Alkyl Halides and Nucleophilic Substitution

Question: Rank the species in each group in order of increasing nucleophilicity.

a. CH₃CH₂S^- ,CH₃CH₂O^- ,CH₃CO₂^- in CH₃OH

b. CH₃NH₂ ,CH₃SH ,CH₃OH in acetone

c. ^-OH ,F^- ,Cl^- in acetone

d. HS^- ,F^- ,I^- in CH₃OH

Question: Classify each solvent as protic or aprotic.

1. (CH₃)₂CHOH
2. CH₃NO₂
3. CH₂Cl₂
4. NH₃
5. N(CH₃)₃
6. HCONH₂

Question: Why is the amine N atom more nucleophilic than the amide N atom  CH₃CONHCH₂CH₂CH₂NHCH₃?

Question: Consider the following S_N2 reaction.

1. Draw a mechanism using curved arrows.
2. Draw an energy diagram. Label the axes, the reactants, products, E_a , and $∆\mathrm{H}°$. Assume that the reaction is exothermic.
3. Draw the structure of the transition state.
4. What is the rate equation?
5. What happens to the reaction rate in each of the following instances? [1] The leaving group is changed from Br^- to I^- ;[2] The solvent is changed from acetone to CH₃CH₂OH ; [3] The alkyl halide is changed from CH₃(CH₂)₄Br  to CH₃CH₂CH₂CH(Br)CH₃ ; [4] The concentration of CN^- is increased by a factor of five; and [5] The concentrations of both the alkyl halide and  CN^- are increased by a factor of five.

Question: Pick the reactant or solvent in each part that gives the faster S_N2 reaction.

1. reaction of with OH^- or CH₃CH₂Br 
2. reaction of CH₃CH₂CH₂Cl NaOH or NaOCOCH₃
3. reaction of  CH₃CH₂CH₂I with ^-OCH₃ in or DMSO

Question: Draw the products of each reaction and indicate the stereochemistry where appropriate.

a.

b.

c.

Question: Classify the carbocations  $1°,2° \mathrm{or} 3°$as or and rank the carbocations in each group in the order of increasing stability.

a.

b.

Question: Which of the following carbocations (A or B) is more stable? Explain your choice.

A.

B.

Question: Consider the following  S_N1 reaction.

1. Draw a mechanism for this reaction using curved arrows.
2. Draw an energy diagram. Label the axes, starting material, product E_a and $∆\mathrm{H}°$. Assume that the starting material and product are equal in energy.
3. Draw the structure of any transition states.
4. What is the rate equation for this reaction?
5. What happens to the reaction rate in each of the following instances? [1] The leaving group is changed from I^- to Cl^- ; [2] The solvent is changed from H₂O to DMF; [3] The alkyl halide is changed from (CH₃)₂ C(I) CH₂CH₃ to (CH₃) CHCH(I)CH₃ ; [4] The concentration of H₂O is increased by a factor of five; and [5] The concentrations of both the alkyl halide and H₂O are increased by factor of five.

Question: Pick the reactant or solvent in each part that gives the faster S_N1 reaction.

1. Reaction of  H₂O with (CH₃)CCl  or (CH₃)₃Cl
2. Reaction of  CH₃OH with (CH₃)CBr or  (CH₃)₂CHCH₂Br
3. Reaction of   CH₃CH₂CH(I)CH₃ with CH₃CH₂OH  in water or DMSO

Question: Draw the products of each S_N1 reaction and indicate the stereochemistry when necessary. 

a.

b.

Draw a stepwise mechanism for the following reaction that illustrates how two substitution products are formed. Explain why 1-bromohex-2-ene reacts rapidly with a weak nucleophile (CH₃OH) under reaction conditions, even though it is a $1°$ alkyl halide.

Question: Fluticasone, the chapter-opening molecule, can be prepared by the following reaction. Draw a stepwise mechanism for this reaction.

Question: (a) Rank A, B, and C in order of increasing  S_N2 reactivity. (b) Rank A, B, and C in order of increasing S_N1 reactivity.

Question: Determine the mechanism of nucleophilic substitution of each reaction and draw the products, including stereochemistry.

a.

b.

c.

d.

e.

f.

