The following drugs are synthesized using the methods in

Ketones and aldehydes react with primary amines to give imines. They react with secondary amines to give enamines (vinyl amines). (a) For review, propose a mechanism for the following formation of an imine. \(\mathrm{CH}_{3} \mathrm{NH}_{2}\) \(\mathrm{NHCH}_{3}\) \(\mathrm{H}_{2} \mathrm{O}\) (b) Now give a mechanism for a similar reaction that gives an enamine. \(\mathrm{H}_{2} \mathrm{O}\) (c) Explain why the reaction with the secondary amine gives an enamine rather than an imine. Equation transcription: Text transcription: {CH}{3}{NH}{2} {NHCH}{3} {H}{2}{O}

Problem 2P Draw the structures of the following compounds: (a) tert-butylamine (b) ?- aminopropionaldehyde (c) 4-(dimethylamino)pyridine (d) 2-methylaziridine (e) N-ethyl-N-methylhexan-3-amine (f) m-chloroaniline

Give correct names for the following amines: \(\mathrm{CH}_{3}-\mathrm{CH}_{2}-\mathrm{CH}_{2}-\mathrm{CH}-\mathrm{CH}_{3}\) \(\mathrm{CH}_{3}-\mathrm{CH}_{2} \mathrm{CH}-\mathrm{CH}_{3}\) \(\mathrm{NH}_{2}\) \(\mathrm{CH}_{3}\) Equation transcription: Text transcription: {CH}{3}-CH}_{2}-{CH}_{2}-{CH}-{CH}{3} {CH}{3}-{CH}_{2}{CH}-{CH}{3} {NH}{2} {CH}{3}

Problem 4P Which of the amines listed next can be resolved into enantiomers? In each case, explain why interconversion of the enantiomers would or would not take place. (a) cis-2-methylcyclohexanamine (b) N-ethyl-N-methylcyclohexanamine (c) N-methylaziridine (d) ethylmethylanilinium iodide (e) methylethylpropylisopropylammonium iodide

Problem 5P Rank each set of compounds in order of increasing boiling points. (a) triethylamine, di-n-propylamine, n-propyl ether (b) ethanol, dimethylamine, dimethyl ether (c) diethylamine, diisopropylamine, trimethylamine

Problem 1P Determine which of the heterocyclic amines just shown are aromatic. Give the reasons for your conclusions.

Rank each set of compounds in order of increasing basicity. (a) \(\mathrm{NaOH}, \mathrm{NH}_{3}, \mathrm{CH}_{3} \mathrm{NH}_{2}, \mathrm{Ph}-\mathrm{NH}_{2}\) (b) aniline, ????-methylaniline, ????-nitroaniline (c) aniline, pyrrole, pyridine, piperidine (d) pyrrole, imidazole, 3-nitropyrrole Equation transcription: Text transcription: {NaOH},{NH}{3},{CH}{3}{NH}{2},{Ph}-{NH}{2}

Problem 9P The carbon NMR chemical shifts of diethylmethylamine, piperidine, propan-1-ol, and propanal follow. Determine which spectrum corresponds to each structure, and show which carbon atom(s) are responsible for each absorption. (a) 25.9, 27.8, 47.9 (b) 12.4, 41.0, 51.1 (c) 7.9, 44.7, 201.9 (d) 10.0, 25.8, 63.6

(a) Show how fragmentation occurs to give the base peak at \(m / z 58\) in the mass spectrum of ethyl propyl amine (N-ethylpropan-1-amine), shown below. (b) Show how a similar cleavage in the ethyl group gives an ion of \(m / z 72\). (c) Explain why the peak at \(m / z 72\) is much weaker than the one at \(m / z 58\). Equation transcription: Text transcription: m / z 72 m / z 58

The proton and \({ }^{13} C\) NMR spectra of a compound of formula \(C_{4} H_{11} N\) are shown here. Determine the structure of this amine, and give peak assignments for all of the protons in the structure. Equation transcription: Text transcription: ^{13} C C{4} H{11} N

The following partial IR spectra correspond to a primary amine, a secondary amine, and an alcohol. Give the functional group for each spectrum.

