Advanced Organic Chemistry. Part A. Structure and Mechanisms

Francis A. Carey, Richard J. Sundberg

Chapter 4 Nucleophilic Substitution - all with Video Answers

Educators

Chapter Questions

Problem 1

Provide an explanation for the relative reactivity relationships revealed by the following data.
a. The relative rates of solvolysis in aqueous acetone of several tertiary $p$-nitrobenzoate esters:
b. For solvolysis of $a$-substituted 1 -aryl-1-ethyl sulfonates, the value of $\rho^{+}$varies with the substituent.
c. The rates of solvolysis for a series of 2 -alkyl-2-adamantyl $p$-nitrobenzoates in $80 \%$ aqueous acetone at $25^{\circ} \mathrm{C}$ are: $\mathrm{R}=\mathrm{CH}_{3}: 1.4 \times 10^{-10} \mathrm{~s}^{-1}$;
$\mathrm{C}_{2} \mathrm{H}_{5}: 1.1 \times 10^{-9} \mathrm{~s}^{-1} ; \quad i-\mathrm{C}_{3} \mathrm{H}_{7}: 5.0 \times 10^{-9} \mathrm{~s}^{-1} ; \quad t-\mathrm{C}_{4} \mathrm{H}_{9}: 3.4 \times 10^{-5} \mathrm{~s}^{-1} ;$ $\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CCH}_{2}: 1.5 \times 10^{-9} \mathrm{~s}^{-1}$.
<smiles>[R]C1(O)CC2CCC1C2</smiles>
d. The relative rates of methanolysis of a series of $w$-phenylthioalkyl chlorides depend on the chain length: $n=1: 3.3 \times 10^{4} ; n=2: 1.5 \times 10^{2} ; n=3: 1 ; n=$ $4: 1.3 \times 10^{2} ; n=5: 4.3$.

Lottie Adams

Numerade Educator

08:02

Problem 2

Suggest reasonable mechanisms for each of the following reactions. The starting materials are racemic, unless otherwise stated.

Nicholas Sacco

Numerade Educator

06:47

Problem 3

Which reaction in each pair would be expected to be faster? Explain.

Allison Krajewski

Numerade Educator

06:24

Problem 4

The solvolysis of $2 R, 3 S-3-(4-$ methoxyphenyl $)$ but $-2-\mathrm{yl}$ tosylate in acetic acid can be followed by several kinetic measurements: (a) rate of decrease of observed rotation $\left(k_{\alpha}\right)$; rate of release of the leaving group $\left(k_{t}\right)$; and (c) when ${ }^{18} \mathrm{O}$-labeled sulfonate is used, the rate of equilibration of the sulfonate oxygens in the reactant $\left(k_{e x}\right) .$ At $25^{\circ} \mathrm{C}$ the rate constants are:
$$
k_{\alpha}=25.5 \times 10^{-6} \mathrm{~s}^{-1} ; k_{t}=5.5 \times 10^{-6} \mathrm{~s}^{-1} ; k_{e x} 17.2 \times 10^{-6} \mathrm{~s}^{-1}
$$
Indicate the nature of the process that is measured by each of these rate constants and devise an overall mechanism that includes each of these processes. Rationalize the order of the rates $k_{\alpha}>k_{e x}>k_{t}$.

Anil Kumar Singh

Numerade Educator

07:30

Problem 5

Both endo- and exo-norbornyl brosylates react with $\mathrm{R}_{4} \mathrm{P}^{+} \mathrm{N}_{3}^{-}(\mathrm{R}$ is a long-chain alkyl) in toluene to give azides of inverted configuration. The yield from the endo and exo reactant is 95 and $80 \%$, respectively. The remainder of the exo reactant is converted to nortricyclane (tricyclo[2.2.1.0 $^{2.6}$ ]heptane.) The measured rates of azide formation are first order in both reactant and azide ion. The endo isomer reacts about twice as fast as the exo isomer. Both react considerably more slowly than cyclohexyl brosylate under the same conditions. No rearrangement of deuterium is observed when deuterium-labeled reactants are used. What conclusions about the mechanism of the substitution process can you draw from these results? How do the reaction conditions relate to the mechanism you have suggested? How is the nortricyclane formed?

