Chapter 10 — Exercises
Sixty-five problems on the $S_N2$ mechanism. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.
Section A — Identifying SN2 components
10.1∗ (routine) For each reaction, identify (a) the substrate, (b) the nucleophile, (c) the electrophilic atom, (d) the leaving group, and (e) the product:
(a) $CH_3CH_2Br + NaOH \to CH_3CH_2OH + NaBr$ (b) $CH_3I + KCN \to CH_3CN + KI$ (c) $(CH_3)_2CHCH_2Cl + NaSH \to (CH_3)_2CHCH_2SH + NaCl$ (d) $CH_3CH_2OTs + NaN_3 \to CH_3CH_2N_3 + NaOTs$ (e) $PhCH_2Br + KOAc \to PhCH_2OAc + KBr$
10.2 (routine) A bottle of methyl iodide reacts with sodium ethoxide to give a colorless liquid product. Predict the product and explain why this is an $S_N2$ reaction (not $S_N1$).
10.3 (routine) Why is $CN^-$ called a nucleophile in this reaction but $H_2O$ is sometimes called an electrophile in others? What property determines whether a species is acting as a nucleophile?
10.4 (moderate) Explain in your own words why the leaving group is properly called a "leaving group" rather than a "nucleofuge." Are these terms synonymous?
10.5 (challenge) A student says "the nucleophile attacks first; then the leaving group departs." Critique this statement.
Section B — Drawing mechanisms
10.6∗ (routine) Draw the full $S_N2$ mechanism (showing both arrows and the transition state) for the reaction of methyl bromide with hydroxide ion in DMSO.
10.7 (routine) Draw the full mechanism for ethyl iodide + cyanide in DMF.
10.8 (routine) Draw the mechanism for the reaction of (CH₃)₃C–CH₂Br (neopentyl bromide) with NaSH in DMSO. Then explain why this reaction is dramatically slower than for ethyl bromide despite both being "primary."
10.9 (moderate) Draw the mechanism for $(R)$-2-bromobutane + sodium iodide in acetone. Show explicit stereochemistry of the product. Will the product be $(R)$ or $(S)$?
10.10 (moderate) Draw the transition state of the reaction in 10.9. Indicate the partial bonds, the trigonal-bipyramidal geometry, and the position of the nucleophile, the leaving group, and the three observer substituents.
10.11 (challenge) Draw the mechanism of $S_N2$ on a cyclohexyl bromide where the bromine is in the axial position of the chair. Explain why this orientation is required and why the equatorial-bromine chair cannot react.
10.12 (challenge) A student draws the $S_N2$ arrow from $X$ to $C$ (instead of from the bond to $X$). Explain what is wrong with this and how to correct it.
Section C — Stereochemistry
10.13∗ (moderate) Predict the stereochemistry of the product of $(R)$-2-bromobutane + NaCN in DMF. Draw the product clearly. Assign the $R/S$ configuration and explain why the letter does or does not change from the starting material.
10.14 (moderate) Repeat 10.13 for $(S)$-2-iodopentane + NaSCN in DMF.
10.15 (moderate) Predict the product (with stereochemistry) of $(R)$-1-phenyl-2-bromopropane + NaOMe.
10.16 (challenge) A student reports that $S_N2$ on $(R)$-2-bromobutane with $HO^-$ gave 80% $(S)$-2-butanol and 20% $(R)$-2-butanol. The student claims this is consistent with $S_N2$ inversion. Critique this claim.
10.17 (challenge) Design an experiment to determine whether a given alkyl halide undergoes $S_N2$ or $S_N1$ based purely on stereochemistry of the product. What starting material and conditions would you use?
10.18 (challenge) Why is "Walden inversion" the historical name for this stereochemistry pattern? Look up Paul Walden's 1896 experiment and explain.
Section D — Kinetics
10.19∗ (routine) For $CH_3Br + I^-$ in DMSO at 25 °C, the rate constant is $k = 0.014\, M^{-1}s^{-1}$. Compute the initial rate when [CH₃Br] = 0.1 M and [I⁻] = 0.5 M.
10.20 (routine) If the reaction in 10.19 is run at higher temperature (50 °C instead of 25 °C), the rate roughly doubles. Estimate the activation energy using the Arrhenius equation. ($R = 1.987 \times 10^{-3}$ kcal/(mol·K))
10.21 (moderate) A reaction is found to be first order in substrate and zero order in nucleophile across a wide range of nucleophile concentrations. Is this consistent with $S_N2$? With $S_N1$? Justify.
10.22 (moderate) A reaction is first order in substrate and first order in nucleophile, but only at low [nucleophile]; at high [Nu] the rate plateaus. Propose an explanation.
