Organic chemistry with biological applications

John E. McMurry

Chapter 18

Amines and Heterocycles - all with Video Answers

Educators

Chapter Questions

Problem 1

Name the following compounds:
$$\text { (a) } \mathrm{CH}_{3} \mathrm{NHCH}_{2} \mathrm{CH}_{3}$$
b)
c)
d)
e)
f)

Allison Krajewski

Allison Krajewski

Numerade Educator

Problem 2

Draw structures corresponding to the following IUPAC names:
(a) Triisopropylamine
(b) Diallylamine
(c) $N$ -Methylaniline
(d) $N$ -Ethyl- $N$ -methylcyclopentylamine
(e) $N$ -Isopropylcyclohexylamine
(f) $N$ -Ethylpyrrole

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 3

Draw structures for the following heterocyclic amines:
(a) 5 -Methoxyindole
(b) 1,3 -Dimethylpyrrole
(c) $4-(N, N$ -Dimethylamino)pyridine
(d) 5-Aminopyrimidine

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 4

Which compound in each of the following pairs is more basic?
(a) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{NH}_{2}$ or $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CONH}_{2}$
(b) $\mathrm{NaOH}$ or $\mathrm{CH}_{3} \mathrm{NH}_{2}$
(c) $\mathrm{CH}_{3} \mathrm{NHCH}_{3}$ or pyridine

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 5

The benzylammonium ion $\left(\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{NH}_{3}^{+}\right)$ has $\mathrm{pK}_{\mathrm{a}}=9.33,$ and the propyl-ammonium ion has $\mathrm{pK}_{\mathrm{a}}=10.71$. Which is the stronger base, benzylamine or propylamine? What are the $\mathrm{pK}_{\mathrm{b}}$ 's of benzylamine and propylamine?

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 6

Rank the following compounds in order of increasing basicity:
(a) $p$ -Nitroaniline, $p$ -aminobenzaldehyde, $p$ -bromoaniline
(b) $p$ -Chloroaniline, $p$ -aminoacetophenone, $p$ -methylaniline
(c) $p$ -(Trifluoromethyl)aniline, $p$ -methylaniline, $p$ -(fluoromethyl)aniline

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 7

Calculate the percentages of neutral and protonated forms present in a solution of $0.0010 \mathrm{M}$ pyrimidine at $\mathrm{pH}=7.3 .$ The $\mathrm{p} K_{\mathrm{a}}$ of pyrimidinium ion is 1.3 .

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 8

Propose structures for either a nitrile or an amide that might be a precursor of each of the following amines:
(a) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{NH}_{2}$
(b) $\left(\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CH}_{2}\right)_{2} \mathrm{NH}$
(c) Benzylamine, $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{NH}_{2}$
(d) $N$ -Ethylaniline

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 9

Show two methods for synthesizing dopamine, a neurotransmitter involved in regulation of the central nervous system.

VS

Vivek Singh

Numerade Educator

Problem 10

How might the following amines be prepared using reductive amination reactions? Show all precursors if more than one is possible.
(a)
(b)
(c)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 11

How could you prepare the following amine using a reductive amination reaction?

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 12

What products would you expect from Hofmann elimination of the following amines? If more than one product is formed, tell which is major.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 13

What product would you expect from Hofmann elimination of a heterocyclic amine such as piperidine? Write all the steps.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 14

Propose a synthesis of the drug sulfathiazole from benzene and any necessary amine.

Kendrick Buford

Kendrick Buford

Numerade Educator

Problem 15

Propose syntheses of the following compounds from benzene:
(a) $N, N$ -Dimethylaniline
(b) $p$ -Chloroaniline
(c) $m$ -Chloroaniline

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 16

Draw an orbital picture of thiazole. Assume that both the nitrogen and sulfur atoms are $s p^{2}$ -hybridized, and show the orbitals that the lone pairs occupy.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 17

What is the percent protonation of the imidazole nitrogen atom in histidine at a physiological $\mathrm{pH}$ of $7.3 ?$

David Collins

Numerade Educator

Problem 18

Electrophilic aromatic substitution reactions of pyridine normally occur at C3. Draw the carbocation intermediates resulting from reaction of an electrophile at $\mathrm{C} 2, \mathrm{C} 3,$ and $\mathrm{C} 4,$ and explain the observed result.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 19

Which nitrogen atom in the hallucinogenic indole alkaloid $N, N$ -dimethyltryptamine is more basic? Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 20

Indole reacts with electrophiles at C3 rather than at C2. Draw resonance forms of the intermediate cations resulting from reaction at $\mathrm{C} 2$ and $\mathrm{C} 3,$ and explain the observed results.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 21

Name the following amines, and identify each as primary, secondary, or tertiary:

Ronald Prasad

Numerade Educator

Problem 22

The following compound contains three nitrogen atoms. Rank them in order of increasing basicity.