Zubair Abdulla

Numerade Educator

12:08

Problem 6

The following observations have been made concerning the reaction of $Z$-1-phenyl-1,3-butadiene (6-A) and Z-4-phenyl-3-buten-2-ol (6-B) in $3-7 \mathrm{MH}_{2} \mathrm{SO}_{4}$ and $0.5-3 \mathrm{MHClO}_{4}$
a. Both compounds are converted to a mixture of the corresponding $E$-isomers with the rate governed by Rate $=k[$ reactant $]\left[\mathrm{H}^{+}\right]$, where $\left[\mathrm{H}^{+}\right]$is measured by the $H_{0}$ acidity function.
b. The rate of isomerization of $\mathbf{6}-\mathbf{A}$ is slower in deuterated $\left(\mathrm{D}_{2} \mathrm{SO}_{4}-\mathrm{D}_{2} \mathrm{O}\right)$ media by a factor of 2 to 3 . For 6 - $\mathbf{B}$, the rate of isomerization is faster in by a factor of $2.5$.
c. When ${ }^{18} \mathrm{O}$-labeled 6-B is used, the rate of loss of ${ }^{18} \mathrm{O}$ to the solvent is equal to the rate of isomerization.
d. The measured activation energies for 6-A is $19.5 \pm 1 \mathrm{kcal} / \mathrm{mol}$ and $22.9 \pm$ $0.7 \mathrm{kcal} / \mathrm{mol}$ for 6 -B.

Nicholas Sacco

Numerade Educator

02:35

Problem 7

Treatment of 2 -(4-hydroxyphenyl)ethyl bromide with basic alumina produces a white solid, $\mathrm{mp}, 40-43^{\circ} \mathrm{C}$; IR $1640 \mathrm{~cm}^{-1}$; UV $_{\max } 282 \mathrm{~nm}$ in $\mathrm{H}_{2} \mathrm{O}$; NMR two singlets of equal intensity at $1.69$ and $6.44 \mathrm{ppm}$ from TMS; anal: C $79.98 \% \mathrm{H}$, $6.71 \%$. Suggest a possible structure for this product and explain how it could be formed.

Raghvendra Singh

Numerade Educator

05:36

Problem 8

In the discussion of the $5 y n$ - and $a n t i$-norborn-2-en-7-yl tosylates (p. $422-423$ ) it was pointed out that, relative to the saturated norborn-7-yl tosylate, the reactivities of the syn and anti isomers were $10^{4}$ and $10^{11}$, respectively. Whereas the anti isomer gives a product of retained configuration, the syn isomer gives a bicyclo[ $[3.2 .0]$ hept-2-enyl derivative. The high reactivity of the anti isomer was attributed to participation of the carbon-carbon bond. What explanation can you offer for the $10^{4}$ acceleration of the $s y n$ isomer relative to the saturated system?

Sana Riaz

Numerade Educator

03:26

Problem 9

Indicate the structure of the final stable ion that would be formed from each of the following reactants in superacid media.

Madeline Currie

Numerade Educator

06:41

Problem 10

A series of ${ }^{18} \mathrm{O}$-labeled sulfonate esters was studied to determine the extent of ${ }^{18} \mathrm{O}$ scrambling that accompanies solvolysis. The rate of ${ }^{18} \mathrm{O}$ exchange was compared with that of solvolysis and the results are shown below. Discuss the variation in the ratio $k_{\text {sol }}: k_{\text {exch }}$ and offer an explanation for the absence of exchange in the

