Advanced Organic Chemistry. Part A. Structure and Mechanisms

Francis A. Carey, Richard J. Sundberg

Chapter 7 Addition, Condensation and Substitution Reactions of Carbonyl Compounds - all with Video Answers

Educators

Chapter Questions

Problem 1

The hydrates of aldehydes and ketones are considerably more acidic than alcohols ( $\mathrm{p} K$ 16-19). Some values are shown below. How do you account for this enhanced acidity? Explain the relative order of acidity for the compounds in the list.

Katie Miller

Numerade Educator

08:45

Problem 2

Suggest explanations for each of the following observations:
a. The equilibrium constant for cyanohydrin formation for 3,3 -dimethyl-2butanone (pinacolone) is 40 times larger than for acetophenone.
b. The ester $\mathbf{2 - A}$ undergoes alkaline hydrolysis 8300 faster than the unsubstituted analog 2-B.
c. Under comparable conditions, the general base-catalyzed elimination of bisulfite ion from $\mathbf{2 - C}$ is about 10 times faster than for 2-D.
d. The rates of isotopic exchange of the carbonyl oxygen in tropone $(2-E)$ and 2,3 -diphenyl-cyclopropenone (2-F) are much less than for acetophenone.

Nima Gharibi

Numerade Educator

01:36

Problem 3

Arrange each series of compounds in order of decreasing rate of acid-catalyzed hydrolysis of the corresponding diethyl acetals. Explain your reasoning.
a. acetaldehyde, chloroacetaldehyde, buten-2-al
b. acetaldehyde, formaldehyde, acetone
c. cyclopentanone, cyclohexanone, camphor
d. acetone, 3,3-dimethyl-2-butanone, 4,4-dimethyl-2-butanone
e. benzaldehyde, 4-methoxybenzaldehyde, butanal

Aadit Sharma

Numerade Educator

05:13

Problem 4

The acid-catalyzed hydrolysis of 2 -alkoxy-2-phenyl-1,3-dioxolane exhibits general acid catalysis of the initial rate-determining cleavage under some circumstances, as is indicated by the rate law:
The Brønsted relationship (see Section 3.7.1.2 to review the Brønsted catalysis law) shows a correlation with the identity of the alkoxy group. The alkoxy groups derived from more acidic alcohols have lower Brønsted coefficients $\alpha$.
What information about the reaction mechanism does this correlation provide? Interpret the results in terms of a More O'Ferrall-Jencks two-dimensional potential energy diagram.

Niamat Khuda

Numerade Educator

10:06

Problem 5

Each of the following molecules is capable of some form of intramolecular catalysis of ester hydrolysis. For each reactant, indicate one or more possible mechanisms for intramolecular catalysis. Indicate the relationship that you would expect to exist between the catalytic mechanism and the $\mathrm{pH}$. Determine if that relationship is consistent with the experimental $\mathrm{pH}$-rate profile shown in Fig. 7.P5. Depict a mechanism showing the proposed catalysis.

Crystal Wang

Numerade Educator

02:02

Problem 6

Derive the general expression for the observed rate of hydrolysis of compound 6-A as a function of pH. Assume that intramolecular general acid catalysis outweighs specific acid catalysis in the region between $\mathrm{pH} 3$ and $\mathrm{pH} 9$.

Kartik Indoliya

Numerade Educator

05:29

Problem 7

Enantiomerically pure dipeptide is obtained when the 4-nitrophenyl ester of $N$ benzoyl-L-leucine is coupled with ethyl glycinate in ethyl acetate. If, however, the leucine ester is treated with 1-methylpiperidine in chloroform for $30 \mathrm{~min}$ prior to coupling, the dipeptide in nearly completely racemized. Treatment of the leucine ester with 1-methylpiperidine leads to formation of a crystalline material of composition $\mathrm{C}_{13} \mathrm{H}_{15} \mathrm{NO}_{2}$, which has strong IR bands at 1832 and $1664 \mathrm{~cm}^{-1}$. Explain how racemization occurs and suggest a reasonable structure for the crystalline material.

Nicholas Sacco

Numerade Educator

00:24

Problem 8

Provide an explanation in terms of structure and mechanism for the following observations:
a. The bicyclic lactam 8-A hydrolyzes $10^{7}$ times faster than the related monocyclic compound 8-B
b. Leaving groups $\mathrm{X}$ solvolyze from the bicyclic structure $\mathbf{8 - C}$ at a rate that is $10^{-13}$ less than for the monocyclic analog 8-D.

Aadit Sharma

Numerade Educator

07:56

Problem 9

Analyze the factors that determine the stereoselectivity of the addition of organometallic compounds to the following ketones. Predict the stereochemistry of the major product.

Dr. Satish Ingale

Numerade Educator

04:12

Problem 10

Indicate which of the compounds of each of the following pairs will have the more negative free-energy change for hydrolysis at $\mathrm{pH}$ 7. Explain your reasoning.