Question: Uridine monophosphate (UMP) is one of the four nucleotides that compose RNA, the nucleic acid that translates the genetic information of DNA into proteins needed by cells for proper function and development. A key step in the synthesis of UMP is the reaction of A with B to form C, which is then converted to UMP in one step. Draw a stepwise mechanism for this S_N1 reaction.

Question: Diphenhydramine, the antihistamine in Benadryl, can be prepared by the following two-step sequence.  What is the structure of diphenhydramine?

Question: Draw a stepwise, detailed mechanism for the following reaction. Use curved arrows to show the movement of electrons.

Question: When a single compound contains both a nucleophile and a leaving group, an intramolecular reaction may occur. With this in mind, draw the product of the following reaction. 

Question: Nicotine can be made when the following salt is treated with Na₂Co₃ . Draw a stepwise mechanism for this reaction.

Question: Quinapril (trade name Accupril) is used to treat high blood pressure and congestive heart failure. One step in the synthesis of quinapril involves the reaction of the racemic alkyl bromide A with a single enantiomer of the amino ester B. (a) What two products are formed in this reaction? (b) Given the structure of quinapril, which one of these two products is needed to synthesize the drug?

quinapril

Question: Draw a stepwise, detailed mechanism for the following reaction.

Question: When (R)-6-bromo-2,6-dimethylnonane is dissolved in  , nucleophilic substitution yields an optically inactive solution. When the isomeric halide (R)-2-bromo-2,5- dimethylnonane is dissolved in   under the same conditions, nucleophilic substitution forms an optically active solution. Draw the products formed in each reaction, and explain why the difference in optical activity is observed.

Question: Fill in the appropriate reagent or starting material in each of the following reactions:

a.

b.

c. 

d.

Question: Device a synthesis of each compound from an alkyl halide using any other organic or inorganic reagents.

a.

b.

c.

d.

Question: Suppose you have compounds A–D at your disposal. Using these compounds, devise two different ways to make E. Which one of these methods is preferred, and why?

Question: Muscalure, the sex pheromone of the common housefly, can be prepared by a reaction sequence that uses two nucleophilic substitutions. Identify compounds A–D in the following synthesis of muscalure. 

Question: You will often return to nucleophilic substitution, in particular the  S_N2 reaction, in subsequent chapters and concentrate on the nucleophile rather than the alkyl halide. By using different nucleophiles, nucleophilic substitution allows the synthesis of a wide variety of organic compounds with many different functional groups. With this in mind, draw the products of each two-step sequence.  (Hint: Step [1] in each part involves an acid-base reaction that removes the most acidic hydrogen from the starting material.)

a.

b.

c.

Question: Explain why quinuclidine is a much more reactive nucleophile than triethylamine, even though both compounds have N atoms surrounded by three R groups.

Question: Draw a stepwise mechanism for the following reaction sequence.

Classify each reaction as a substitution, an elimination, or neither. Identify the leaving group in each reaction, and the nucleophile in substitutions.

Question: As you will learn in Chapter 9, the epoxide is an ether with an oxygen atom in a three-membered ring. Epoxides can be made by intramolecular S_N2  reactions of intermediates that contain a nucleophile and a leaving group on adjacent carbons, as shown.

Assume that each of the following starting materials can be converted to an epoxide by this reaction. Draw the product formed (including stereochemistry) from each starting material. Why might some of these reactions be more difficult than others in yielding nucleophilic substitution products?

a.

b.

c.

d.

Question: When trichloride J is treated with CH₃OH , nucleophilic substitution forms the dihalide K. Draw a mechanism for this reaction and explain why one Cl is much more reactive than the other two Cl’s so that a single substitution product is formed.

Question: In some nucleophilic substitutions under  S_N1 conditions, complete racemization does not occur, and a small excess of one enantiomer is present. For example, treatment of optically pure 1-bromo-1-phenylpropane with water forms 1-phenylpropan-1-ol. a. Calculate how much of each enantiomer is present using the given optical rotation data. b. Which product predominates—the product of inversion or the product of retention of configuration? c. Suggest an explanation for this phenomenon.