Anupa Sharad Medhekar

Anupa Sharad Medhekar

Numerade Educator

Problem 23

Name the following amine, including $R, S$ stereochemistry, and draw the product of its reaction with excess iodomethane followed by heating with $\mathrm{Ag}_{2} \mathrm{O}$ (Hofmann elimination). Is the stereochemistry of the alkene product $Z$ or $E$ ? Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 24

The following molecule has three nitrogen atoms. List them in order of increasing basicity, and explain your ordering.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 25

The following molecule can be prepared by reaction between a primary amine and a dihalide. Identify the two reactants, and write the reaction.

Preeti Kumari

Numerade Educator

Problem 26

Name the following compounds:

Nicholas Sacco

Numerade Educator

Problem 27

Draw structures corresponding to the following IUPAC names:
(a) $N, N$ -Dimethylaniline
(b) (Cyclohexylmethyl)amine
(c) $N$ -Methylcyclohexylamine
(d) (2-Methylcyclohexyl)amine
(e) $3-(N, N$ -Dimethylamino)propanoic acid

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 28

Propose structures for substances that fit the following descriptions:
(a) A chiral quaternary ammonium salt
(b) A six-membered heterocyclic diamine
(c) A secondary amine, $\mathrm{C}_{6} \mathrm{H}_{11} \mathrm{~N}$

Ramesh Singh

Numerade Educator

Problem 29

Classify each of the amine (not amide) nitrogen atoms in the following substances as primary, secondary, or tertiary:

Vasu Makani

Numerade Educator

Problem 30

There are eight isomeric amines with the formula $\mathrm{C}_{4} \mathrm{H}_{11} \mathrm{~N}$. Draw them, name them, and classify each as primary, secondary, or tertiary.

Sulav Pokhrel

Numerade Educator

Problem 31

Which compound do you think is more basic, $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{NH}_{2}$ or $\mathrm{CF}_{3} \mathrm{CH}_{2} \mathrm{NH}_{2}$ ? Explain.

Lara Gossage

Numerade Educator

Problem 32

Which compound do you think is more basic, $p$ -aminobenzaldehyde or aniline? Explain.

Narayan Hari

Numerade Educator

Problem 33

Although pyrrole is a much weaker base than most other amines, it is a much stronger acid $\left(\mathrm{p} K_{\mathrm{a}} \approx 15\right.$ for the pyrrole versus 35 for diethylamine). The N-H proton is readily abstracted by base to yield the pyrrole anion, $\mathrm{C}_{4} \mathrm{H}_{4} \mathrm{~N}^{-} .$ Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 34

Histamine, whose release in the body triggers nasal secretions and constricted airways, has three nitrogen atoms. List them in order of increasing basicity, and explain your ordering.

Colton K

Numerade Educator

Problem 35

Protonation of an amide using strong acid occurs on oxygen rather than on nitrogen. Suggest a reason for this behavior, taking resonance into account.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 36

$p$ -Nitroaniline $\left(\mathrm{p} K_{\mathrm{a}}=1.0\right)$ is less basic than $m$ -nitroaniline $\left(\mathrm{p} K_{\mathrm{a}}=2.5\right)$ by a factor of $30 .$ Explain, using resonance structures. (The $\mathrm{p} K_{\mathrm{a}}$ values refer to the corresponding ammonium ions.)

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 37

How would you prepare the following amines from butan-1-ol?
(a) Butylamine
(b) Dibutylamine
(c) Pentylamine
(d) Butanamide

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 38

How would you prepare benzylamine, $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{NH}_{2},$ from benzene? More than one step is needed.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 39

How might you prepare pentylamine from the following starting materials?
(a) Pentanamide
(b) Pentanenitrile
(c) But-1-ene
(d) Butan-1-ol
(e) Pentanoic acid

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 40

How might a reductive amination be used to synthesize ephedrine, an amino alcohol that is widely used for the treatment of bronchial asthma?

