Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

What product would you expect from a nucleophilic substitution reaction of (S) -2-bromohexane with acetate ion, CH₃CO₂^- ? Assume that inversion of configuration occurs, and show the stereochemistry of both the reactant and

product.

What product would you expect to obtain from reaction of with (R)-2-bromobutane? Show the stereochemistry of both the reactant and product.

Assign configuration to the following substance, and draw the structure of the product that would result from nucleophilic substitution reaction with  (reddish brown =Br):

What product would you expect to obtain from ${\mathbf{S}}_N\mathbf{2}$ reaction of  ${\mathbf{OH}}^{-}$with (R)-2-bromobutane? Show the stereochemistry of both the reactant and product.

What product would you expect from ${\mathbf{S}}_{\mathbf{N}}\mathbf{2}$ reaction of 1-bromobutane with each of the following?

(a) NaI (b) KOH (c) $\mathbf{H}\mathbf{—}\mathbf{C}\equiv \mathbf{C}\mathbf{—}\mathbf{Li}$ (d) ${\mathbf{NH}}_{\mathbf{3}}$

Which substance in each of the following pairs is more reactive as a nucleophile? Explain.

(a) ${\left({\mathbf{CH}}_{\mathbf{3}}\right)}_{\mathbf{2}}{\mathbf{N}}^{\mathbf{-}}\mathbf{or}{\left({\mathbf{CH}}_{\mathbf{3}}\right)}_{\mathbf{2}}\mathbf{NH}$(b) ${\left(C{H}_3\right)}_{\mathbf{3}}\mathbf{B}\mathbf{ }\mathit{o}\mathit{r}\mathbf{ }{\left(C{H}_3\right)}_{\mathbf{3}}\mathbf{N}$(c) ${\mathbf{H}}_{\mathbf{2}}\mathbf{O}\mathbf{ }\mathbf{or}\mathbf{ }{\mathbf{H}}_{\mathbf{2}}\mathbf{S}$ 

Rank the following compounds in order of their expected reactivity toward ${\mathbf{S}}_{\mathbf{N}}\mathbf{2}$ reaction:

${\mathbf{CH}}_{\mathbf{3}}\mathbf{Br}\mathbf{,}{\mathbf{CH}}_{\mathbf{3}}\mathbf{OTos}\mathbf{,}{\left(\mathbf{CH}\mathbf{3}\right)}_{\mathbf{3}}\mathbf{CCl}\mathbf{,}{\left(\mathbf{CH}\mathbf{3}\right)}_{\mathbf{2}}\mathbf{CHCl}$

Organic solvents like benzene, ether, and chloroform are neither protic nor strongly polar. What effect would you expect these solvents to have on the reactivity of a nucleophile in ${\mathbf{S}}_{\mathbf{N}}\mathbf{2}$ reactions?

What product(s) would you expect from reaction of (S)-3-chloro-3-methyloctane with acetic acid? Show the stereochemistry of both reactant and product

Among the many examples of reactions that occur with incomplete racemization, the optically pure tosylate of 2,2-dimethyl-1-phenyl-1-propan (${\left[\alpha \right]}_{\mathbf{D}}$= 230.3) gives the corresponding acetate (${\left[\alpha \right]}_{\mathbf{D}}$= 15.3) when heated in acetic acid. If complete inversion had occurred, the optically pure acetate would have had ${\left[\alpha \right]}_{\mathbf{D}}$= 153.6. What percentage racemization and what percentage inversion occurred in this reaction?

Assign configuration to the following substrate, and show the stereochemistry and identity of the product you would obtain by reaction with water (reddish-brown=Br):

Rank the following substances in order of their expected ${\mathbf{S}}_{\mathbf{N}}\mathbf{1}$ reactivity:

3-Bromo-1-butene and 1-bromo-2-butene undergo ${\mathbf{S}}_{\mathbf{N}}\mathbf{1}$ reaction at nearly the same rate, even though one is a secondary halide and the other is primary. Explain.

