Arylamines are usually prepared by nitration of an aromatic starting material, followed by reduction of the nitro group (Section 16.2). The reduction step can be carried out in many different ways, depending on the circumstances. Catalytic hydrogenation over platinum works well but is often incompatible with the presence elsewhere in the molecule of other reducible groups, such as $\mathrm{C}=\mathrm{C}$ bonds or carbonyl groups. Iron, zinc, tin, and tin(II) chloride $\left(\mathrm{SnCl}_{2}\right)$ are also effective when used in acidic aqueous solution. Tin(II) chloride is particularly mild and is often used when other reducible functional groups are present.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0859.jpg?height=207&width=904&top_left_y=1731&top_left_x=605)
p-tert-Butylnitrobenzene
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0859.jpg?height=144&width=536&top_left_y=2056&top_left_x=626)
m-Nitrobenzaldehyde
p-tert-Butylaniline (100\%)
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m-Aminobenzaldehyde (90\%)


Reduction of Nitriles, Amides, and Nitro Compounds -

PROBLEM Propose structures for either a nitrile or an amide that might be a precursor of each of the following 24-8 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


$\mathrm{S}_{\mathrm{N}} 2$ Reactions of Alkyl Halides -

Ammonia and other amines are good nucleophiles in $S_{N} 2$ reactions. As a result, the simplest method of alkylamine synthesis is by $\mathrm{S}_{\mathrm{N}} 2$ alkylation of ammonia or an alkylamine with an alkyl halide. If ammonia is used, a primary amine results; if a primary amine is used, a secondary amine results; and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, $\mathrm{R}_{4} \mathrm{~N}^{+} \mathrm{X}^{-}$.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0860.jpg?height=435&width=1234&top_left_y=452&top_left_x=440)


Unfortunately, these reactions don't stop cleanly after a single alkylation has occurred. Because ammonia and primary amines have similar reactivity, the initially formed monoalkylated substance often undergoes further reaction to yield a mixture of products. Even secondary and tertiary amines undergo further alkylation, although to a lesser extent. For example, treatment of 1-bromooctane with a twofold excess of ammonia leads to a mixture containing only $45 \%$ octylamine. A nearly equal amount of dioctylamine is produced by double alkylation, along with smaller amounts of trioctylamine and tetraoctylammonium bromide.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0860.jpg?height=267&width=1229&top_left_y=1165&top_left_x=445)


A better method for preparing primary amines is to use azide ion, $\mathrm{N}_{3}{ }^{-}$, rather than ammonia, as the nucleophile for $\mathrm{S}_{\mathrm{N}} 2$ reaction with a primary or secondary alkyl halide. The product is an alkyl azide, which is not nucleophilic, so overalkylation can't occur. Subsequent reduction of the alkyl azide with $\mathrm{LiAlH}_{4}$ then leads to the desired primary amine. Although this method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0860.jpg?height=320&width=1177&top_left_y=1675&top_left_x=471)


Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide $(\mathbf{O}=\mathbf{C}-\mathbf{N}-\mathbf{C}=\mathbf{O})$ is similar to a $\beta$-keto ester in that the acidic $\mathrm{N}-\mathrm{H}$ hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the $N$-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7).
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0861.jpg?height=532&width=1234&top_left_y=184&top_left_x=440)


PROBLEM Write the mechanism of the last step in Gabriel amine synthesis, the base-promoted hydrolysis of a 24-9 phthalimide to yield an amine plus phthalate ion.


PROBLEM Show two methods for the synthesis of dopamine, a neurotransmitter involved in regulation of the
24-10 central nervous system. Use any alkyl halide needed.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0861.jpg?height=286&width=551&top_left_y=952&top_left_x=424)


Dopamine -


Reductive Amination of Aldehydes and Ketones -

Amines can be synthesized in a single step by treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent, a process called reductive amination. For example, amphetamine, a central nervous system stimulant, is prepared commercially by reductive amination of phenyl-2-propanone with ammonia using hydrogen gas over a nickel catalyst as the reducing agent. In the laboratory, either $\mathrm{NaBH}_{4}$ or the related $\mathrm{NaBH}(\mathrm{OAc})_{3}$ is commonly used ( $\mathrm{OAc}=$ acetate ).
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0861.jpg?height=196&width=985&top_left_y=1577&top_left_x=565)


Reductive amination takes place by the pathway shown in FIGURE 24.6. An imine intermediate is first formed by a nucleophilic addition reaction (Section 19.8), and the $\mathrm{C}=\mathrm{N}$ bond of the imine is then reduced to the amine, much as the $\mathrm{C}=\mathrm{O}$ bond of a ketone can be reduced to an alcohol.