Sima Sarker

Numerade Educator

02:15

Problem 11

Sodium acetate reacts with 4-nitrophenyl benzoates to give mixed anhydrides when the reaction is conducted in a polar aprotic solvent in the presence of a crown ether. The reaction is strongly accelerated by a quaternary nitrogen substituent in the ortho position. Suggest an explanation for this substituent effect.

Raghvendra Singh

Numerade Educator

01:01

Problem 12

The kinetics of the hydrolysis of a series of imines derived from benzophenone and primary amines reveals a normal dependence of mechanism on $\mathrm{pH}$ with rate-determining nucleophilic attack at high $\mathrm{pH}$ and rate-determining decomposition of the tetrahedral intermediate at low pH. The primary amines show a linear correlation between the rate of nucleophilic addition and the basicity of the amine. Several diamines, in particular 12-A, 12-B, and 12-C, all showed positive (more reactive) deviation from the correlation line for other primary amines. Why might these amines be more reactive than predicted on the basis of their basicity?

Narayan Hari

Numerade Educator

02:11

Problem 13

The following data give the dissociation constants and rate of acetaldehyde hydration catalysis by each acid. Treat the data according to the Brønsted equation and discuss the mechanistic significance of the results.

Adriano Chikande

Numerade Educator

10:50

Problem 14

1,1 -(Diphenylthio)alkanes react with mercuric fluoride to give 1-fluoro-1(phenylthio)alkanes. Provide a likely mechanism for this reaction. Consider
such questions as: (1) is the reaction an $\mathrm{S}_{N} 1$ or $\mathrm{S}_{N} 2$ process? Would NaF cause the same reaction? Why is only one of the phenylthio groups replaced?

Dr. Satish Ingale

Numerade Educator

01:42

Problem 15

The acid-catalyzed hydrolysis of thioacetanilide can follow two different courses.
The product composition is a function of acid concentration, as shown below. Provide a mechanism that accounts for the change in product composition as a function of acid concentration.
$\begin{array}{llllllll}\mathrm{H}_{2} \mathrm{SO}_{4} \text { (\% by weight) } & 1.1 & 3.2 & 6.1 & 12 & 18 & 36 & 48 \\ \% \text { formed by path A } & 20 & 50 & 55 & 65 & 75 & 96 & 100\end{array}$

Mikayla Stephens

Numerade Educator

01:01

Problem 16

A comparison of the kinetics of hydrolysis and isotopic exchange of amides 16-A and 16-B gave the data below for reactions conducted in $0.1-1.0 M$ $[-\mathrm{OH}]$. An interesting observation is that there is more $\mathrm{C}=\mathrm{O}$ exchange for 16-A than for 16-B. From this information and the other data given, propose a stepwise mechanism for hydrolysis of each amide. Make a qualitative comparison of the behavior of the substituent effects on the various steps in the mechanisms.

Narayan Hari

Numerade Educator

10:39

Problem 17

Data pertaining to substituent effects on the acid-catalyzed hydrolysis of mixed aryl-methyl acetals of benzaldehyde are given below. The reactions exhibited general acid catalysis, and the Brønsted $\alpha$ values are tabulated for a series of substituents in both the benzaldehyde ring and the phenoxy group. Discuss the information that these data provide about the nature of the TS for the first hydrolysis step, making reference to a three-dimensional energy diagram.

Ian Kaigh

Numerade Educator

04:04

Problem 18

The introduction of an additional carboxy function into the structure of aspirin results in a significant rate enhancement of hydrolysis. The hydrolysis is 6300 times faster than for the monoanion of aspirin. 3-Hydroxyphthalic anhydride is an observable intermediate. The pH-rate profile is shown in Figure 7.P18. Suggest a mechanism to account for the accelerated hydrolysis involving both of the carboxy derivatives.

Crystal Wang

Numerade Educator

02:12

Problem 19

The hydrolysis of the lactone 19-A shows catalysis by acetate ion, with the rate expression being
$$
k_{\text {obs }}=1.6 \times 10^{-6}+6.4 \times 10^{-4}\left[\mathrm{H}^{+}\right]+2.08 \times 10^{-5}\left[{ }^{-} \mathrm{OAc}\right]+49\left[{ }^{-} \mathrm{OH}\right] \mathrm{s}^{-1}
$$
This expression results in a pH-rate profile shown in Figure 7.P19, with acetate catalysis being significant in the $\mathrm{pH}$ range 3-6. The reaction shows a solvent isotope effect of $2.65$. Discuss how the catalysis by acetate might occur. What are the likely mechanisms for hydrolysis at $\mathrm{pH}<1$ and $\mathrm{pH}>7$, where the rates are linearly dependent on $\left[\mathrm{H}^{+}\right]$and $\left[{ }^{-} \mathrm{OH}\right]$, respectively?

Lottie Adams

Numerade Educator

08:51

Problem 20

Some data on substituent effects for the reaction of trifluoroacetanilides with
methoxide ion in methanol and methanol-OD are given below. Calculate the
isotope effect for each reactant. Plot the rate data against appropriate Hammett
substituent constants. What facets of the data are in specific agreement with
the normal addition-intermediate mechanism proceeding through a tetrahedral
intermediate? What facets of the data suggest other complications? Propose a
mechanism that is consistent with the data given.

