
5.66. Chirality
Which of the following have a stereogenic center(s)? Which are chiral molecules?
5.67. R,S Nomenclature
Determine whether each of the following is R or S.
5.68. Distinguishing Molecules
For each of the pairs of compound, 12-17, classify them as a) identical, b) enantiomers, c) diastereomers, or d) constitutional isomers?
5.69. Drawing Enantiomers and R,S Nomenclature
Draw the enantiomer of 18 and 19. Also, determine whether the compound given is
R or S.
5.70. Chiral Centers
Find all the chirality centers in 20, streptimidone, an antibiotic, and determine for
each whether it is R or S.
Chm 222
Exercise Set 5
5.72
Chm 222
12
Exercise Set 5
5.80
13
5.71. R,S Nomenclature
Determine if 23A is R or S. How about 23B?
5.72. Review of Reactions
How would you convert 23A into 23B?
5.73. Thinking About Stereochemistry*
Would you really get 23B, and only 23B, in the last problem? Explain your reasoning.
5.74. Enantiomeric Pairs and Diastereomers
Draw all possible structures for 1,2-dihydroxycyclopentane. Are there any enantiomeric pairs. Is there a meso compound? Are there any diastereomers?
5.75. R,S Nomenclature
In 21, 22, and 23 are drawings of 2-chlorobutane. For each compound, answer the
question: Is this a drawing of the R or S enantiomer of 2-chlorobutane?
5.76. Chirality
Is 24 chiral? HINT: Tricky question.
5.77. Enantiomers and Diastereomers
Draw stereorepresentations for all stereoisomers of 24. Label those that are meso
compounds and those that are enantiomers.
5.78. Enantiomers and Diastereomers
Draw stereorepresentations for all stereoisomers of 24A. Label those that are meso
compounds and those that are enantiomers.
5.79. R,S Nomenclature
Is compound 25 R or S (or neither)?
Chm 222
Exercise Set 5
5.91
14
5.80. Isolating Enantiomers
A chemist makes 2-hydroxy-2-phenylacetic acid (2-hydroxy-2-phenylethanoic acid).
She reacts this acid with the natural enantiomer of cinchonine, a base (formula
C19 H22 N20 ) isolated from cinchona bark (and used to treat malaria) and carefully
crystallizes the solution. The very first material to precipitate is separated from that
which is the last to precipitate. When acidified, she finds the first material is (R)2-hydroxy-2-phenylacetic acid and the second is (S)-2-hydroxy-2-phenylacetic acid.
Explain.
5.81. Enantiomer
Ibuprofen has the structure 26, but only the S enantiomer is active as an antinflammatory. Draw it.
5.82. Chirality
Does (1,3)-di-tert-butyl allene have an enantomeric pair? HINT: Allene is “C double
bond C double bond C.”
5.83. R,S Nomenclature and Predictive Thinking
Pretend those guys in Switzerland that developed the rules for R,S designation tried
to name 27. Assume reasonable logic and decide if it is R or S. What is your “logic”?
5.84. Chirality
Is 28 chiral?
5.85. Meso Compounds
Is 29 a meso compound? Why or why not?
5.86. Meso Compounds
Is 30 a meso compound? Why or why not?
5.87. R,S Nomenclature
Assign R or S to each chiral (stereogenic) center in 31. HINT: Remember N inversion
is fast (although P is not).
5.88. R,S Nomenclature Is Useful
Consider a general molecule with three chiral centers. How many isomers are possible?
5.89. R,S Nomenclature Is Useful*
Let the three centers in the molecule of the last problem be labeled consecutively as,
for instance, RRS. What is the relationship between RRS and SRS? between RRS
and SSR? between RSR and SRR?
5.90. R,S Nomenclature and Predictive Thinking
When (S)-1-chloro-2-methylbutane reacts with Cl2 (by a mechanism that we have not
covered) the product is 1,4-dichloro-2-methylbutane. Is the product R or S? What
assumption(s) did you make, if any?
Chm 222
Exercise Set 5
5.91
Chm 222
15
Exercise Set 5
5.102
16
5.91. R,S Nomenclature
Draw all possible structures of 2,3,4-tribromopentane and find the relationships between them. HINT: From a mathematical point of view, with all carbon atoms in the
plane of the paper, the bromine atoms on C2, C3, and C4 can point either in or out:
that gives 23 possible arrangements, all of which may not be distinguishable.
5.92. Chiral Compounds
Is it true or false to say “Every chiral compound has a diastereomer”? Explain your
answer.
5.93. SN 2 Attack and Stereochemistry
Let CH3 SC(H)(I)CH3 be attacked in an SN 2 reaction with azide ion, N–3 , as shown in
32. Is the product R or S? Did the configuration invert during the reaction? Did the
name (that is, R or S) change? Why or why not?
5.94. R, S, and Configuration Change
Is it possible for that a substitution of X for Y in a molecule (where all other groups
stay in the same absolute position) will lead to a change in name (R or S)? Is it possible
for the name to not change with a change in configuration? Comment. HINT: Think
about the rules for naming chiral centers.
5.95. 3D Shape
Draw an accurate representation of the three dimensional shape of (S)-1,3-dichloropentane.
5.96. Reactions and Stereochemistry
Treat 33 with AlH–4 followed by H+ . What is the product? Pay attention to stereochemistry.
5.97. Reactions and Stereochemistry
Treat 33 with dilute H+ in ethanol. What is the product? Pay attention to stereochemistry.
5.98. Reactions and Stereochemistry
If (R)-1-bromo-1-deutero-ethane is treated with triphenylphosphine to form the Wittig cation, what is the configuration (R or S) of that cation? HINT: Remember this
is an SN 2 backside attack.
5.99. Chirality
Is 34 chiral?
5.100. Chirality
Is 35 chiral?
5.101. Chirality
Is 36 chiral?
Chm 222
Exercise Set 5
5.103
17
5.102. Chirality
Is 37 chiral?
5.103. Enantiomers, Diasteriomers, Same Molecule
What is the relationship between the pairs of compounds, 38, 39, and 40? Choices
are “same molecule” (which includes conformers), “enantiomers,” or “diastereomers.”
HINT: Remember the easy way to answer this kind of question is to name the compounds.
Chm 222
Exercise Set 5