Amines

Explain the observed difference in the $p{K}_a$  values of the conjugate acids of amines A and B.

Why is pyrrole more acidic than pyrrolidine?

What amide(s) can be used to prepare each amine by reduction?

 (a)

(b)

(c)

What carbonyl and nitrogen compounds are needed to make each compound by reductive amination? When more than one set of starting materials is possible, give all possible methods.

(a)

(b)

(c)

Draw the product of each reductive amination reaction.

(a)

(b)

(c)

(d)

How would you separate toluene ($C_6{H}_{5}C{H}_3$ ), benzoic acid ($C_6{H}_{5}C{O}_{2}H$ ), and aniline ($C_6{H}_{5}N{H}_2$ ) by an extraction procedure?

Draw the products formed when p-methylaniline ( $p-C_6{H}_{4}N{H}_2$ ) is treated with each reagent.

1. HCl
2.  $C{H}_{3}COCl$
3.  ${\left(C{H}_{3}CO\right)}_{2}O$
4. Excess  $C{H}_{3}I$
5.  ${\left(C{H}_3\right)}_{2}C=O$
6.  $C{H}_{3}COCl, AlC{l}_3$
7.  $C{H}_{3}C{O}_{2}H$
8.  $NaN{O}_2,HCl$
9. Part (b), then $C{H}_{3}COCl,AlC{l}_3$  
10.  $C{H}_{3}CHO,NaB{H}_{3}CN$

Draw the products formed when each amine is treated with [1]  $C{H}_{3}I$ (excess); [2] $A{g}_{2}O$ ; [3] $∆$ . Indicate the major product when a mixture results.

a

b

c

d

Answer the following questions about benzphetamine, a habit-forming diet pill sold under the trade name Didrex

1. Label the stereogenic center(s).
2. What amide(s) can be reduced to form benzphetamine?
3. What carbonyl compound and amine can be used to make benzphetamine by reductive amination? Draw all possible methods.
4. What products are formed by Hofmann elimination from benzphetamine? Label the major product.

Question: Identify the intermediates (A–C) in the following reaction sequence, which was used to prepare racemic ofloxacin. One enantiomer of the product, levofloxacin, is an antibiotic used to treat severe bacterial infections that have not responded to other drugs.

Draw the organic products formed in each reaction.

a

b

c

d

e

f

g

h

i

j

What is the major Hofmann elimination product formed from each amine?

a

b

c

Identify A, B, and C, three intermediates in the synthesis of the pain reliever and anesthetic fentanyl.

Question: Devise a synthesis of each compound from benzene. You may use any other organic or inorganic reagents.

a.

b.

c.

d.

e.

f.

Draw the product formed when A is treated with each series of reagents.

a. [1] $H_{2}O$  ; [2] NaH; [3]  $C{H}_{3}Br$ 

b. [1] CuCN; [2] DIBAL-H; [3]  $H_{2}O$

c. [1] $C_6{H}_{5}N{H}_2$ ; [2]   $C{H}_{3}COCl$

A chiral amine A having the R configuration undergoes Hofmann elimination to form an alkene B as the major product. B is oxidatively cleaved with ozone, followed by $C{H}_{3}SC{H}_3$  , to form $C{H}_2=O$  and $C{H}_{3}C{H}_{2}C{H}_{2}CHO$  . What are the structures of A and B?

Draw a stepwise mechanism for each reaction.

Draw a stepwise mechanism for the following reaction.

Alkyl diazonium salts decompose to form carbocations, which go on to form products of substitution, elimination, and (sometimes) rearrangement. Keeping this in mind, draw a stepwise mechanism that forms all of the following products.

Tertiary ( $3^{°}$) aromatic amines react with $NaN{O}_2$  and HCl to afford products of electrophilic aromatic substitution. Draw a stepwise mechanism for this nitrosation reaction and explain why it occurs only on benzene rings with strong ortho, para activating groups.

Question: Safrole, which is isolated from sassafras (Problem 21.33), can be converted to the illegal stimulant MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”) by a variety of methods. (a) Devise a synthesis that begins with safrole and uses a nucleophilic substitution reaction to introduce the amine. (b) Devise a synthesis that begins with safrole and uses reductive amination to introduce the amine.

Question: Synthesize each compound from benzene. Use a diazonium salt as one of the synthetic intermediates.

Devise a synthesis of each compound from aniline $\left(C_6{H}_{5}N{H}_2\right)$ as starting material.

a

b

c

Devise at least three different methods to prepare N-methylbenzylamine  $PhC{H}_{2}NHC{H}_3$ from benzene, any one-carbon organic compounds, and any required reagents.

Synthesize each compound from benzene. Use a diazonium salt as one of the synthetic intermediates.

Devise a synthesis of each biologically active compound from benzene.

Devise a synthesis of each compound from benzene, any organic alcohols having four carbons or fewer, and any required reagents.

a

b

c

Three isomeric compounds, A, B, and C, all have molecular formula $C_8{H}_{11}N$ . The  ${}^{1}H$NMR and IR spectral data of A, B, and C are given below. What are their structures?

Treatment of compound D with $LiAl{H}_4$  followed by $H_{2}O$ forms compound E. D shows a molecular ion in its mass spectrum at m/z = 71 and IR absorptions at $3600-3200 c{m}^{-1}$  and . E shows a molecular ion in its mass spectrum at m/z = 75 and IR absorptions at  $3636 c{m}^{-1}$ and $3600-3200 c{m}^{-1}$ . Propose structures for D and E from these data and the given 1H NMR spectra.

Question: The pKa of the conjugate acid of guanidine is 13.6, making it one of the strongest neutral organic bases. Offer an explanation.

The pKa of the conjugate acid of guanidine is 13.6, making it one of the strongest neutral organic bases. Offer an explanation.

Question: Rank the following compounds in order of increasing basicity and explain the order you chose.

Rank the following compounds in order of increasing basicity and explain the order you chose.

Question: Draw the product Y of the following reaction sequence. Y was an intermediate in the remarkable synthesis of cyclooctatetraene by Wilstatter in 1911.

Draw the product Y of the following reaction sequence. Y was an intermediate in the remarkable synthesis of cyclooctatetraene by Wilstatter in 1911.

Question: Devise a synthesis of each compound from the given starting material(s). Albuterol is a bronchodilator and proparacaine is a local anesthetic.

Devise a synthesis of each compound from the given starting material(s). Albuterol is a bronchodilator and proparacaine is a local anesthetic.

(a)

(b)

Question: Heating compound X with aqueous formaldehyde forms Y $\left(C_{17}{H}_{23}NO\right)$ ,which has been converted to a mixture of lupinine and epilupinine, alkaloids isolated from lupin, a perennial ornamental plant commonly seen on the roadside in parts of Alaska (Section 25.10). Identify Y and explain how it is formed.

Heating compound X with aqueous formaldehyde forms Y $\left(C_{17}{H}_{23}NO\right)$ , which has been converted to a mixture of lupinine and epilupinine, alkaloids isolated from lupin, a perennial ornamental plant commonly seen on the roadside in parts of Alaska (Section 25.10). Identify Y and explain how it is formed.