10.23 (challenge) Draw a reaction-coordinate diagram for an $S_N2$ reaction. Indicate the position of the transition state, the activation energy, and $\Delta G$ (assume an exergonic reaction). Explain why there is no intermediate (no second peak).
10.24 (challenge) The reaction of $CH_3Br$ with $HO^-$ has activation energy ~24 kcal/mol in water, but only ~16 kcal/mol in DMSO. Explain why the activation energy is lower in the polar aprotic solvent.
10.25 (challenge) Kinetic isotope effects: the reaction of $CH_3Br$ with $HO^-$ is about 10–15% slower if the methyl is replaced by $CD_3$. What does this secondary kinetic isotope effect tell us about the transition state geometry?
Section E — Substrate effects
10.26∗ (routine) Rank the following by $S_N2$ rate with $HO^-$ in DMSO (fastest first): - $CH_3Cl$ - $(CH_3)_2CHCl$ - $CH_3CH_2Cl$ - $(CH_3)_3CCl$
10.27 (routine) Why is neopentyl bromide ($(CH_3)_3CCH_2Br$) such a poor $S_N2$ substrate, even though the carbon bearing $Br$ is technically primary? Use a 3D model or wedge drawing to support your explanation.
10.28 (moderate) Predict whether each substrate undergoes $S_N2$ rapidly, slowly, or not at all: (a) methyl iodide (b) 1-bromobutane (c) 2-bromobutane (d) 2-bromo-2-methylbutane (tertiary) (e) bromobenzene (f) benzyl bromide (g) allyl chloride (h) 1-bromocyclohexane (i) neopentyl bromide
10.29 (moderate) Bromobenzene ($C_6H_5Br$) does not undergo $S_N2$ even though it has a small substrate. Why? (Hint: think about the hybridization of the C-Br carbon.)
10.30 (challenge) Cyclohexyl bromide reacts in $S_N2$ much more slowly than 1-bromobutane. What conformational requirement explains this?
10.31 (challenge) Allyl bromide ($CH_2=CH-CH_2Br$) and benzyl bromide ($PhCH_2Br$) both react faster than $S_N2$ would predict from steric class. Draw the transition state and explain the rate enhancement.
10.32 (challenge) Predict which reacts faster in $S_N2$ with cyanide: 1-bromopropane or 1-bromo-2,2-dimethylpropane? Explain quantitatively.
Section F — Nucleophiles
10.33∗ (routine) Rank the following nucleophiles for reaction with methyl iodide in DMSO (fastest first): - $HO^-$ - $H_2O$ - $F^-$ - $NH_3$ - $CH_3O^-$ - $CN^-$
10.34 (routine) Same nucleophiles as 10.33, but in methanol (polar protic). Will the order be different? If so, how?
10.35 (moderate) Why is $t$-butoxide ($t$-BuO⁻) a strong base but a weak nucleophile? What does it preferentially do to a primary alkyl halide?
10.36 (moderate) Sodium azide ($NaN_3$) reacts rapidly with primary alkyl halides in DMF. Explain why $N_3^-$ is a particularly good nucleophile.
10.37 (moderate) Hydroperoxide ($HOO^-$) is more reactive than hydroxide ($HO^-$) toward most electrophiles, despite being a weaker base. Look up the alpha effect and explain.
10.38 (challenge) Glutathione (GSH) is a tripeptide containing a free $-SH$ group. It is the cellular workhorse for $S_N2$ detoxification reactions. Why is its sulfur atom a particularly good nucleophile in physiological conditions?
10.39 (challenge) Design a strategy to convert $CH_3OH$ to $CH_3CH_3$ by $S_N2$. Why can't $CH_3OH$ react directly? What activation step would you do first?
Section G — Leaving groups
10.40∗ (routine) Rank the following leaving groups (best first): $Cl^-$, $I^-$, $TsO^-$, $F^-$, $HO^-$, $RO^-$, $H_2O$ (from $R-OH_2^+$).
10.41 (routine) Why is fluoride a poor leaving group despite fluorine being highly electronegative? Use $pK_a$ to justify.
10.42 (routine) $Cl^-$ has $pK_a$ of $HCl = -7$. Hydroxide has $pK_a$ of water = 15.7. Compute the ratio of leaving-group abilities and explain.
10.43 (moderate) Why is a tosylate ($-OTs$) a better leaving group than chloride? Compare $pK_a$ values.
10.44 (moderate) Outline three different methods to convert an alcohol into something with a good leaving group. Draw the relevant intermediates.
10.45 (challenge) Diazomethane ($CH_2N_2$) can convert a carboxylic acid ($RCOOH$) to its methyl ester ($RCO_2CH_3$) via $S_N2$. The leaving group is $N_2$ (gas). Explain why $N_2$ is an extraordinarily good leaving group.
