Advanced Organic Chemistry. Part A. Structure and Mechanisms

Francis A. Carey, Richard J. Sundberg

Chapter 2 Stereochemistry, Conformation, and Stereoselectivity - all with Video Answers

Educators

Chapter Questions

Problem 1

Indicate whether the following pairs of compounds are identical, enantiomers, diastereomers, or structural isomers.
a.
<smiles> N C ( C O ) C ( O ) C ( C</smiles>
b.
<smiles>CC1(C)C=CCCC1</smiles>
<smiles>CC1C=CCCC1</smiles>
c.
<smiles>O=C1CC2CCC1C2</smiles> and
<smiles>O=C1CC2CCC1C2</smiles>
d.
<smiles>CC(C)(C)CCCS(=O)CCC(C)(C)C</smiles>
e.
<smiles>O=C1C=CC(Cl)C1</smiles> and
<smiles>O=C1C=CC(Cl)C1</smiles>
f.
<smiles> Cl C 1 C C ( Br ) C (</smiles> and
<smiles> C C 1 C C C C (</smiles>
2.2. Use the sequence rule to specify the configuration of the stereogenic center in each of the following molecules.

Akhil Choudhary

Numerade Educator

03:42

Problem 2

Use the sequence rule to specify the configuration of the stereogenic center in each of the following molecules.
a.
<smiles>CCC1C=CCC=C1</smiles>
b.
<smiles>O=C(c1ccc(Br)cc1)C(c1ccccc1)c1ccccc1</smiles>
<smiles>CC1(C)COC(=O)C1O</smiles>
d.
<smiles> C C 1 = C ( C ) C ( C (</smiles>
e.
<smiles>CC1=CC(=O)CC(C)(C)C1(C)O</smiles>
f.
<smiles>NC1CC2CCC1C2C(=O)O</smiles>
g.
<smiles>Cc1ccc(S(C)=O)cc1</smiles>

Chloe Schroeder

Numerade Educator

15:40

Problem 3

Draw structural formulas for each of the following compounds, clearly showing all aspects of the stereochemistry.
a. $E-3,7$-dimethyl-2,6-octadien-1-ol (geraniol)
b. $R-4-$ methyl $-4$-phenylcyclohex-2-enone
c. L-erythro-2-(methylamino)-1-phenylpropan-1-ol [(-)-ephedrine]
d. $7 R, 8 S-7,8$-epoxy-2-methyloctadecane (dispalure, a pheromone of the female gypsy moth)e. methyl $1 S$-cyano- $2 R$-phenylcyclopropanecarboxylate
f. $Z-2$-methyl-2-buten-1-ol
g. $E$-(3-methyl-2-pentenylidene)triphenylphosphorane

Zubair Abdulla

Numerade Educator

02:50

Problem 4

Draw the structures of the product(s) described for each reaction. Specify all aspects of the stereochemistry.
a. stereospecific anti addition of bromine to cis- and trans-cinnamic acid.
b. methanolysis of $S-3$-bromooctane with $6 \%$ racemization.
c. stereospecific syn thermal elimination of acetic acid from $1 R, 2 S$ diphenylpropyl acetate
d. stereoselective epoxidation of bicyclo[2.2.1]hept-2-ene proceeding $94 \%$ from the exo face.

Dalton Hilovsky

Numerade Educator

01:56

Problem 5

The preferred conformation of 1-methyl-1-phenylcyclohexane has the phenyl group in the axial orientation ( $\Delta G=-0.32 \mathrm{kcal} / \mathrm{mol}$ ) even though its conformational free energy $(2.9 \mathrm{kcal} / \mathrm{mol})$ is greater than that of methyl $(1.8 \mathrm{kcal} / \mathrm{mol})$. Explain.

Madeline Currie

Numerade Educator

00:57

Problem 6

The computed $\left(\mathrm{HF} / 6-31 \mathrm{G}^{*}\right)$ rotational profiles for acetone (2-propanone), 2 -butanone, and 3 -methyl-2-butanone are given in Figure $2.6 \mathrm{P}$. Draw Newman projections corresponding to each clear maximum and minimum in the curves for each compound. Analyze the factors that stabilize/destabilize each conformation and discuss the differences among them.
Fig. 2.6P. Rotational profile for acetone (A, solid line), 2-butanone (B, dashed line), and 3-methyl-2-butanone (C, dotdashed line). Reproduced by permission of the American Chemical Society.