Problem 11P Propose a mechanism for nitration of pyridine at the 4-position, and show why this orientation is not observed.

Problem 12P Propose a mechanism for the sulfonation of pyridine, pointing out why sulfonation occurs at the 3-position.

Problem 13P We have considered nucleophilic aromatic substitution of pyridine at the 2-position and 3-position but not at the 4-position. Complete the three possible cases by showing the mechanism for the reaction of methoxide ion with 4-chloropyridine. Show how the intermediate is stabilized by delocalization of the charge onto the nitrogen atom.

Problem 14P (a) Propose a mechanism for the reaction of 2-bromopyridine with sodium amide to give 2-aminopyridine. (b) When 3-bromopyridine is used in this reaction, stronger reaction conditions are required and a mixture of 3-aminopyridine and 4-aminopyridine results. Propose a mechanism to explain this curious result.

Problem 15P Propose a mechanism to show the individual alkylations that form this quaternary ammonium salt.

Problem 16P Show how you would use direct alkylation to synthesize the following compounds. (a) benzyltrimethylammonium iodide (b) pentan-1-amine (c) benzylamine

Give the products expected from the following reactions. (a) acetyl chloride + ethylamine \(\left(C H_{3}\right)_{2} N H\) \(\mathrm{CH}_{3}-\left(\mathrm{CH}_{2}\right)-\mathrm{C}-\mathrm{Cl}+\mathrm{NH}\) Equation transcription: Text transcription: (C H{3}){2} N H {CH}{3}-({CH}{2})-{C}-{Cl}+{NH}

Problem 18P What would happen in the synthesis of sulfanilamide if the amino group were not protected as an amide in the chlorosulfonation step?

Show how you would use the same sulfonyl chloride as used in the sulfanilamide synthesis to make sulfathiazole and sulfapyridine. \(H_{2} N\) Equation transcription: Text transcription: H{2} N

Predict the major products formed when the following amines undergo exhaustive methylation, treatment with \(\mathrm{Ag}_{2} \mathrm{O}\), and heating. (a) hexan-2-amine (b) 2-methylpiperidine (c) N-ethylpiperidine Equation transcription: Text transcription: {Ag}{2} {O}

Problem 21P Give the products expected when the following tertiary amines are treated with a peroxyacid and heated. (a) N,N-dimethylhexan-2-amine (b) N,N-diethylhexan-2-amine (c) cyclohexyldimethylamine (d) N-ethylpiperidine

Problem 23P Predict the products from the reactions of the following amines with sodium nitrite in dilute HCl. (a) cyclohexanamine (b) N-ethylhexan-2-amine (c) piperidine (d) aniline

When the (R,R) isomer of the amine shown is treated with an excess of methyl iodide, then silver oxide, then heated, the major product is the Hofmann product. (a) Draw the structure of the major (Hofmann) product. (b) Some Zaitsev product is also formed. It has the (E) configuration. When the same amine is treated with MCPBA and heated, the Zaitsev product has the (Z) configuration. Use stereochemical drawings of the transition states to explain these observations.

Problem 24P Propose a mechanism for the synthesis of methyl orange.

Show how you would convert aniline to the following compounds. (a) fluorobenzene (b) chlorobenzene (c) 1,3,5-trimethylbenzene (d) bromobenzene (e) iodobenzene (f) benzonitrile (g) phenol

Show how to synthesize the following amines from the indicated starting materials by reductive amination. (a) benzylmethylamine from benzaldehyde (b) N-benzylpiperidine from piperidine (c) N-cyclohexylaniline from cyclohexanone (d) cyclohexylamine from cyclohexanone \(\mathrm{NH}_{2}\) \(\mathrm{PhCH}_{2} \mathrm{CHCH}_{3}\) \(\text { PhCH }_{2} \mathrm{CCH}_{3}\) Equation transcription: Text transcription: {NH}{2} {PhCH}{2}{CHCH}{3} { PhCH }{2}{CCH}{3}

Problem 27P Show how to synthesize the following amines from the indicated starting materials by acylation–reduction. (a) N-butylpiperidine from piperidine (b) N-benzylaniline from aniline

Problem 28P Addition of one equivalent of ammonia to 1-bromoheptane gives a mixture of heptan-1-amine, some dialkylamine, some trialkylamine, and even some tetraalkylammonium bromide. (a) Give a mechanism to show how this reaction takes place, as far as the dialkylamine. (b) How would you modify the procedure to get an acceptable yield of heptan-1-amine?

