# Lecture 15: Reactions of Amines and Diazonium Chemistry
## Organic Chemistry II
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Describe the reactions of amines as nucleophiles and bases
2. Write the mechanism for the formation of diazonium salts from primary aromatic amines
3. Predict the products of diazonium salt reactions (Sandmeyer and related reactions)
4. Describe the Hofmann and Cope eliminations
5. Explain the use of diazonium chemistry in azo dye synthesis
6. Apply amine and diazonium chemistry in multi-step synthesis planning
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## Lecture Content
### I. Amines as Nucleophiles
Amines participate in a wide range of nucleophilic reactions. Alkylation with alkyl halides proceeds by SN2, though overalkylation remains a persistent concern since each successive amine product is a better nucleophile. Acylation with acid chlorides converts amines to amides, and because the amide nitrogen is deactivated by the electron-withdrawing acyl group, overacylation does not occur. The Hinsberg test exploits this chemistry to distinguish among amine classes using benzenesulfonyl chloride. Amines also react with carbonyl compounds to form imines and enamines, open epoxides to give beta-amino alcohols, and participate in the Mannich reaction, in which formaldehyde, an amine, and an enolizable ketone combine to produce a beta-amino ketone (Mannich base).
### II. The Hinsberg Test
The Hinsberg test uses benzenesulfonyl chloride (PhSO2Cl) to distinguish primary, secondary, and tertiary amines. Primary amines react to form a sulfonamide (PhSO2NHR) that is soluble in aqueous NaOH because the remaining N-H is acidic (pKa approximately 10) and can be deprotonated. Secondary amines also form a sulfonamide (PhSO2NR2), but this product has no N-H bond and is therefore insoluble in NaOH. Tertiary amines lack N-H bonds altogether and do not react with the sulfonyl chloride, remaining unchanged.
### III. Hofmann Elimination
The Hofmann elimination begins with exhaustive methylation of an amine, converting it to a quaternary ammonium iodide (R-NMe3+ I-) by treatment with excess methyl iodide. The iodide counterion is then exchanged for hydroxide using silver oxide and water (or an ion-exchange resin). Heating the quaternary ammonium hydroxide induces E2 elimination, producing an alkene and trimethylamine.
The distinctive feature of Hofmann elimination is its regiochemistry: the less substituted alkene (the Hofmann product) predominates, in contrast to the Zaitsev product favored in most eliminations. The bulky trimethylammonium leaving group forces the small hydroxide base to abstract the less sterically hindered beta hydrogen. Historically, this reaction was used to determine the structures of alkaloids and other nitrogen-containing natural products.
### IV. Cope Elimination
The Cope elimination offers an alternative route to alkenes from amines. A tertiary amine is first oxidized to an amine N-oxide using mCPBA or hydrogen peroxide. Pyrolysis of the N-oxide at moderate temperatures (around 150 degrees C) proceeds through a concerted, syn elimination via a five-membered cyclic transition state. The N-oxide oxygen abstracts a beta hydrogen, the N-O bond breaks, and the alkene forms in a single step. The products are the alkene and an N,N-dialkylhydroxylamine. Like the Hofmann elimination, the Cope elimination favors the less substituted (Hofmann) alkene. Its syn stereochemistry requires that the hydrogen and the N-oxide depart from the same face of the molecule.
### V. Formation of Diazonium Salts
Treatment of a primary aromatic amine with nitrous acid (generated in situ from NaNO2 and HCl) at 0 to 5 degrees C produces an arenediazonium salt (ArN2+ Cl-). The mechanism begins with formation of the nitrosonium ion (NO+) from HNO2 and acid. The amine nitrogen attacks NO+ to form an N-nitrosoamine, which undergoes proton transfers and tautomerism to give a diazohydroxide. Protonation and loss of water then produce the diazonium ion (ArN2+).
Aromatic diazonium salts are relatively stable at 0 to 5 degrees C because the positive charge is resonance-stabilized by the aromatic ring. Aliphatic diazonium salts, in contrast, are extremely unstable and decompose immediately via carbocation intermediates to give uncontrollable mixtures of products, making them synthetically useless. Secondary amines react with HNO2 to form N-nitrosamines (R2N-N=O), which are potent carcinogens. Aromatic tertiary amines undergo C-nitroso substitution on the ring.