Dr. Satish Ingale

Numerade Educator

06:11

Problem 11

The relative stabilities of 1-phenylvinyl cations can be measured by determining the gas phase basicity of the corresponding alkynes. The table below gives data on free energy of protonation for substituted phenyethynes and phenylpropynes. These data give rise to the corresponding Yukawa-Tsuno relationships:
$$
\begin{aligned}
\text { For } \mathrm{ArC} \equiv \mathrm{CH}: \delta \Delta G^{\circ} &=-14.1\left(\sigma^{\circ}+1.21 \sigma_{\mathrm{R}}^{+}\right) \\
\text {For } \mathrm{ArC} \equiv \mathrm{CCH}_{3}: \delta \Delta G^{\circ} &=-13.3\left(\sigma^{\circ}+1.12 \sigma_{\mathrm{R}}^{+}\right)
\end{aligned}
$$
How do you interpret the values of $\rho$ and $r$ in these equations? Which system is more sensitive to the aryl substituents? How do you explain the difference in sensitivity? Sketch the resonance, polar, and hyperconjugative interactions that contribute to these substituent effects. What geometric constraints do these interactions place on the ions?

Vivek Singh

Numerade Educator

03:25

Problem 12

Studies of the solvolysis of 1-phenylethyl chloride and its 4-substituted derivatives in aqueous trifluoroethanol containing azide anion provide information relative to the mechanism of nucleophilic substitution in this system.
a. The reaction rate is independent of the azide ion concentration for substituents that have $\sigma^{+}$values more negative than $-0.3$, but is first order in $\left[\mathrm{N}_{3}^{-}\right]$for substituents with $\sigma^{+}$less negative than $-0.08$.
b. When other good nucleophiles, e.g., $\mathrm{C}_{3} \mathrm{H}_{7} \mathrm{SH}$, are present, they can compete with azide ion. The reactants that are zero order in $\left[\mathrm{N}_{3}^{-}\right]$show little selectivity among competing nucleophiles.
c. For reactants that solvolyze at rates independent of $\left[\mathrm{N}_{3}^{-}\right]$, the ratio of 1 -arylethyl azide to 1 -arylethanol in the product increases as $\sigma^{+}$of the substituent becomes more negative.
d. The major product in reactions that are first order in $\left[\mathrm{N}_{3}^{-}\right]$are 1 -arylethyl azides.

Consider these results in relation to the mechanism outlined in Figure $4.6$ (p. 400 ). On the basis of the data given above, delineate the types of 1 -arylethyl chlorides that react with azide ion according to those mechanistic types.

Lottie Adams

Numerade Educator

01:26

Problem 13

Offer a mechanistic interpretation of the following observations.
a. Although there is a substantial difference in the rate at which 13-A and 13-B solvolyze (13-A reacts $4.4 \times 10^{4}$ times faster than 13-B in acetic acid), both compounds give products of completely retained configuration.
b. The solvolysis of 13-C is much more sensitive to aryl substituent effects than that of 13-D.
c. Although stereoisomers $13-E$ and $13-F$ solvolyze in aqueous acetone at similar rates, the reaction products are quite different.
d. Solvolysis of compounds 13-I and 13-J exhibits rate enhancement relative to a homoadamantane analog and gives product mixtures that are quite similar
On the other hand, compound $\mathbf{1 3}-\mathbf{K}$ is less reactive than the saturated analog and gives a different product mixture.
e. The solvolysis of both stereoisomers of 5 -fluoro- and 5 -trimethylstannyl-2adamantyl tosylate has been examined and the two have been compared. The relative rates and stereochemistry are summarized below.

Aadit Sharma

Numerade Educator

02:35

Problem 14

The six structures below are all found to be minima on the $\left[\mathrm{C}_{4} \mathrm{H}_{5}\right]^{+}$energy surface. The relative energies from MP2/6-311G $(d, p)$ calculations are shown in $\mathrm{kcal} / \mathrm{mol}$. Comment on the stabilizing features that are present in each of these cations.