FIGURE 24.6 MECHANISM -

Mechanism for reductive amination of a ketone to yield an amine. Details of the imine-forming step are shown in FIGURE 19.7.
(1) Ammonia adds to the ketone carbonyl group in a nucleophilic addition reaction to yield an intermediate carbinolamine.


FIGURE 24.6 MECHANISM -


FIGURE 24.6 MECHANISM -

Ammonia, primary amines, and secondary amines can all be used in the reductive amination reaction, yielding primary, secondary, and tertiary amines, respectively.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0862.jpg?height=462&width=825&top_left_y=1604&top_left_x=653)


FIGURE 24.6 MECHANISM -

Reductive aminations also occur in various biological pathways. In the biosynthesis of the amino acid proline, for instance, glutamate 5 -semialdehyde undergoes internal imine formation to give 1-pyrrolinium 5 -carboxylate, which is then reduced by nucleophilic addition of hydride ion to the $\mathrm{C}=\mathrm{N}$ bond. Reduced nicotinamide adenine dinucleotide, NADH, acts as the biological reducing agent.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0863.jpg?height=332&width=1171&top_left_y=189&top_left_x=477)


WORKED EXAMPLE 24.1 -


Using a Reductive Amination Reaction -

How might you prepare $N$-methyl-2-phenylethylamine using a reductive amination reaction?
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0863.jpg?height=142&width=798&top_left_y=742&top_left_x=661)


Strategy -

Look at the target molecule, and identify the groups attached to nitrogen. One of the groups must be derived from the aldehyde or ketone component, and the other must be derived from the amine component. In the case of N -methyl-2-phenylethylamine, two combinations can lead to the product: phenylacetaldehyde plus methylamine or formaldehyde plus 2-phenylethylamine. It's usually better to choose the combination with the simpler amine component-methylamine in this case-and to use an excess of that amine as reactant.


Strategy -

Solution
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0863.jpg?height=237&width=1259&top_left_y=1237&top_left_x=433)


Strategy -


Strategy -

PROBLEM How could you prepare the following amine using a reductive amination reaction?
24-12
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0863.jpg?height=319&width=643&top_left_y=1849&top_left_x=416)


Hofmann and Curtius Rearrangements -

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement. Although the Hofmann rearrangement involves a primary amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms.
Hofmann
rearrangement
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0864.jpg?height=134&width=651&top_left_y=188&top_left_x=859)


Hofmann and Curtius Rearrangements -

An amide


Curtius rearrangement -


An acyl azide -

Hofmann rearrangement occurs when a primary amide, $\mathrm{RCONH}_{2}$, is treated with $\mathrm{Br}_{2}$ and base (FIGURE 24.7). The overall mechanism is lengthy, but most of the individual steps have been encountered before. Thus, the bromination of an amide in steps 1 and 2 is analogous to the base-promoted bromination of a ketone enolate ion (Section 22.6), and the rearrangement of the bromoamide anion in step 4 is analogous to a carbocation rearrangement (Section 7.11). Nucleophilic addition of water to the isocyanate carbonyl group in step 5 is a typical carbonyl-group process (Section 19.4), as is the final decarboxylation step 6 (Section 22.7).


FIGURE 24.7 MECHANISM -

Mechanism of the Hofmann rearrangement of an amide to an amine. Each step is analogous to a reaction studied previously.