Problem 29P Show how Gabriel syntheses might be used to prepare the following amines. (a) benzylamine (b) hexan-1-amine (c) ?-aminobutyric acid

Problem 31P Show how you would prepare the following aromatic amines by aromatic nitration, followed by reduction. You may use benzene and toluene as your aromatic starting materials. (a) aniline (b) p-bromoaniline (c) m-bromoaniline (d) m-aminobenzoic acid

Show how you would accomplish the following synthetic conversions. (a) benzyl bromide benzylamine (b) 1-bromo-2-phenylethane 3-phenylpropan-1-amine (c) pentanoic acid pentan-1-amine (d) pentanoic acid hexan-1-amine (e) (R)-2-bromobutane (S)-butan-2-amine (f) (R)-2-bromobutane (S)-2-methylbutan-1-amine (g) hexan-2-one 1-amino-2-methylhexan-2-ol

For each compound, (1) classify the nitrogen-containing functional groups. (2) provide an acceptable name.

Rank the amines in each set in order of increasing basicity. \(\mathrm{NH}_{2}\) \(H_{3} C\) \(O_{2} N\) \(\mathrm{CH}_{2} \mathrm{NH}_{2}\) \(\mathrm{CONH}_{2}\) Equation transcription: Text transcription: {NH}{2} H{3} C O{2} N {CH}{2}{NH}{2} {CONH}{2}

Complete the following proposed acid–base reactions, and predict whether the reactants or products are favored. \(\mathrm{CH}_{3} \mathrm{COOH}\) \(\mathrm{NH}_{3} \mathrm{Cl}^{-}\) \(\mathrm{Cl}^{-}\) Equation transcription: Text transcription: {CH}{3}{COOH} {NH}{3}{Cl}^{-} {Cl}^{-}

Which of the following compounds are capable of being resolved into enantiomers? \(\mathrm{Cl}^{-}\) \(\mathrm{CH}_{3}\) \(\mathrm{CH}_{2} \mathrm{CH}_{3}\) Equation transcription: Text transcription: {Cl}^{-} {CH}{3} {CH}{2}{CH}{3}

Predict the products of the following reactions:

Show how m-toluidine can be converted to the following compounds, using any necessary reagents. \(C H_{3}\) \(\mathrm{NH}_{2}\) \(\mathrm{CH}_{2} \mathrm{NH}_{2}\) \(O_{2} N\) Equation transcription: Text transcription: C H{3} {NH}{2} {CH}{2}{NH}{2} O{2} N

The mass spectrum of tert-butylamine follows. Use a diagram to show the cleavage that accounts for the base peak. Suggest why no molecular ion is visible in this spectrum. \(\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CNH}_{2}\) Equation transcription: Text transcription: ({CH}{3}){3}{CNH}{2}

Using any necessary reagents, show how you would accomplish the following syntheses.

Propose mechanisms for the following reactions. \(\left(C H_{3}\right)_{2} N H\) \(\frac{\mathrm{NaBH}(\mathrm{OAc})_{3}}{H^{+}}\) \(\mathrm{N}\left(\mathrm{CH}_{3}\right)_{2}\) \(\frac{H_{z^{\prime}}, P t}{H^{+}}\) Equation transcription: Text transcription: (C H_{3}){2} N H {{NaBH}({OAc}){3}}{H^{+}} {N}({CH}{3}){2} frac{H{z^{prime}}, P t}{H^{+}}