Mahipal Kumawat

Numerade Educator

02:37

Problem 15

The rates of solvolysis of four stereoisomeric tricyclo[3.2.1.0 $\left.^{2.4}\right]$ octan-8-yl systems have been determined. After accounting for leaving group and temperature, the relative rates are as shown. In aqueous dioxane, the endo-anti isomer gives a product mixture consisting of the rearranged alcohol and the corresponding PNB ester (from leaving-group capture). The other isomers gave complex product mixtures that were not fully characterized. Explain the trend in rates and discuss the reason for the stereochemical outcome in the case of the

Lottie Adams

Numerade Educator

05:42

Problem 16

The ${ }^{13} \mathrm{C}$-NMR chemical shift of the trivalent carbon is a sensitive indicator of carbocation structure. Generally, the greater the chemical shift value, the lower the electron density at the carbon. Data for three different cations with aryl substituents are given below. How do you explain the close similarity of the trend for the first two series and the opposite trend of the third?

Dan Ni

Numerade Educator

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Problem 17

Relative rate data are available for a wide range of reactivities for rings related to the bicyclo[2.2.1]heptyl (norbornyl) system. Offer a discussion of the structural effects that are responsible for the observed relative rates.

Lainey Roebuck

Numerade Educator

05:35

Problem 18

Fujio and co-workers studied the reaction of pyridine with a wide range of 1 -arylethyl bromides in acetonitrile. By careful analysis of the kinetic data, they were able to dissect each reaction into a first-order and a second-order component, as shown in the table below. The first-order components were correlated by a Yukawa-Tsuno equation: $\log k / k_{o}=5.0\left(\sigma^{\circ}+1.15 \bar{\sigma}^{+}\right)$. The second-order component gave a curved plot, as shown in Figure 4.P18. Analyze the responses of the reaction to the aryl substituents in terms of transition state structures.

Stephen Ho

Numerade Educator

02:09

Problem 19

The Yukawa-Tsuno equation $r$ values have been measured for the solvolysis reactions of substituted benzyl cations and $\alpha$-substituted analogs. HF/6-31G^ charges and bond orders have been calculated for the presumed cationic intermediates. Analyze the data for relationships between $r$ and the structural parameters.

Alkendra Singh

Numerade Educator

01:45

Problem 20

Reactions of substituted cumyl benzoates in $50: 50$ trifluoroethanol-water show no effect of $\left[\mathrm{NaN}_{3}\right]$ on the rate of reaction between 0 and $0.5 M$ for either EWG or ERG substituents. The product ratio, however, as shown in the figure, is highly dependent on the cumyl substituent. ERG substituents favor azide formation, whereas EWG groups result in more solvent capture. Formulate a reaction mechanism that is consistent with these observations.

Raghvendra Singh

Numerade Educator

04:48

Problem 21

The comparison of activation parameters for reactions in different solvents requires consideration of solvation differences of both the reactants and the transition states. The comparison can be done by using potential energy diagrams, such as that illustrated below for two different solvents A and B. It is possible to measure $\Delta H_{\text {transfer }}$ values, which correspond to the enthalpy change associated with transfer of a solute from one solvent to another.
$-\mathrm{TS}$ in $\mathrm{A}$
$-\mathrm{TS}$ in $\mathrm{B}$
$\Delta H_{\text {transfer }}$ data for $n$-hexyl tosylate and several nucleophilic anions are given in Table 4.P1.21. In Table 4.P2.21, the activation parameters for $S_{N} 2$ displacement reactions with $n$-hexyl tosylate are given. Use these data to construct a potential energy comparison for each of the nucleophiles. Use these diagrams to interpret the relative reactivity data given in Table 4.P3.21. Discuss the following aspects of the data.
a. Why is $\mathrm{Cl}^{-}$more reactive than $\mathrm{Br}^{-}$in DMSO, whereas the reverse is true in methanol?
b. Why does the rate of thiocyanate $\left(\mathrm{SCN}^{-}\right)$ion change the least of the five nucleophiles on going from methanol to DMSO?
c. Why does thiocyanate have the most negative entropy of activation?