Christopher Nilsen

Numerade Educator

02:12

Problem 21

The order of the reactivity of the cyclic acetals toward hydrolysis is $\mathbf{2 1 - A}<<$ 21-B $<<21$-C. Offer an explanation for the large differences in reactivity of these acetals.

Nicholas Sacco

Numerade Educator

01:37

Problem 22

Examine the structure of the following reactants and the corresponding $\mathrm{pH}$-rate profiles. Offer mechanisms for each reaction that is consistent with the $\mathrm{pH}-\mathrm{rate}$ profile. Indicate the most likely mechanism corresponding to each feature of the profile.

Farhana Sharmin

Numerade Educator

02:37

Problem 23

The pH-rate profiles for 2 -carboxy- and 4 -carboxy benzylidene acetals of the trans-1,2-cyclohexanediol are shown in Figure 7.P23a (page 708). Figure 7.P23b is the pH-rate profile of 3-(trans-2-hydroxycyclohexyloxy) phthalide, an intermediate isolated from the 2-carboxy derivative. Interpret both the relative rates and the form of the $\mathrm{pH}$-rate profiles.

David Collins

Numerade Educator

02:13

Problem 24

The rates of both formation and hydrolysis of dimethyl acetals of $p-$
substituted benzaldehydes are substituent dependent. Do you expect the rate
of formation to increase or decrease with the increasing EWG strength of
the substituent? How do you expect the rate of hydrolysis to respond to
the nature of the substituent? The equilibrium constant for acetal formation
is determined by these two rates. How do you expect $K$ to vary with
substitution?

Deepanshu Kumar

Numerade Educator

13:13

Problem 25

Figure 7.P25 (page 709) gives the pH-rate profile for conversion of the acid $25-A$ to the anhydride in aqueous solution. Note that the rate of the reaction increases with the size of the alkyl substituent, and, although not shown, the compound with both $\mathrm{R}^{1}$ and $\mathrm{R}^{2}=\mathrm{CH}_{3}$ is still more reactive. Suggest a mechanism for the reaction, including the structure of any intermediate. How do you account for the effect of the alkyl substituents on the reaction rate?

Susan Hallstrom

Numerade Educator

09:38

Problem 26

Assume that the general mechanism for imine hydrolysis described on p. 647-648 is operative. Assume that a steady state approximation can be applied to the tetrahedral intermediate. Derive the kinetic expression for the observed rate of imine hydrolysis. What variables have to be determined to construct the $\mathrm{pH}$-rate profile? What simplifying assumptions can be justified at very high and very low $\mathrm{pH}$ values? What are the kinetic expressions that result from these assumptions?

Zubair Abdulla

Numerade Educator

03:35

Problem 27

Give the expected structure, including stereochemistry if appropriate, for the products of the following reactions:

Madi Sousa

Numerade Educator

03:10

Problem 28

Figure $7 . \mathrm{P} 28$ (page 710 ) gives the pH-rate profile for the hydrolysis of thioesters 28-A-D and indicates differing dependence on pH, depending on the thiol substituents. Propose a mechanism that would account for the observed $\mathrm{pH}$ dependence in each case.

Zubair Abdulla

Numerade Educator

00:47

Problem 29

Figure $7 . \mathrm{P} 29$ gives the pH-rate profile for alkaline hydrolysis of two substituted salicylate amides, as compared with benzamide. Consider whether the $\mathrm{pH}$-rate profiles for the salicylamides are more consistent with mechanism (A), intramolecular basic catalysis of water attack, or (B), intramolecular acid catalysis of hydroxide ion attack.

Aadit Sharma

Numerade Educator

04:43

Problem 30

The hydrolysis of the ester group in 2-acetoxybenzaldehyde is accelerated by about $10^{4}$, relative to the 4 -isomer. The rate of hydrolysis in the $\mathrm{pH}$ range 6.0-8.5 follows the rate expression
$$
\text { Rate }=k_{0}+k\left[{ }^{-} \mathrm{OH}\right]
$$
Both the $k_{0}$ and $k\left[^{-} \mathrm{OH}\right]$ terms are larger than for the 4 -isomer. When the hydrolysis is carried out in ${ }^{18} \mathrm{O}$-labeled water, the acetic acid contains $50 \%$ ${ }^{18} \mathrm{O}$. Suggest a mechanism that is consistent with these observations.

Zubair Abdulla

Numerade Educator

03:10

Problem 31

The pH-rate profile for the hydrolysis of 4-nitrophenyl 2-aminobenzoate is given in Figure $7.13$ (p. 674). The reaction exhibits a solvent isotope effect of $\sim 0.5$ in $\mathrm{D}_{2} \mathrm{O}$. Suggest possible mechanisms for the reaction, based on the shape of the $\mathrm{pH}$-rate profile and chemical structure considerations. Derive the kinetic expression for the most likely mechanism.

Zubair Abdulla

Numerade Educator