The following drugs are synthesized using the methods in this chapter and in previous chapters. Devise a synthesis for each, starting with any compounds containing no more than six carbon atoms. (a) Phenacetin, used with aspirin and caffeine in pain-relief medications. (b) Methamphetamine, once considered a safe diet pill, but now known to be addictive and destructive to brain tissue. (c) Dopamine, one of the neurotransmitters in the brain. Parkinson’s disease is thought to result from a dopamine deficiency. \(\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{O}\) \(N H-C-C H_{3}\) \(\mathrm{NHCH}_{3}\) \(\mathrm{CH}_{2}-\mathrm{CH}-\mathrm{CH}_{3}\) \(\mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{NH}_{2}\) Equation transcription: Text transcription: {CH}{3}{CH}{2}{O} N H-C-C H{3} {NHCH}{3} {CH}{2}-{CH}-{CH}{3} {CH}{2}{CH}{2}{NH}{2}

The two most general amine syntheses are the reductive amination of carbonyl compounds and the reduction of amides. Show how these techniques can be used to accomplish the following syntheses. (a) benzoic acid benzylamine (b) benzaldehyde benzylamine (c) pyrrolidine -ethylpyrrolidine (d) cyclohexanone -cyclohexylpyrrolidine (e) \(\mathrm{HOOC}-\left(\mathrm{CH}_{2}\right)_{3}-\mathrm{COOH} \rightarrow\) pentane- 1,5 -diamine (cadaverine) Equation transcription: Text transcription: {HOOC}-({CH}{2}){3}-{COOH} rightarrow

Several additional amine syntheses are effectively limited to making primary amines. The reduction of azides and nitro compounds and the Gabriel synthesis leave the carbon chain unchanged. Formation and reduction of a nitrile adds one carbon atom. Show how these amine syntheses can be used for the following conversions. (a) allyl bromide allylamine (b) ethylbenzene -ethylaniline (c) 1-bromo-3-phenylheptane 3-phenylheptan-1-amine (d) 1 -bromo-3-phenylheptane -phenyloctan-1-amine

(a) Guanidine (shown) is about as strong a base as hydroxide ion. Explain why guanidine is a much stronger base than most other amines. (b) Show why -nitroaniline is a much weaker base (\(3 p K_{b}\) units weaker) than aniline. (c) Explain why -tetramethylaniline (shown) is a much stronger base than -dimethylaniline. \(H_{2} N-C-N H_{2}\) \(H_{3} C\) \(\mathrm{CH}_{3}\) Equation transcription: Text transcription: 3 p K{b} H{2} N-C-N H{2} H{3} C {CH}{3}

Using any necessary reagents, show how you would accomplish the following multistep syntheses. \(\mathrm{NH}_{2}\) \(\mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{3}\) \(\mathrm{CH}_{3}\) \(C H=C H_{2}\) Equation transcription: Text transcription: {NH}{2} {CH}{2}{CH}{2}{CH}{2}{CH}{3} {CH}{3} C H=C H{2}

Show how you would synthesize the following compounds starting with benzene, toluene, and alcohols containing no more than four carbon atoms as your organic starting materials. Assume that para is the major product (and separable from ortho) in ortho, para mixtures.

Problem 47SP The alkaloid coniine has been isolated from hemlock and purified. Its molecular formula is C8H17N.Treatment of coniine with excess methyl iodide, followed by silver oxide and heating, gives the pure (S)-enantiomer of N,N-dimethyloct-7-ene-4-amine. Propose a complete structure for coniine, and show how this reaction gives the observed product.

Section 17-12 showed how nucleophilic aromatic substitution can give aryl amines if there is a strong electron-withdrawing group ortho or para to the site of substitution. Consider the following example. (a) Propose a mechanism for this reaction. (b) We usually think of fluoride ion as a poor leaving group. Explain why this reaction readily displaces fluoride as the leaving group. (c) Explain why this reaction stops with the desired product, rather than reacting with another dinitrofluorobenzene. \(\mathrm{NO}_{2}\) \(\frac{\mathrm{CH}_{3} \mathrm{NH}_{2}}{\mathrm{NaHCO}_{3}}\) \(\mathrm{NHCH}_{3}\) Equation transcription: Text transcription: {NO}{2} frac{{CH}{3}{NH}{2}}{{NaHCO}{3}} {NHCH}{3}

