Chapter 23: Amines

 23.1: Structure and Classification

o Classes of amines
• Primary amine: one carbon group attached to N
• Secondary amine: two carbon groups attached to N
• Tertiary amine: three carbon groups attached to N
• Quaternary ammonium salt: four carbon groups attached to N. N has positive
charge.
• Aniline: amine attached to a benzene ring
• Heterocyclic amine: amine that is part of a non-aromatic ring
• Heterocyclic aromatic amines: aromatic compounds with nitrogen in the ring
 23.2: Nomenclature
o Primary amines can be named in two ways. Name alkyl chain with –yl ending and add
amine to the end (i.e. butylamine). The more formal name is to drop the e and add –
amine as a suffix (i.e. butanamine).
o Secondary and tertiary amines:
• Symmetric secondary and tertiary amines are named using the di- or tri- prefix (i.e.,
triethyl amine or dimethylamine).
• With different substituents on N a more systematic approach is used. The longest
carbon chain is the parent. Other substituents attached to N are named as normal with
the N-prefix to indicate the group is attached to nitrogen (i.e. N-methyl-2-
butanamine).
o Many cyclic amines have specific names, particularly the aromatic nitrogen heterocycles.
See page 948-9.
 23.3: Chirality of Amines and Quaternary Ammonium ions
o As we discussed last semester, any tetrahedral atom can be chiral. A lone pair can be one
of the four substituents.
o Amines can be chiral if there are three different substituents on the nitrogen, but the R
and S forms rapidly interconvert by inversion of the lone pair. As a result, amines are
effective achiral.
o Quaternary ammonium ions have stable chiral configurations if there are four different
substituents on the nitrogen.
 23.4: Properties of amines
o The N–H—N hydrogen bond is weaker than the O–H—O hydrogen bond. As a result,
amines have lower boiling points than similar alcohols. For example, methanamine boils
at -6 °C, while methanol boils at 65 °C.
 23.5: Basicity of amines
 o The lone pair of an amine is basic. Amines are the primary bases in organic chemistry.
o The basicity of amines can be compared by comparing the pKa of the conjugate acid. A
low pKa for the conjugate acid indicates a weak base, while a large pKa for the conjugate
base indicates a strong base.
o Typical conjugate acid pKa values (Table 3.2)
• Amines: 10-11 (most basic)
• aniline: 4.63
• pyridine: 5.25
• imidazole: 6.95
o Alkyl amines: Alkyl amines are the most basic amines because the nitrogen lone pair is
localized on the nitrogen with no resonance.
o Aromatic Amines: Aniline is less basic than an alkyl amine because the lone pair is
resonance delocalized. This makes the lone pair less available, and hence less basic.
Electron-withdrawing groups make the N less basic, while electron donors make it more
basic.
o Heterocyclic aromatic amines
• Pyrrole: The singly bonded nitrogen in this 5-membered ring has its lone pair as part
of the aromatic system. It is very weakly basic because protonation of the nitrogen
would disrupt the aromatic π system. The pKa of the conjugate acid is 0.4.
• Pyridine: The nitrogen in this 6-membered ring is π-bonded, so it's lone pair is not
part of the aromatic system and can act as a base. The pyridine nitrogen has a pKa of
5.25, which is much lower than alkyl amines due to the sp2 hybridization of the
nitrogen.
• Imidazole has both a π-bonded nitrogen like pyridine and a singly-bonded nitrogen
like pyrrole. The π-bonded nitrogen acts as the base and has a conjugate acid pKa of
6.95, which is higher than pyridine. The singly-bonded nitrogen acts as an electron
donor, which makes the π-bonded nitrogen more basic.
• Pyrimidine and pyrazine are 6-membered rings with two nitrogens in a 1,3- and 1,4-
arrangement, respectively. The nitrogens in these rings are significantly less basic.
The pKa of the conjugate acids of pyrimidine and pyrazine are 1.1 and 0.37,
respectively. The π-bonded nitrogens act as electron-withdrawing groups. Therefore,
they make the nitrogens in the ring less basic.
o Guanidine: Guanidine is a strong nitrogen base found in biology, such as the amino acid
arginine. The positive charge of the protonated guanidinium is stabilized by resonance
donantion from the other two nitrogens.
 23.6: Protonation of amines
o Amines will react with any acid having a lower pKa than the resulting ammonium ion.
The protonated amine is often water soluble.
 23.7: Synthesis of amines