Aadit Sharma

Numerade Educator

02:05

Problem 7

Predict the stereochemical outcome of the following reactions:

Grigoriy Sereda

Numerade Educator

11:59

Problem 8

Estimate $\Delta H$ for each of the following conformational equilibria.

Susan Hallstrom

Numerade Educator

03:52

Problem 9

Estimate the free-energy difference between the stable and unstable chair conformations of the following trimethylcyclohexanes.

Amruta Pandit

Numerade Educator

01:20

Problem 10

Predict the preferred conformation of the stereoisomeric $E$-enones $\mathbf{1 0}-\mathbf{A}$. How would you expect the conformational equilibrium to change as $R$ becomes progressively larger?

Anthony Han

Numerade Educator

01:01

Problem 11

-Diphenyl-1-propanol can be prepared by hydride reduction of 1,2 -diphenyl1-propanone or by addition of phenylmagnesium bromide to 2-phenylpropanal.

Narayan Hari

Numerade Educator

01:24

Problem 12

What is the basis of the chemoselectivity observed between the two different double bonds in the following reaction?

Anupa Sharad Medhekar

Numerade Educator

01:27

Problem 13

Assign configuration, using the sequence rule, to each stereocenter in the stereoisomers citric acids shown below and convert the Fischer projections to extended chain representations.

Sohini Lahiri

Numerade Educator

15:50

Problem 14

The following questions illustrate how stereochemical considerations can be used to elucidate aspects of biological mechanisms and reactions.
a. A mixture of ${ }^{3} \mathrm{H}$-labeled 14-A and 14-B was carried through the reaction sequence shown:

D-amino acid oxidase will oxidize only serine having $R$ configuration at $\mathrm{C}(2)$. Glycolate oxidase will remove only the pro- $R$ hydrogen of glycolic acid. Does the product $\left(\mathrm{O}=\mathrm{CHCO}_{2} \mathrm{H}\right)$ contain tritium? Explain your reasoning.
b. Enzymatic oxidation of naphthalene by bacteria proceeds by way of the intermediate cis-diol shown. Which prochiral face of $\mathrm{C}(1)$ and $\mathrm{C}(2)$ of naphthalene is hydroxylated in this process?
<smiles>OC1C=Cc2ccccc2C1O</smiles>c. The biosynthesis of valine by bacteria involves the following sequence:
<smiles>CC(O)C(O)C(=O)O</smiles>
<smiles>CC(C)C(N)C(=O)O</smiles>
The stereochemistry of the reaction has been examined using the starting diol in which each methyl group was separately replaced by $\mathrm{CD}_{3}$. The diol- $d_{3}$ of the $2 R, 3 R$ configuration produces $2 S, 3 S$-valine- $d_{3}$, whereas the $2 R, 3 S$ diol $-d_{3}$ produces $2 S, 3 R$-valine- $d_{3}$. From this information deduce whether the $\mathrm{C}(2)$ and $C(3)$ hydroxy are replaced with inversion or retention of configuration. Show the basis for your conclusion.
d. A synthesis of the important biosynthetic intermediate mevalonic acid starts with the enzymatic hydrolysis of the diester 14-C by pig liver esterase. The pro- $R$ ester group is selectively hydrolyzed. Draw a three-dimensional structure of the product.

Niamat Khuda

Numerade Educator

00:54

Problem 15

The structure of nonactin is shown below without any specification of stereochemistry. It is isolated as a pure substance from natural sources and gives no indication of being a mixture of stereoisomers. Although it is not optically active, it does not appear to be a racemic mixture, because it does not yield separate peaks on chiral HPLC columns. When completely hydrolyzed, it yields racemic nonactic acid. Deduce the stereochemical structure of nonactin from this information.

Alkendra Singh

Numerade Educator

06:41

Problem 16

(a) The signals for the benzylic hydrogens in the ${ }^{1} \mathrm{H}$ NMR spectra of the cis and trans isomers of 1-benzyl-2,6-dimethylpiperidine have distinctly different appearances, as shown in Figure $2.16 \mathrm{~Pa}$. Answer the following questions about these spectra: (a) Which isomer corresponds to which spectrum and why do they have the appearances they do? (b) Only one isomer shows a multiplet corresponding to ring $\mathrm{C}-\mathrm{H}$ hydrogens adjacent to nitrogen near $3 \mathrm{ppm}$. Why are these signals not visible in the other partial spectrum? (b) The partial ${ }^{1} \mathrm{H}$ NMR spectra corresponding to each benzyl ether of the diastereomeric $2,6=$ dimethylcyclohexanols are shown in Figure $2.16 \mathrm{~Pb}$. Assign the stereochemistry of each isomer.