FIGURE 24.7 MECHANISM -

Amide
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0865.jpg?height=170&width=280&top_left_y=430&top_left_x=1172)
© || proton, yielding an amide anion.
(2) The anion reacts with bromine in an $\alpha$-substitution reaction to give an N -bromoamide.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0865.jpg?height=408&width=708&top_left_y=612&top_left_x=947)


FIGURE 24.7 MECHANISM -


FIGURE 24.7 MECHANISM -

Carbamic acid
(6) The carbamic acid
spontaneously loses $\mathrm{CO}_{2}$ to give an amine.


(6) -

![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0865.jpg?height=117&width=343&top_left_y=2267&top_left_x=1173)
alkylamines. For example, the appetite-suppressant drug phentermine is prepared commercially by Hofmann rearrangement of a primary amide. Commonly known by the name Fen-Phen, the combination of phentermine with another appetite-suppressant, fenfluramine, is suspected of causing heart damage.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0866.jpg?height=207&width=1023&top_left_y=344&top_left_x=546)


(6) -

2,2-Dimethyl-3-phenyl-
Phentermine propanamide
The Curtius rearrangement, like the Hofmann rearrangement, involves migration of an -R group from the $\mathrm{C}=\mathrm{O}$ carbon atom to the neighboring nitrogen with simultaneous loss of a leaving group. The reaction takes place on heating an acyl azide that is itself prepared by nucleophilic acyl substitution of an acid chloride.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0866.jpg?height=367&width=1218&top_left_y=779&top_left_x=448)


(6) -

Also like the Hofmann rearrangement, the Curtius rearrangement is often used commercially. The antidepressant drug tranylcypromine, for instance, is made by Curtius rearrangement of 2-phenylcyclopropanecarbonyl chloride.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0866.jpg?height=226&width=768&top_left_y=1296&top_left_x=684)
trans-2-Phenylcyclo-
Tranylcypromine propanecarbonyl chloride


WORKED EXAMPLE 24.2 -


Using the Hofmann and Curtius Rearrangements -

How would you prepare o-methylbenzylamine from a carboxylic acid, using both Hofmann and Curtius rearrangements?


Strategy -

Both Hofmann and Curtius rearrangements convert a carboxylic acid derivative-either an amide (Hofmann) or an acid chloride (Curtius)-into a primary amine with loss of one carbon, RCOY $\rightarrow \mathrm{RNH}_{2}$. Both reactions begin with the same carboxylic acid, which can be identified by replacing the $-\mathrm{NH}_{2}$ group of the amine product by a $-\mathrm{CO}_{2} \mathrm{H}$ group. In the present instance, $o$-methylphenylacetic acid is needed.


Solution -


Solution - 24.7 Reactions of Amines


Alkylation and Acylation -

We've already studied the two most general reactions of amines-alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Section 21.4 and Section 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0867.jpg?height=177&width=823&top_left_y=950&top_left_x=632)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0867.jpg?height=182&width=836&top_left_y=1145&top_left_x=642)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0867.jpg?height=186&width=839&top_left_y=1349&top_left_x=643)


Hofmann Elimination Reaction -

Like alcohols, amines can be converted into alkenes by an elimination reaction. But because an amide ion, $\mathrm{NH}_{2}{ }^{-}$, is such a poor leaving group, it must first be converted into a better leaving group. In the Hofmann elimination reaction, an amine is completely methylated by reaction with an excess amount of iodomethane to produce the corresponding quaternary ammonium salt. This salt then undergoes elimination to give an alkene on heating with a base, typically silver oxide, $\mathrm{Ag}_{2} \mathrm{O}$. For example, 1-methylpentylamine is converted into 1-hexene.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0867.jpg?height=133&width=1397&top_left_y=1923&top_left_x=364)


Hofmann Elimination Reaction -

1-Methylpentylamine
(1-Methylpentyl)trimethyl-
1-Hexene (60\%) ammonium iodide
Silver oxide acts by exchanging iodide ion for hydroxide ion in the quaternary salt, thus providing the base necessary for elimination. The actual elimination step is an E2 reaction (Section 11.8) in which hydroxide ion removes a proton while the positively charged nitrogen atom leaves.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0868.jpg?height=323&width=1003&top_left_y=191&top_left_x=561)