Predict whether each of the following substitution reactions is likely to be ${\mathbf{S}}_{\mathbf{N}}\mathbf{1}$or${\mathbf{S}}_{\mathbf{N}}\mathbf{2}$:

(a)

(b)

Question: Review the mechanism of geraniol biosynthesis shown in Figure 11-15, and propose a mechanism for the biosynthesis of limonene from linalyl diphosphate.

Question: Ignoring double-bond stereochemistry, what products would you expect from elimination reactions of the following alkyl halides? Which product will be the major product in each case?

What alkyl halides might the following alkenes have been made from ?

(a) 

(b) 

What stereochemistry do you expect for the alkene obtained by E2 elimination of (1R, 2R)-1,2-dibromo-1,2-diphenylethane? Draw a Newman projection of the reacting conformation.

What stereochemistry do you expect for the trisubstituted alkene obtained by E2 elimination of the following alkyl halide on treatment with KOH? (Reddish brown = Br.)

Question: What stereochemistry do you expect for the alkene obtained by E2 elimination of (1R, 2R)-1,2-dibromo-1,2-diphenylethane? Draw a Newman projection of the reacting conformation.

Which isomer would you expect to undergo E2 elimination faster, trans-1-bromo-4-tert-butylcyclohexane or cis-1-bromo-4-tert-butylcyclohexane? Draw each molecule in its more stable chair conformation, and explain your answer.

Tell whether each of the following reactions is likely to be S_N1, S_N2, E1, E1cB or E2:

a) 

Tell whether each of the following reactions is likely to be S_N1, S_N2, E1, E1cB or E2:

b)

Tell whether each of the following reactions is likely to be S_N1, S_N2, E1, E1cB or E2:

c) 

d) Tell whether each of the following reactions is likely to be S_N1, S_N2, E1, E1cB or E2:

(S)-2-Butanol slowly racemizes on standing in dilute sulfuric acid. Explain.

The reaction of HBr with (R)-3-methyl-3-hexanol leads to racemic 3-Bromo-3-methyl hexane. Explain.

Propose a structure for an alkyl halide that gives only (E)-3-methyl-2-phenyl-2-pentene on ${\mathbf{E}}_{\mathbf{2}}$ elimination. Make sure you indicate the stereochemistry.

Although anti-periplanar geometry is preferred for E2 reactions, it isn’t absolutely necessary. The deuterated Bromo compound shown here reacts with a strong base to yield an undeuterated alkene. Clearly, a syn elimination has occurred. Make a molecular model of the reactant, and explain the result.

In light of your answer to Problem 11-74, explain why one of the following isomers undergoes E2 reaction approximately 100 times as fast as the other. Which isomer is more reactive, and why?

The reaction of 1-chlorooctane with CH₃CO₂ 2 to give octyl acetate is greatly accelerated by adding a small quantity of iodide ion. Explain

The amino acid methionine is formed by a methylation reaction of homocysteine with N-methyltetrahydrofolate. The stereochemistry of the reaction has been probed by carrying out the transformation using a donor with a “chiral methyl group” that contains protium (H), deuterium (D), and tritium (T) isotopes of hydrogen. Does the methylation reaction occur with inversion or retention of configuration?

Amines are converted into alkenes by a two-step process called Hofmann elimination. SN₂ reaction of the amine with an excess of ${\mathbf{CH}}_3\mathbf{I}$ in the first step yields an intermediate that undergoes E₂ reaction when treated with silver oxide as base. Pentylamine, for example, yields 1-pentene. Propose a structure for the intermediate, and explain why it readily undergoes elimination.

${\mathbf{CH}}_{\mathbf{3}}{\mathbf{CH}}_{\mathbf{2}}{\mathbf{CH}}_{\mathbf{2}}{\mathbf{CH}}_{\mathbf{2}}{\mathbf{CH}}_{\mathbf{2}}{\mathbf{NH}}_{\mathbf{2}}\underset{\mathbf{2.}{\mathbf{\text{ Ag}}}_{\mathbf{2}}\mathbf{O}\mathbf{,}{\mathbf{\text{ H}}}_{\mathbf{2}}\mathbf{O}}{\overset{\mathbf{1.}{\mathbf{\text{ Excess CH}}}_{\mathbf{3}}\mathbf{I}}{\mathbf{\to }}}{\mathbf{CH}}_{\mathbf{3}}{\mathbf{CH}}_{\mathbf{2}}{\mathbf{CH}}_{\mathbf{2}}\mathbf{CH}\mathbf{=}{\mathbf{CH}}_{\mathbf{2}}$

The antipsychotic drug flupentixol is prepared by the following scheme:

(a) What alkyl chloride B reacts with amine A to form C?