Dr. Satish Ingale

Numerade Educator

07:06

Problem 17

The trans: cis ratio of equilibrium for $4-t$-butylcyclohexanol has been determined in several solvents near $80^{\circ} \mathrm{C}$. From the data, calculate the conformational free energy, $-\Delta G_{c}$, for the hydroxy group in each solvent. What correlation do find between the observed conformational equilibria and properties of the solvent?

Ronald Prasad

Numerade Educator

02:36

Problem 19

The two stereoisomers (19-A and 19-B) of the structure shown below have distinctly different NMR spectra. Isomer 19-A shows single signals for the methylThe trans:cis ratio of equilibrium for 4-t-butylcyclohexanol has been determined in several solvents near $80^{\circ} \mathrm{C}$. From the data, calculate the conformational free energy, $-\Delta G_{c}$, for the hydroxy group in each solvent. What correlation do find between the observed conformational equilibria and properties of the solvent?

Grigoriy Sereda

Numerade Educator

17:09

Problem 20

Compound 20-A can be resolved to give an enantiomerically pure substance with $[\alpha]_{D}=-124$. Oxidation gives an enantiomerically pure ketone $\mathbf{2 0}$ - $\mathbf{B}$, $[\alpha]_{\mathrm{D}}=-439$. Heating $\mathbf{2 0}-\mathbf{A}$ establishes an equilibrium with a stereoisomer with $[\alpha]_{\mathrm{D}}=+22$. Oxidation of this compound gives the enantiomer of $\mathbf{2 0}-\mathbf{B}$. Heating either enantiomer of $\mathbf{2 0}$-B leads to racemization with $\Delta G^{\ddagger}=25 \mathrm{kcal} / \mathrm{mol}$. Deduce the stereochemical relationship between these compounds.

Zubair Abdulla

Numerade Educator

04:07

Problem 21

When partially resolved samples of $S-5$-(hydroxymethyl)pyrrolidin-2-one are allowed to react with benzaldehyde in the presence of an acid catalyst, two products 21-A $\left(\mathrm{C}_{12} \mathrm{H}_{13} \mathrm{NO}_{2}\right)$ and 21-B $\left(\mathrm{C}_{24} \mathrm{H}_{26} \mathrm{~N}_{2} \mathrm{O}_{4}\right)$ are formed. The ratio of 21-A:21-B depends on the enantiomeric purity of the starting material. When it is enantiomerically pure, only $\mathbf{2 1 - A}$ is formed, but if it is racemic only 21-B is formed. Partially resolved samples give 21-A and 21-B in a ratio corresponding to the e.e. The rotation of $21-\mathbf{A}$ is $[\alpha] D=+269.6$, but $21-B$ is not optically active. Develop an explanation for these observations including likely structures for 21-A and 21-B. Assign the configuration of all the stereogenic centers in the products you propose.
<smiles>CN1C(=O)CCC1CO</smiles>

Madeline Currie

Numerade Educator

05:35

Problem 22

Figure $2.22 \mathrm{~Pa}, \mathrm{~b}$ shows energy as a function of rotation for a series of 2 -substituted acetaldehydes, with $\theta=0^{\circ}$ in the syn conformation and $\theta=180^{\circ}$ in the anti conformation. The calculations were done by the PM3 method. Figure 2.P22a represents the isolated molecule, while Figure 2.P22b represents an elliptical solvent cavity with a dielectric constant of $4.7$, approximating $\mathrm{CHCl}_{3}$. The Table $2.22 \mathrm{P}$ gives the calculated rotational barriers. Discuss the following aspects of the data. (a) Rationalize the $\mathrm{Br}>\mathrm{Cl}>\mathrm{F}$ order of preference for anti conformation in the gas phase; (b) Why does the polar medium shift the equilibrium to favor more of the $s y n$ conformation?

Rajesh Singh

Numerade Educator

00:47

Problem 23

Provide a mechanistic explanation, including proposed transition structure(s), to account for the stereoselectivity observed in the following reactions:
a.