Pyrrole undergoes electrophilic aromatic substitution more readily than benzene, and mild reagents and conditions are sufficient. These reactions normally occur at the 2-position rather than the 3-position, as shown in the following example. \(C H_{3}-C-O-C-C H_{3}\) \(\mathrm{CH}_{3}+\mathrm{CH}_{3}-\mathrm{C}-\mathrm{OH}\) (a) Propose a mechanism for the acetylation of pyrrole just shown. You may begin with pyrrole and the acylium ion, \(C H_{3}-C=O^{+}\) .Be careful to draw all the resonance structures of the intermediate. (b) Explain why pyrrole reacts more readily than benzene, and also why substitution occurs primarily at the 2-position rather than the 3-position. Equation transcription: Text transcription: C H{3}-C-O-C-C H_{3} {CH}_{3}+{CH}{3}-{C}-{OH} C H{3}-C=O^{+}

Problem 52SP (A true story.) A drug user responded to an ad placed by a DEA informant in a drug-culture magazine. He later flew from Colorado to Maryland, where he bought some 1-phenyl-2-propanone (P2P) from the informant. The police waited nearly a month for the suspect to synthesize something, then obtained a search warrant and searched the residence. They found the unopened bottle of P2P; apparently the suspect was not a good chemist and was unable to follow the instructions the informant gave him. They also found pipes and bongs with residues of marijuana and cocaine, plus a bottle of methylamine hydrochloride, some muriatic acid (dilute HCl), zinc strips, flasks, and other equipment. (a) Assume you are consulting for the police. Show what synthesis the suspect was prepared to carry out, to provide probable cause for the charge of attempting to manufacture a controlled substance. (b) Assume you are a member of the jury. Would you convict the defendant of attempting to manufacture a controlled substance?

An unknown compound shows a weak molecular ion at in the mass spectrum, and the only large peak is at . The IR spectrum follows. The NMR spectrum shows only three singlets: one of area 9 at \(\delta 0.9\), one of area 2 at \(\delta 1.0\), and one of area 2 at \(\delta 2.4\). The singlet at disappears on shaking with . Determine the structure of the compound, and show the favorable fragmentation that accounts for the ion at . Equation transcription: Text transcription: \delta 1.0 \delta 0.9 \delta 2.4 D_{2} O

Show how you might synthesize the following tertiary amine three different ways, each using a different secondary amine and adding the final substituent by (a) reductive amination (3 ways). (b) acylation–reduction (3 ways).

A compound of formula \(C_{11} H_{16} N_{2}\) gives the IR, \({ }^{1} H N M R\), and \({ }^{13} \mathrm{C}\) NMR spectra shown. The proton NMR peak at disappears on shaking with \(D_{2} O\). Propose a structure for this compound, and show how your structure accounts for the observed absorptions. Equation transcription: Text transcription: C{11} H{16} N{2} ^{1} H N M R ^{13}{C} D{2} O

In Section 19-10B, we saw that pyridine undergoes electrophilic aromatic substitution reluctantly, requiring strong conditions and giving disappointing yields. In contrast, pyridine N-oxide undergoes EAS under moderate conditions, giving good yields of substitution on C2 and C4. Explain this surprising difference.

The following spectra for A and B correspond to two structural isomers. The NMR singlet at \(\delta 1.16\) in spectrum A disappears when the sample is shaken with \(\mathrm{D}_{2} \mathrm{O}\). The singlet at \(\delta 0.6 \mathrm{ppm}\) in the spectrum of B disappears on shaking with \(\mathrm{D}_{2} \mathrm{O}\). Propose structures for these isomers, and show how your structures correspond to the spectra. Show what cleavage is responsible for the base peak at \(m / z 44\) in the mass spectrum of A and the prominent peak at \(m / z 58\) in the mass spectrum of B. Equation Transcription: Text Transcription: delta 1.16 D2 O delta 0.6ppm m/z44 m/z58