10.46 (challenge) Why does an amine ($R-NH_2$) not undergo $S_N2$ at the C-N carbon? Compare to alcohol activation.
Section H — Solvents
10.47∗ (routine) Why does $S_N2$ run faster in DMSO than in methanol? Explain using solvation.
10.48 (routine) A reaction is run in three solvents: water, DMF, methanol. Rank by $S_N2$ rate (fastest first).
10.49 (moderate) The Finkelstein reaction (alkyl chloride + NaI in acetone) drives the equilibrium forward by precipitating NaCl. Explain why acetone is the perfect solvent for this reaction (consider both polarity and solubility).
10.50 (moderate) Hexane is a nonpolar solvent. Why doesn't it dissolve NaCN, and why does it not work as a solvent for $S_N2$ reactions involving ionic nucleophiles?
10.51 (challenge) Modern green-chemistry alternatives to DMSO/DMF include cyclic carbonates and ionic liquids. Why might these be preferable from an environmental standpoint? Why might they be slower in some cases?
Section I — Common SN2 reactions
10.52∗ (moderate) Williamson ether synthesis: outline the synthesis of methyl ethyl ether starting from methanol and ethanol. What are the steps?
10.53 (moderate) Outline the conversion of 1-bromopropane into propanenitrile via $S_N2$ with $NaCN$, then into propanoic acid via Chapter 26 hydrolysis.
10.54 (moderate) Outline the synthesis of 1-azidobutane from 1-bromobutane via $NaN_3$.
10.55 (challenge) A medicinal chemist needs to install a methyl group on a nitrogen of a complex molecule. The amine has $pK_{aH} \approx 10$. Propose a sequence using methyl iodide. What is the major issue, and how do you avoid over-methylation?
10.56 (challenge) Mitsunobu reaction: look up the mechanism. What is the role of triphenylphosphine? Of DEAD?
Section J — Biological SN2
10.57 (moderate) Explain why SAM (S-adenosylmethionine) is such a good electrophile for biological methylation. Identify the leaving group and compute the rate of departure heuristically using $pK_a$.
10.58 (moderate) Glutathione conjugation in the liver detoxifies many electrophilic drugs. Suppose you have a drug containing an α,β-unsaturated ketone (a Michael acceptor). How might glutathione attack it? What kind of mechanism is this?
10.59 (challenge) DNA methyltransferases catalyze a single $S_N2$ reaction at extraordinarily high rate (kcat ~ 1 s⁻¹, vs. uncatalyzed rate of ~10⁻¹² s⁻¹). What enzymatic strategies achieve the $10^{12}$-fold rate enhancement?
10.60 (challenge) Methylated DNA has different optical and chemical properties than unmethylated. Specifically, 5-methylcytosine is more readily oxidized by Tet enzymes (5-mC → 5-hydroxymethyl-C). What organic chemistry transformations are involved?
Section K — Distinguishing SN2 from SN1
10.61∗ (challenge) A student observes the following experimental results for an unknown reaction: - The rate is first-order in substrate and zero-order in nucleophile. - The product is racemic. - Adding $LiClO_4$ to the solution increases the rate. - The substrate is tertiary.
Identify the mechanism. Justify with each observation.
10.62 (challenge) Repeat 10.61 for the following observations: - Second-order kinetics. - 100% inverted product. - Reaction works only with primary or secondary halides. - Polar aprotic solvent dramatically accelerates.
10.63 (challenge) A reaction shows: - Mixed kinetics — partly 1st order, partly 2nd order in [Nu]. - Mostly inverted product but with some retention. - Solvent affects both pathways.
Propose a model that explains these observations.
Section L — Cumulative & integrative
10.64 (challenge) A student plans to install an azide group on $(R)$-2-octanol. They want the product to have $(S)$-azide configuration. Outline a 2-step sequence starting from $(R)$-2-octanol.
10.65 (challenge, integrative) Combine Chapter 3 (acid-base), Chapter 5 (kinetics), and Chapter 10 ($S_N2$) to design an experimental protocol that distinguishes between $S_N2$ and $S_N1$ on a substrate of unknown class. List the experiments you would run and the expected results for each mechanism.
Preview of Chapter 11
Chapter 11 introduces $S_N1$ — the carbocation-mediated cousin of $S_N2$. The contrast (1st vs 2nd order; racemization vs inversion; polar protic vs polar aprotic; tertiary preferred vs primary preferred) will sharpen your understanding of both. Bring the $pK_a$ framework, mechanism-drawing skill, and stereochemistry vocabulary developed here.