(b) Compound C is treated with ${\mathbf{SOCl}}_2$ , and the product is allowed to react with magnesium metal to give a Grignard reagent D. What is the structure of D?

(c) We’ll see in Section 19-7 that Grignard reagents add to ketones, such as E, to give tertiary alcohols, such as F. Because of the newly formed chirality center, compound F exists as a pair of enantiomers. Draw both, and assign R,S configuration.

(d) Two stereoisomers of flupentixol are subsequently formed from F, but only one is shown. Draw the other isomer, and identify the type of stereoisomerism.

The following tertiary alkyl bromide does not undergo a nucleophilic substitution reaction by either SN1 or SN2 mechanisms. Explain.

Write the product you would expect from reaction of each of the following alkyl halides with (1)Na^+-SCH₃ and (2)Na^+-OH  (green = Cl):

a) 

Write the product you would expect from reaction of each of the following alkyl halides with (1)Na^+-SCH₃ and (2)Na^+-OH  (green = Cl):

b) 

Write the product you would expect from reaction of each of the following alkyl halides with (1)Na^+-SCH₃ and (2)Na^+-OH  (green = Cl):

c) 

From which alkyl bromide was the following alkyl acetate made S_N2 by  reaction? Write the reaction, showing all stereochemistry.

Assign R or S configuration to the following molecule, write the product you would expect from S_N2 reaction with NaCN, and assign R or S configuration to the product (green = Cl):

Draw the structure and assign Z or E stereochemistry to the product you expect from E2 reaction of the following molecule with NaOH (green = Cl):

We saw in Section 8-7 that bromohydrins are converted into epoxides when treated with base. Propose a mechanism, using curved arrows to show the electron flow.

Metabolism of S-adenosylhomocysteine (Section 11-6) involves the following sequence. Propose a mechanism for the second step.

Reaction of iodoethane with  yields a small amount of isonitrile,${\mathrm{CH}}_3{\mathrm{CH}}_2\mathrm{N}\equiv \mathrm{C}$, along with the nitrile ${\mathrm{CH}}_3{\mathrm{CH}}_2\mathrm{C}\equiv \mathrm{N}$ as the major product. Write electron-dot structures for both products, assign formal charges as necessary, and propose mechanisms to account for their formation.

One step in the urea cycle for ridding the body of ammonia is the conversion of argininosuccinate to the amino acid arginine plus fumarate. Propose a mechanism for the reaction, and show the structure of arginine.

Methyl esters (${\mathrm{RCO}}_2{\mathrm{CH}}_3$) undergo a cleavage reaction to yield carboxylate ions plus iodomethane on heating with LiI in dimethylformamide:

The following evidence has been obtained: (1) The reaction occurs much faster in DMF than in ethanol. (2) The corresponding ethyl ester (${\mathrm{RCO}}_2{\mathrm{CH}}_2{\mathrm{CH}}_3$) cleaves approximately 10 times more slowly than the methyl ester. Propose a mechanism for the reaction. What other kinds of experimental evidence could you gather to support your hypothesis?

S_N2 reactions take place with inversion of configuration, and  S_N1 reactions take place with racemization. The following substitution reaction, however, occurs with complete retention of configuration. Propose a mechanism.

 .

Which compound in each of the following pairs will react faster in an S_N2 reaction with?

a) CH₃Br or CH₃I

Which compound in each of the following pairs will react faster in an S_N2 reaction with OH^- ?

(b) CH₃CH₂I in ethanol or dimethyl sulfoxide 

Which compound in each of the following pairs will react faster in an S_N2 reaction with OH^- ?

(c) ${\left({\mathrm{CH}}_3\right)}_3\mathrm{CCl} \mathrm{or} {\mathrm{CH}}_3\mathrm{Cl}$