Raghvendra Singh

Numerade Educator

04:12

Problem 24

Either oxaborazolidine-catalysis (Me-CBS) or (Ipc) ${ }_{2} \mathrm{BCl}$ reductions can be used to prepare 24-A a precursor of Fluoxetine (Prozac)® in good yield and high e.e. Suggest transition structures that account for the observed enantioselectivity.

Madeline Currie

Numerade Educator

00:54

Problem 25

Some of the compounds shown below contain enantiotopic or diastereotopic atoms or groups. Which possess this characteristic? For those that do, indicate the atoms or groups that are diastereotopic and assign the groups as pro- $R$ and pro-S.

Ronald Prasad

Numerade Educator

01:01

Problem 26

ndicate which of the following structures are chiral. For each molecule that is ichiral, indicate an element of symmetry that is present in the molecule.

Narayan Hari

Numerade Educator

07:51

Problem 27

Predict the absolute configuration of the diols obtained from each of the following alkenes using either a dihydroquinidine or a dihydroquinine type dihydroxylation catalysts.
(a) $\mathrm{Ph} \mathrm{CH}=\mathrm{CH}_{2}$
(b)
<smiles>C=CCOC1=CCC=C1C=CC</smiles>

Nicholas Sacco

Numerade Educator

06:10

Problem 28

Based on the standard transition state models, predict the absolute configuration of the products of the following reactions:
a. Reduction of 1-phenyl-1-propanone by $\mathrm{BH}_{3}$-THF using the oxaborazolidine catalyst derived from $(S)-\alpha, \alpha$-diphenylpyrrolidine-2-methanol.
b. Reduction of $1,1,1$-trifluorodec-3-yn-one by $(S)$-Alpine borane.
c. Sharpless asymmetric epoxidation of $E$-hex-2-en-1-ol using $(+)$-diethyl tartrate.

Nicholas Sacco

Numerade Educator

03:36

Problem 29

Ibuprofen, an example of an NSAID, is the active ingredient in several popular over-the-counter analgesics. In the United States, it is sold in racemic form, even though only the $S$-enantiomer is pharmacologically active. Suggest methods that might be used to obtain or prepare ibuprofen in enantiomerically pure form, based on processes and reactions discussed in chapter $2 .$

Ramesh Singh

Numerade Educator

07:40

Problem 30

Ab initio MO calculations (HF/4-31G) indicate that the eclipsed conformation of acetaldehyde is about $1.1 \mathrm{kcal}$ more stable than the staggered conformation. Provide an explanation of this effect in terms of MO theory. Construct a qualitative MO diagram and point out the significant differences that favor the eclipsed conformation. Identify the interactions that are stabilizing and those that are destabilizing. Identify other factors that need to be considered to analyze the origin of the rotational barrier.

Niamat Khuda

Numerade Educator

01:19

Problem 31

Treatment of alkylphosphoryl dichlorides with 1 equiv. of $L$-proline ethyl ester in the presence of 1-methylimidazole (acting as an acid-scavenger) leads to formation of a monophosphoramidate with low $(<20 \%$ diastereoselectivity). Addition of $0.25$ equiv. of 4-nitrophenol then gives a 4nitrophenylphosphoramidate with high $(98 \%)$ diastereoselectivity, which in turn can be treated with methanol to isolate the methyl 4-nitrophenylphosphonate ester in high enantiomeric purity. This constitutes a kinetic resolution process. Write a mechanistic scheme that accounts for this series of transformations.

Grigoriy Sereda

Numerade Educator

02:31

Problem 32

Use an appropriate computation program to compare the TS energies for hydroboration of the following alkenes by $\left(\mathrm{CH}_{3}\right)_{2} \mathrm{BH}$. Predict the exo:endo ratio for each compound. What factor might complicate the interpretation of the exo:endo ratio?

Ian Kaigh

Numerade Educator

03:35

Problem 33

9-BBN exhibits a high degree of stereoselectivity toward 1,3-dimethyl cycloalkenes such as 1,3-dimethylcyclopentene and 1,3-dimethylcyclohexene, giving exclusively the trans, trans-2,6-dimethyl cycloalkanols. Offer an explanation.

Zubair Abdulla

Numerade Educator

03:09

Problem 34

Diastereoselective reduction of a number of 4 -alkylideneprolinols has been accomplished. With a silyl protecting group in place, using Raney nickel, thecis isomers are formed in ratio of about $15: 1$. When the unprotected alcohols are used with the Crabtree catalyst, quite high selectivity for the trans isomer is found. Explain these results.

Prashant Singh

Numerade Educator