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 o Reduction: amines are often made by reducing oxidized nitrogen functional groups.
• Nitriles: Nitriles can be reduced by LiAlH4. The nitrile can be made from an alkyl
halide. This process produces a primary amine with 1 more carbon than the starting
alkyl halide.
• Amides: Amides can also be reduced to amines with LiAlH4. Primary, secondary,
and tertiary amines can be made this way. The amide is made by reaction of an
amine with an acid chloride or anhydride.
• Nitro groups: Aromatic nitro groups can be reduced with H2 and Ni or Fe/HCl to
give aromatic amines.
o Reductive amination
• Reaction of an amine with a ketone or aldehyde will give an imine (ammonia or
primary amine) or enamine (secondary amine). The imine or enamine can be reduced
to an amine with NaBH4. In practice, NaBH3CN is used, which is more stable.
• Ammonia plus an aldehyde or ketone will give a primary amine.
• A primary amine with an aldehyde or ketone will give secondary amine
• A secondary amine with an aldehyde or ketone will give a tertiary amine
o SN2 reactions
• Ammonia or amines: Ammonia and amines are nucleophilic and can be alkylated
using alkyl halides by an SN2 reaction. This procedure does not work well to prepare
primary amines from ammonia or secondary amines from primary amines because
over alkylation often occurs. Alkylation of amines should not be used to make
amines.
• Azide: NaN3 can be used as an alternate nitrogen nucleophile. Azide can only be
monoalkylated, so over alkylation cannot occur. The azide can be reduced to an
amine with LiAlH4. This process provides a primary amine with the same number of
carbons as the alkyl halide.
• Secondary and tertiary amines should be made by either reductive amination or
formation of an amide followed by reduction.
 23.8: Reactions with nitrous acid
o Nitrous acid (HONO) is an unstable acid prepared by protonation of NaNO2 with H2SO4.
Under acidic conditions, HONO can be dehydrated to give the nitrosyl cation (NO+).
Nitrosyl cation is an electrophile that reacts with primary and secondary amines.
• Secondary amines: The NO+ group reactions with the nitrogen to give an N-
nitrosoamine (R2N-N=O). These compounds are potent carcinogens and raise
concerns about the use of sodium nitrite to preserve meat.
• Primary amines react with NO+ to form diazonium ions (R-NN+). Alkyl diazonium
ions are very unstable and decompose to a primary carbocation, which will then do
subsitution and elimination reactions, and N2. This reaction is not synthetically
useful.

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 o Aryldiazonium salts: Primary aryl amines (anilines) react with NO+ to give aryl
diazonium ions, which are more stable than the alkyl versions.
o The mechanism for formation of the diazonium involves the amine attacking the
positively charged nitrogen of NO+ followed by deprotonation to give an N-nitrosoamine.
This structure can tautomerize to a diazotic acid (Ar-N=N-OH). Protonation of the O
followed by loss of water gives the diazonium ion.
o Aryl diazonium ions can be used to do nucleophilic substitution because the N2+ group is
a great leaving group.
• Reaction of a diazonium salt with HBF4 replaces the N2 group with F.
• Reaction of a diazonium salt with CuCl/HCl replaces the N2 group with Cl.
• Reaction of a diazonium salt with CuBr/HBr replaces the N2 group with Br.
• Reaction of a diazonium salt with KI replaces the N2 group with I.
• Reaction of a diazonium salt with CuCN replaces the N2 group with CN.
• Reaction of a diazonium salt with Cu2O/Cu(NO3)2, H2O replaces the N2 group with
OH.
• Reaction of a diazonium salt with H3PO2 replaces the N2 group with H.
o The Sandmeyer reaction allows synthesis of functional groups that can't be made by SEAr
reactions (i.e., CN, OH) using a sequence involving nitration, reduction to the amine,
conversion to the diazonium ion, and substitution.
o The replacement of the diazonium ion with H allows the use of the amine group to
activate the ring. The amine can then be removed by diazotization and reaction with
H3PO2.
o Synthesis of amides: As discussed in Chapter 21, reaction of amines with acid chlorides
or anhydrides gives amides.
 23.9: Hofmann elimination
o Elimination of amines generally does not occur because R2N– is a very poor leaving
group. Converting the amine to a quaternary ammonium salt with methyl iodide makes
the N a better leaving group. Elimination will now occur using Ag2O as the base.
o The Hofmann elimination occurs to give elimination from the less-substituted side. This
preference is opposite to what is seen in most elimination reactions. The less substituted
alkene is formed because the ammonium group is so large that the base removes the most
accessible proton.
 23.10: Cope elimination
o A similar reaction can be done by oxidizing the amine to an amine oxide with hydrogen
peroxide. Heating the amine oxide results in an elimination of hydroxylamine.
o The reaction occurs with syn selectivity and is concerted. The elimination is not
regioselective if more than one ß-hydrogen is present, however.
o The reaction is named after Arthur C. Cope, who was a faculty member at MIT.