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 41

Give the structures of the major organic products you would expect from reaction of $m$ -toluidine (m-methylaniline) with the following reagents:
(a) $\mathrm{Br}_{2}$ ( 1 equivalent)
(b) $\mathrm{CH}_{3} \mathrm{I}$ (excess)
(c) $\mathrm{CH}_{3} \mathrm{COCl}$ in pyridine
(d) The product of (c), then $\mathrm{HSO}_{3} \mathrm{Cl}$

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 42

Show the products from reaction of $p$ -bromoaniline with the following reagents:
(a) $\mathrm{CH}_{3} \mathrm{I}$ (excess)
(b) HCl
(c) $\mathrm{CH}_{3} \mathrm{COCl}$
(d) $\mathrm{CH}_{3} \mathrm{MgBr}$

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 43

What are the major products you would expect from Hofmann elimination of the following amines?

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 44

Show the mechanism of reductive amination of cyclohexanone and dimethylamine with $\mathrm{NaBH}_{4}$.

Tom Rutherford

Numerade Educator

Problem 45

Fill in the missing reagents a-d in the following synthesis of racemic methamphetamine from benzene:

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 46

How would you prepare benzylamine, $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}_{2} \mathrm{NH}_{2}$, from each of the following starting materials?

Colton K

Numerade Educator

Problem 47

Phenacetin, a substance formerly used in over-the-counter headache remedies, has the formula $\mathrm{C}_{10} \mathrm{H}_{13} \mathrm{NO}_{2} .$ Phenacetin is neutral and does not dissolve in either acid or base. When warmed with aqueous $\mathrm{NaOH}$, phenacetin yields an amine, $\mathrm{C}_{8} \mathrm{H}_{11} \mathrm{NO},$ whose ${ }^{1} \mathrm{H}$ NMR spectrum is shown. When heated with HI, the amine is cleaved to an aminophenol, $\mathrm{C}_{6} \mathrm{H}_{7} \mathrm{NO} .$ What is the structure of phenacetin, and what are the structures of the amine and the aminophenol?

Nicole Krahulik

Nicole Krahulik

Numerade Educator

Problem 48

Propose structures for amines with the following ${ }^{1} \mathrm{H}$ NMR spectra:

Prashant Bana

Numerade Educator

Problem 49

Oxazole is a five-membered aromatic heterocycle. Draw an orbital picture of oxazole, showing all $p$ orbitals and all lone-pair orbitals. Would you expect oxazole to be more basic or less basic than pyrrole? Explain.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 50

Substituted pyrroles are often prepared by treatment of a 1,4 -diketone with ammonia. Suggest a mechanism.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 51

3,5-Dimethylisoxazole is prepared by reaction of pentane-2,4-dione with hydroxylamine. Propose a mechanism.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 52

Fill in the missing reagents $\mathbf{a}-\mathbf{e}$ in the following scheme:

Tom Rutherford

Numerade Educator

Problem 53

Pyrrole has a dipole moment $\mu=1.8 \mathrm{D}$, with the nitrogen atom at the positive end of the dipole. Explain.

Lottie Adams

Numerade Educator

Problem 54

One problem with reductive amination as a method of amine synthesis is that by-products are sometimes obtained. For example, reductive amination of benzaldehyde with methylamine leads to a mixture of $N$ -methylbenzylamine and $N$ -methyldibenzylamine. How do you suppose the tertiary amine by-product is formed? Propose a mechanism.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 55

Choline, a component of the phospholipids in cell membranes, can be prepared by $S_{N} 2$ reaction of trimethylamine with ethylene oxide. Show the structure of choline, and propose a mechanism for the reaction

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 56

Chlorophyll, heme, vitamin $\mathrm{B}_{12}$, and a host of other substances are biosynthesized from porphobilinogen (PBG), which is itself formed from condensation of two molecules of 5 -aminolevulinate. The two 5-aminolevulinates are bound to lysine (Lys) amino acids in the enzyme, one in the enamine form and one in the imine form, and their condensation is thought to occur by the following steps. Using curved arrows, show the mechanism of each step.

Dominador Tan

Numerade Educator

Problem 57

Cyclopentamine is an amphetamine-like central nervous system stimulant. Propose a synthesis of cyclopentamine from materials of five carbons or less.