Mechanism of diazonium salt formation from aniline. Step 1: Generation of the nitrosonium ion (NO+) from NaNO2 + HCl. Step 2: Nucleophilic attack of the aniline nitrogen on NO+. Step 3: Proton transfers and loss of water through intermediate species (N-nitrosoamine, diazohydroxide). Step 4: Final diazonium ion (PhN2+) shown with resonance structures indicating triple bond character between the two nitrogen atoms. Temperature indicated as 0-5 degrees C throughout.
### VI. Reactions of Arenediazonium Salts
Arenediazonium salts undergo a remarkable array of replacement reactions in which the diazonium group is replaced by another substituent with release of N2 gas. The Sandmeyer reactions use a copper(I) catalyst to introduce chlorine (CuCl), bromine (CuBr), or a cyano group (CuCN) onto the ring. The Schiemann (Balz-Schiemann) reaction converts the diazonium salt to a tetrafluoroborate, which upon heating yields an aryl fluoride -- the best method for putting fluorine on an aromatic ring. Iodide can be introduced simply by treating the diazonium salt with KI, without need for a copper catalyst. Deamination, the replacement of the diazonium group with hydrogen, is accomplished using hypophosphorous acid (H3PO2) or NaBH4 and is useful for removing an amino group after it has served its purpose as a directing group in EAS. Warming the diazonium salt in water provides phenols, and treatment with KSH or a xanthate gives thiophenols.
The synthetic value of diazonium chemistry lies in its versatility. The amino group is introduced by nitration followed by reduction, and it can then direct subsequent EAS reactions as a strongly activating ortho/para director. Once the desired substitution pattern is achieved, the amino group is converted to a diazonium salt and replaced with any of the groups described above, many of which cannot be introduced directly by EAS.
Reaction map centered on an arenediazonium salt (ArN2+) with arrows radiating outward to all possible products. Each arrow is labeled with the specific reagent: CuCl gives ArCl, CuBr gives ArBr, CuCN gives ArCN, HBF4/heat gives ArF, KI gives ArI, H3PO2 gives ArH, H2O/warm gives ArOH, and azo coupling (see below) gives azo dyes. All reactions release N2 gas (except azo coupling). The central diazonium salt is drawn with the resonance structure showing the N-N triple bond.
### VII. Azo Coupling and Dye Chemistry
In azo coupling, the diazonium salt acts as an electrophile and reacts with a strongly activated aromatic ring (one bearing -OH, -NH2, or -NR2) in an electrophilic aromatic substitution. The product is an azo compound (Ar-N=N-Ar'), which contains the characteristic -N=N- (azo) linkage between two aromatic rings. Coupling preferentially occurs at the para position, or ortho if para is blocked.
Azo compounds are highly colored because the extended conjugation through the two aromatic rings and the azo linkage absorbs visible light. Depending on the substituents, azo dyes range from yellow to orange to red to blue. Well-known examples include methyl orange (a pH indicator), para red, and Congo red. The synthetic dye industry, built largely on azo chemistry, was one of the first major chemical industries. Many azo compounds serve as pH indicators because protonation or deprotonation of substituents alters the conjugation pattern and shifts the absorption wavelength.
### VIII. Multi-Step Synthesis Applications
Diazonium chemistry is indispensable for synthesizing aromatic compounds with substitution patterns that are inaccessible by direct EAS. For example, m-bromochlorobenzene cannot be made by direct halogenation because both bromine and chlorine are ortho/para directors. Instead, one can nitrate chlorobenzene, reduce the nitro group to an amine (a strong ortho/para director), brominate at the desired position, diazotize the amine with NaNO2/HCl at 0 degrees C, and finally replace the diazonium group with hydrogen using H3PO2. This synthetic detour illustrates the power of diazonium chemistry for accessing otherwise difficult substitution patterns on aromatic rings.
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