Hofmann Elimination Reaction -

Unlike what happens in other E2 reactions, the major product of Hofmann elimination is the less highly substituted alkene rather than the more highly substituted one, as shown by the reaction of (1-methylbutyl)trimethylammonium hydroxide to give 1-pentene rather than the alternative 2 -pentene. The reason for this non-Zaitsev result is probably steric. Because of the large size of the trialkylamine leaving group, the base must abstract a hydrogen from the more accessible, least hindered position.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0868.jpg?height=820&width=1240&top_left_y=769&top_left_x=429)


Hofmann Elimination Reaction -

The Hofmann elimination reaction is not often currently used in the laboratory, but analogous biological eliminations occur frequently, although usually with protonated ammonium ions rather than quaternary ammonium salts. In the biosynthesis of nucleic acids, for instance, a substance called adenylosuccinate undergoes an elimination of a positively charged nitrogen to give fumarate plus adenosine monophosphate.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0868.jpg?height=500&width=992&top_left_y=1775&top_left_x=564)


WORKED EXAMPLE 24.3 -


Predicting the Product of a Hofmann Elimination -


Strategy -

The Hofmann elimination is an E2 reaction that converts an amine into an alkene and occurs with non-Zaitsev regiochemistry to form the less highly substituted double bond. To predict the product, look at the reactant and identify the positions from which elimination might occur (the positions two carbons away from nitrogen). Then, carry out an elimination using the most accessible hydrogen. In the present instance, there are three possible positions from which elimination might occur-one primary, one secondary, and one tertiary. The primary position is the most accessible and leads to the least highly substituted alkene, ethylene.


Strategy -

Solution
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0869.jpg?height=226&width=1148&top_left_y=814&top_left_x=483)


Strategy -


Strategy -

PROBLEM What product would you expect from Hofmann elimination of a heterocyclic amine such as 24-15 piperidine? Write all the steps.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0869.jpg?height=289&width=394&top_left_y=1628&top_left_x=426)


Strategy - 24.8 Reactions of Arylamines


Electrophilic Aromatic Substitutions -

An amino group is strongly activating and ortho- and para-directing in electrophilic aromatic substitution reactions (Section 16.4). This high reactivity of amino-substituted benzenes can be a drawback at times because it's often difficult to prevent polysubstitution. Reaction of aniline with $\mathrm{Br}_{2}$, for instance, takes place rapidly and yields the 2,4,6-tribrominated product. The amino group is so strongly activating that it's not possible to stop at the monobromo stage.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0870.jpg?height=264&width=519&top_left_y=193&top_left_x=787)


Aniline $\quad$ 2,4,6-Tribromoaniline <br> (100\%) -

Another drawback to the use of amino-substituted benzenes in electrophilic aromatic substitution reactions is that Friedel-Crafts reactions are not successful (Section 16.3). The amino group forms an acid-base complex with the $\mathrm{AlCl}_{3}$ catalyst, which prevents further reaction. Both drawbacks can be overcome, however, by carrying out electrophilic aromatic substitution reactions on the corresponding amide rather than on the free amine.


As we saw in Section 21.5, treatment of an amine with acetic anhydride yields the corresponding acetyl amide, or acetamide. Although still activating and ortho-, para-directing, amido substituents ( $\mathrm{R}-\mathrm{N}-\mathrm{C}=\mathrm{O}$ ) are less strongly activating and less basic than amino groups because their nitrogen lone-pair electrons are delocalized by the neighboring carbonyl group. As a result, bromination of an $N$-arylamide occurs cleanly to give a monobromo product, and hydrolysis of the amide with aqueous base then gives the free amine. For example, p-toluidine (4-methylaniline) can be acetylated, brominated, and hydrolyzed to yield 2-bromo-4-methylaniline. None of the 2,6-dibrominated product is obtained.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0870.jpg?height=465&width=1489&top_left_y=1063&top_left_x=313)


Friedel-Crafts alkylations and acylations of $N$-arylamides also proceed normally. For example, benzoylation of acetanilide ( $N$-acetylaniline) under Friedel-Crafts conditions gives 4-aminobenzophenone in $80 \%$ yield after hydrolysis.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0870.jpg?height=557&width=1408&top_left_y=1662&top_left_x=353)


Moderating the reactivity of an amino-substituted benzene by forming an amide is a useful trick that allows many kinds of electrophilic aromatic substitutions to be carried out that would otherwise be impossible. One example is the preparation of the sulfa drugs, such as sulfanilamide.