Sima Sarker

Numerade Educator

Problem 58

Atropine, $\mathrm{C}_{17} \mathrm{H}_{23} \mathrm{NO}_{3}$, is a poisonous alkaloid isolated from the leaves and roots of Atropa belladonna, the deadly nightshade. In small doses, atropine acts as a muscle relaxant; 0.5 ng (nanogram, $10^{-9} \mathrm{~g}$ ) is sufficient to cause pupil dilation. On basic hydrolysis, atropine yields tropic acid, $\mathrm{C}_{6} \mathrm{H}_{5} \mathrm{CH}\left(\mathrm{CH}_{2} \mathrm{OH}\right) \mathrm{CO}_{2} \mathrm{H},$ and tropine, $\mathrm{C}_{8} \mathrm{H}_{15} \mathrm{NO} .$ Tropine is an optically inactive alcohol that yields tropidene on dehydration with $\mathrm{H}_{2} \mathrm{SO}_{4} .$ Propose a structure for atropine.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 59

Propose a structure for the product with formula $\mathrm{C}_{9} \mathrm{H}_{17} \mathrm{~N}$ that results when 2 -(2-cyanoethyl)cyclohexanone is reduced catalytically.

Benjamin Angeles

Benjamin Angeles

Numerade Educator

Problem 60

Coniine, $\mathrm{C}_{8} \mathrm{H}_{17} \mathrm{~N},$ is the toxic principle of the poison hemlock drunk by Socrates. When subjected to Hofmann elimination, coniine yields $5-(N, N$ -dimethylamino )oct-1-ene. If coniine is a secondary amine, what is its structure?

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 61

How would you synthesize coniine (Problem 18.60) from acrylonitrile $\left(\mathrm{H}_{2} \mathrm{C}=\mathrm{CHCN}\right)$ and ethyl 3 -oxohexanoate $\left(\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{COCH}_{2} \mathrm{CO}_{2} \mathrm{Et}\right) ?$

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 62

Cycloocta-1,3,5,7-tetraene was first synthesized in 1911 by a route that involved the following transformation. How would you accomplish this reaction?

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 63

The following transformation involves a conjugate nucleophilic addition reaction (Section 14-11) followed by an intramolecular nucleophilic acyl substitution reaction (Section $16-2$ ). Show the mechanism.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 64

Propose a mechanism for the following reaction:

Lottie Adams

Numerade Educator

Problem 65

One step in the biosynthesis of morphine is the reaction of dopamine with $p$ -hydroxyphenylacetaldehyde to give (S)-norcoclaurine. Assuming that the reaction is acid-catalyzed, propose a mechanism.

Danielle Ashley

Danielle Ashley

Numerade Educator

Problem 66

The antitumor antibiotic mitomycin C functions by forming cross-links in DNA chains.
(a) The first step is loss of methoxide and formation of an iminium ion intermediate that is deprotonated to give an enamine. Show the mechanism.
(b) The second step is reaction of the enamine with DNA to open the three-membered, nitrogen-containing (aziridine) ring. Show the mechanism.
(c) The third step is loss of carbamate $\left(\mathrm{NH}_{2} \mathrm{CO}_{2}^{-}\right)$ and formation of an unsaturated iminium ion, followed by a conjugate addition of another part of the DNA chain. Show the mechanism.

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Bcrypt_Sha256$$2B$12$Robtujr9L3Df26Glt66Ss.Uw2Kt8Wdwq0Nfds2Ggy2Aewx5U6Voiw Bcrypt_Sha256$$2B$12$Robtujr9L3Df26Glt66Ss.Dgzqci3Fjqnd6Vr5Zzgo/E/U5G11F5C

Numerade Educator

Problem 67

One of the reactions used in determining the sequence of nucleotides in a strand of DNA is reaction with hydrazine. Propose a mechanism for the following reaction, which occurs by an initial conjugate addition followed by internal amide formation:

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 68

$\alpha$ -Amino acids can be prepared by the Strecker synthesis, a two-step process in which an aldehyde is treated with ammonium cyanide followed by hydrolysis of the amino nitrile intermediate with aqueous acid. Propose a mechanism for the reaction.

Grigoriy Sereda

Grigoriy Sereda

Numerade Educator

Problem 69

Tetracaine, a substance used as a spinal anesthetic, can be prepared from benzene by the following route. Show how you could accomplish each of the transformations (a) through (d).

Anish Wadhwa

Numerade Educator

Problem 70

The anti-inflammatory drug celecoxib, marketed as Celebrex, is widely used for treatment of rheumatoid arthritis. Draw a mechanism for the following step used in celecoxib synthesis.

Susan Hallstrom

Susan Hallstrom

Numerade Educator