Eugene Schneider

University of Minnesota - Twin Cities

09:10

Problem 22

The Yukawa-Tsuno parameter $r^{+}$has been measured for several solvolysis reactions. What relationship do you see among the properties of the reactants, the likely nature of the transition structures, and the observed value of $r^{+}$?
a. Solvolysis of benzyl tosylates in acetic acid; $r^{+}=1.3$ compared to solvolysis of 1 -aryl-2,2,2-trifluoroethyl tosylates in $80 \%$ aqueous acetone; $r^{+}=1.39$
b. Aryl-assisted solvolysis of 2 -aryl-2-(trifluoromethyl)ethyl $m$-nitrobenzoates in $80 \%$ aqueous trifluoroethanol; $r^{+}=0.77$ compared to aryl-assisted solvolyis of 2 -arylethyl tosylates; $r^{+}=0.6$

David Collins

Numerade Educator

00:07

Problem 23

Comparison of several series of solvolysis reactions that proceed via carbocation intermediates revealed that an $\alpha$-cyano substituent is rate retarding by a factor of about $10^{-3}$. A $\beta$-cyano is even more rate retarding, with the difference being as much as $10^{-7}$. Why are both $\alpha$ - and $\beta$-cyano rate retarding and why might

Sam Limsuwannarot

Numerade Educator

03:25

Problem 24

Several substituted propyl tosylates with $\gamma$-silicon groups have been studied. For the 2,2 -dimethyl derivatives 24-B, the solvolysis rates are $10^{3}$ to $10^{4}$ greater than for the nonsilyl analogs. The products are rearranged 1,1 -dimethyl derivatives. The reaction shows modest sensitivity to substituents in the aryl group, correlating with a Hammett $\rho$ value of $-1.0$. When the parent system 24-A (without the 2,2-dimethyl substituents) was studied in the nonnucleophilic solvent $97 \%$ TFE, cyclopropane was formed, ranging in yield from $0 \%$ with $\mathrm{EWG}\left(\mathrm{CF}_{3}\right)$ to $100 \%$ with ERG $\left(\mathrm{CH}_{3} \mathrm{O}\right)$. The Hammett correlation gave $\rho=-1.1$ for cyclopropane formation but no significant substituent effect for substitution. Describe a mechanism that is consistent with this information.
a. The stabilization of vinyl cations tends to be somewhat larger than for the corresponding ethyl cation.
b. $\mathrm{F}, \mathrm{OH}$, and $\mathrm{NH}_{2}$ provide less stabilization of vinyl cations than of ethyl cations.
c. $\mathrm{CF}_{3}$ and $\mathrm{CN}$ are less destabilizing of vinyl cations than of ethyl cations.
d. What factors dominate the effect of the $\mathrm{CH}_{2}-\mathrm{X}$ substituents?
e. Compare the $\pi$-donor and polar effects of the $\mathrm{OH}, \mathrm{NH}_{2}$, and $\mathrm{SH}$ substituents.

Lottie Adams

Numerade Educator

03:11

Problem 25

The reaction of several monotosylates derived from 6-hydroxy-2(hydroxymethyl)norbornane were studied under conditions where alkoxide formation would be expected at the nontosylated hydroxy. Compounds $\mathbf{2 5}$ - $\mathbf{C}$ and 25-F showed highly specific product formation, whereas the other compounds gave slower reactions and more complex product mixtures. Identify the structural features that make the observed pathways particularly favorable for $\mathbf{2 5}-\mathbf{C}$ and 25-F. Offer a mechanistic rationale for the formation of the products shown for the other reactants.

Ronald Prasad

Numerade Educator

00:32

Problem 26

Table 4.P26 shows stabilization $(+)$ and destabilization $(-)$ of $\alpha$-substituted ethyl and vinyl cations as determined by the isodesmic reactions shown below. Comment on the following trends in the data.

David Collins

Numerade Educator

03:15

Problem 27

4-Aryl-5-tosyloxyhexanoates are converted to mixtures of lactones when exposed to silica or heated with $p$-toluenesulfonic acid in various solvents. The aryl ring must have an EWG for the reaction to proceed. A similar reaction occurs with 4-aryl-5-tosyloxypentanoates, but in this case only $\gamma$-lactones are formed. Suggest a mechanism that accounts for both the observed regioselectivity and stereoselectivity and the requirement for an ERG on the aryl ring.

Crystal Wang

Numerade Educator