Sulfa drugs were among the first pharmaceutical agents to be used clinically against bacterial infection. Although they have largely been replaced today by safer and more powerful antibiotics, sulfa drugs are credited with saving the lives of thousands of wounded during World War II and are still prescribed for urinary tract infections. They are prepared by chlorosulfonation of acetanilide, followed by reaction of
$p$-( $N$-acetylamino)benzenesulfonyl chloride with ammonia or some other amine to give a sulfonamide. Hydrolysis of the amide then yields the sulfa drug. Note that hydrolysis of the amide can be carried out in the presence of the sulfonamide group because sulfonamides hydrolyze very slowly.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0871.jpg?height=717&width=1500&top_left_y=341&top_left_x=307)


Sulfathiazole -

PROBLEM Propose syntheses of the following compounds from benzene:
24-17 (a) $N, N$-Dimethylaniline
(b) p-Chloroaniline
(c) m-Chloroaniline
(d) 2,4-Dimethylaniline


Diazonium Salts: The Sandmeyer Reaction -

Primary arylamines react with nitrous acid, $\mathrm{HNO}_{2}$, to yield stable arenediazonium salts, $\mathrm{Ar}-\stackrel{+}{\mathrm{N}} \equiv \mathrm{N} \mathrm{X}^{-}$, a process called a diazotization reaction. Alkylamines also react with nitrous acid, but the corresponding alkanediazonium products are so reactive they can't be isolated. Instead, they lose nitrogen instantly to yield carbocations. The analogous loss of $\mathrm{N}_{2}$ from an arenediazonium ion to yield an aryl cation is disfavored by the instability of the cation.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0871.jpg?height=174&width=1226&top_left_y=1794&top_left_x=447)


Arenediazonium salts are useful because the diazonio group ( $-\mathrm{N} \equiv \mathrm{N}$ ) can be replaced by a nucleophile in a substitution reaction.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0871.jpg?height=177&width=966&top_left_y=2064&top_left_x=574)


Many different nucleophiles-halide, hydride, cyanide, and hydroxide among others-react with arenediazonium salts, yielding many different kinds of substituted benzenes. The overall sequence of (1) nitration, (2) reduction, (3) diazotization, and (4) nucleophilic substitution is perhaps the single most versatile method of aromatic substitution.


Aryl chlorides and bromides are prepared by reaction of an arenediazonium salt with the corresponding copper(I) halide, CuX , a process called the Sandmeyer reaction. Aryl iodides can be prepared by direct reaction
with NaI without using a copper(I) salt. Yields generally fall between $60 \%$ and $80 \%$.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0872.jpg?height=240&width=1345&top_left_y=257&top_left_x=387)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0872.jpg?height=180&width=1028&top_left_y=539&top_left_x=386)


Aniline
Iodobenzene (67\%)
Similar treatment of an arenediazonium salt with CuCN yields the nitrile ArCN, which can then be further converted into other functional groups such as carboxyl. For example, Sandmeyer reaction of $o$-methylbenzenediazonium bisulfate with CuCN yields o-methylbenzonitrile, which can be hydrolyzed to give $o$-methylbenzoic acid. This product can't be prepared from $o$-xylene by the usual side-chain oxidation route because both methyl groups would be oxidized.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0872.jpg?height=318&width=1353&top_left_y=1023&top_left_x=386)


The diazonio group can also be replaced by -OH to yield a phenol and by -H to yield an arene. A phenol is prepared by reaction of the arenediazonium salt with copper(I) oxide in an aqueous solution of copper(II) nitrate, a reaction that is especially useful because few other general methods exist for introducing an -OH group onto an aromatic ring.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0872.jpg?height=285&width=911&top_left_y=1538&top_left_x=626)
$\underset{\text { ( } \boldsymbol{p} \text {-Toluidine) }}{\boldsymbol{p} \text {-Methylaniline }}$
p-Cresol
(93\%)
Reduction of a diazonium salt to give an arene occurs on treatment with hypophosphorous acid, $\mathrm{H}_{3} \mathrm{PO}_{2}$. This reaction is used primarily when there is a need for temporarily introducing an amino substituent onto a ring to take advantage of its directing effect. Suppose, for instance, that you needed to make 3,5-dibromotoluene. This product can't be made by direct bromination of toluene because reaction would occur at positions 2 and 4. Starting with $p$-methylaniline ( $p$-toluidine), however, dibromination occurs ortho to the strongly directing amino substituent, and diazotization followed by treatment with $\mathrm{H}_{3} \mathrm{PO}_{2}$ to remove the amino group yields the desired product.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0873.jpg?height=341&width=1419&top_left_y=198&top_left_x=369)
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0873.jpg?height=337&width=535&top_left_y=563&top_left_x=790)


Mechanistically, these diazonio replacement reactions occur through radical rather than polar pathways. In the presence of a copper(I) compound, for instance, it's thought that the arenediazonium ion is first converted to an aryl radical plus copper(II), followed by subsequent reaction to give product plus regenerated copper(I) catalyst.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0873.jpg?height=251&width=1514&top_left_y=1056&top_left_x=300)


WORKED EXAMPLE 24.4 -


Using Diazonium Replacement Reactions -


Strategy -

As always, organic syntheses are planned by working retrosynthetically from the final product, one step at a time. First, identify the functional groups in the product and recall how those groups can be synthesized. $m$-Hydroxyacetophenone has an -OH group and $\mathrm{a}-\mathrm{COCH}_{3}$ group in a meta relationship on a benzene ring. A hydroxyl group is generally introduced onto an aromatic ring by a four-step sequence of nitration, reduction, diazotization, and diazonio replacement. An acetyl group is introduced by a Friedel-Crafts acylation reaction.

Next, ask yourself what an immediate precursor of the target might be. Since an acetyl group is a meta director while a hydroxyl group is an ortho and para director, acetophenone might be a precursor of $m$-hydroxyacetophenone. Benzene, in turn, is a precursor of acetophenone.


Solution -


Solution -

PROBLEM How would you prepare the following compounds from benzene, using a diazonium replacement 24-18 reaction in your scheme?
(a) $p$-Bromobenzoic acid
(b) $m$-Bromobenzoic acid
(c) m-Bromochlorobenzene
(d) $p$-Methylbenzoic acid
(e) 1,2,4-Tribromobenzene


Diazonium Coupling Reactions -

Arenediazonium salts undergo a coupling reaction with activated aromatic rings such as phenols and arylamines to yield brightly colored azo compounds, $\mathbf{A r}-\mathbf{N}=\mathbf{N}-\mathbf{A r}^{\prime}$.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0874.jpg?height=247&width=1126&top_left_y=928&top_left_x=494)


Diazonium Coupling Reactions -

An azo compound


Diazonium Coupling Reactions -

$$
\text { where } \mathrm{Y}=-\mathrm{OH} \text { or }-\mathrm{NR}_{2}
$$


Diazonium Coupling Reactions -

Diazonium coupling reactions are typical electrophilic aromatic substitutions in which the positively charged diazonium ion is the electrophile that reacts with the electron-rich ring of a phenol or arylamine. Reaction usually occurs at the para position.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0874.jpg?height=746&width=1265&top_left_y=1454&top_left_x=430)


Diazonium Coupling Reactions -

Azo-coupled products are widely used as dyes for textiles because their extended conjugated $\pi$ electron system causes them to absorb in the visible region of the electromagnetic spectrum (Section 14.9). p-(Dimethylamino)azobenzene, for instance, is a bright yellow compound that was at one time used as a coloring agent in margarine.
![](https://cdn.mathpix.com/cropped/2025_02_06_5556f7656cbdcaa0f9a7g-0875.jpg?height=388&width=1291&top_left_y=188&top_left_x=409)


Diazonium Coupling Reactions -

PROBLEM Propose a synthesis of $p$-(dimethylamino)azobenzene with benzene as your only organic starting 24-19 material.