Premed · Premed · Organic Chemistry 2
Lecture 14: Amines: Structure, Basicity, and Synthesis
Organic Chemistry II
Learning Objectives
By the end of this lecture, students will be able to:
- Classify amines as primary, secondary, tertiary, or quaternary ammonium salts
- Name amines using IUPAC and common nomenclature
- Describe the structure and bonding of amines
- Explain the basicity of amines and the factors that affect pKb
- Describe the key synthetic methods for preparing amines
- Explain the Gabriel synthesis, reductive amination, and other selective amine syntheses
Lecture Content
I. Classification and Nomenclature
Amines are classified by the number of carbon groups bonded to nitrogen. A primary amine (RNH2) has one carbon group, a secondary amine (R2NH) has two, a tertiary amine (R3N) has three, and a quaternary ammonium salt (R4N+ X-) has four carbon groups and carries a permanent positive charge. Note that this classification scheme differs from that used for alcohols, where the degree is based on the carbon bearing the OH rather than the heteroatom itself.
In IUPAC nomenclature, primary amines are named as alkanamines (methanamine, ethanamine, cyclohexanamine). Substituents on nitrogen are designated with an N- prefix, as in N-methylethanamine or N,N-dimethylpropanamine. Aniline is the accepted parent name for aminobenzene. Common names remain widely used: methylamine, dimethylamine, trimethylamine, aniline, pyridine, and piperidine.
II. Structure and Bonding
In most amines, the nitrogen atom is sp3 hybridized, bearing three bonds and one lone pair in a tetrahedral electron geometry. The molecular geometry is pyramidal, with bond angles slightly compressed from the ideal 109.5 degrees to about 107 degrees due to the greater repulsion exerted by the lone pair.
Nitrogen undergoes rapid pyramidal inversion (umbrella inversion), in which the lone pair passes through a planar sp2 transition state to reach the mirror-image configuration. The inversion barrier is only about 25 kJ/mol, far too low to allow isolation of individual enantiomers at room temperature. If nitrogen were a stereocenter, the two enantiomers would interconvert too quickly to separate. Quaternary ammonium salts with four different groups are the exception; lacking a lone pair, they are configurationally stable and can exhibit chirality.
In aromatic amines such as aniline, the nitrogen lone pair is partially delocalized into the aromatic ring by resonance. This gives nitrogen partial sp2 character and makes the molecule nearly planar around nitrogen. The delocalization has important consequences for basicity.
III. Physical Properties
Primary and secondary amines have higher boiling points than comparable alkanes due to N-H hydrogen bonding, but their boiling points are lower than those of comparable alcohols because N-H...N hydrogen bonds are weaker than O-H...O bonds (nitrogen is less electronegative than oxygen). Tertiary amines, lacking an N-H bond, have lower boiling points still and interact primarily through dipole-dipole forces. Amines with up to five or six carbons are water-soluble, acting as hydrogen-bond donors (primary and secondary) and acceptors (all amines). Low-molecular-weight amines have characteristically unpleasant, fishy odors. Putrescine (1,4-diaminobutane) and cadaverine (1,5-diaminopentane), produced during the decomposition of flesh, are aptly named.
IV. Basicity of Amines
Amines are the most common organic bases, accepting a proton on their lone pair to form ammonium ions. Typical Kb values range from 10^-3 to 10^-5 (pKb approximately 3 to 5). Basicity is often expressed as the pKa of the conjugate acid (RNH3+), which typically falls between 9 and 11 for simple alkylamines.
Several factors govern amine basicity. Inductive effects from electron-donating alkyl groups increase basicity, making alkylamines more basic than ammonia. The pKa values of conjugate acids illustrate this: dimethylamine (10.7) is slightly more basic than methylamine (10.6), and both are more basic than ammonia (9.2). Resonance effects decrease basicity when the lone pair is delocalized into a pi system. Aniline (conjugate acid pKa approximately 4.6) is far less basic than cyclohexylamine (conjugate acid pKa approximately 10.6) because aniline's lone pair is partially delocalized into the ring. Amide nitrogens are even less basic (conjugate acid pKa approximately -1) due to extensive delocalization into the C=O. Hybridization matters as well: sp2-hybridized nitrogen in pyridine (pKa 5.2) is less basic than sp3-hybridized nitrogen in piperidine (pKa 11.1) because sp2 orbitals hold electrons more tightly. Electron-withdrawing groups on the ring reduce basicity further: p-nitroaniline (pKa 1.0) is much less basic than aniline (pKa 4.6), which in turn is less basic than p-methylaniline (pKa 5.1).
Guanidine stands as the strongest common organic neutral base, with a conjugate acid pKa of approximately 13.6. Its exceptional basicity arises because the protonated guanidinium ion is stabilized by three equivalent resonance structures.
<image>Panel A: pKa scale (of conjugate acids) showing the basicity order of amines. From left (weakest base) to right (strongest base): amide nitrogen (pKa approximately -1), aniline (4.6), pyridine (5.2), ammonia (9.2), primary alkylamine (10.6), secondary alkylamine (10.7), guanidine (13.6). Each compound's structure is drawn above its position on the scale. Panel B: Resonance structures of aniline showing delocalization of the nitrogen lone pair into the aromatic ring, explaining its reduced basicity compared to cyclohexylamine.</image>
V. Synthesis of Amines
Direct alkylation of ammonia with an alkyl halide is conceptually simple but practically problematic. Each successive amine product is more nucleophilic than the last, leading to uncontrollable overalkylation through the primary, secondary, and tertiary amines all the way to the quaternary ammonium salt. This method is practical only when a vast excess of ammonia is used to favor monoalkylation.
The Gabriel synthesis provides a clean route to primary amines without overalkylation. Potassium phthalimide undergoes SN2 alkylation with an alkyl halide to give an N-alkylphthalimide, in which the nitrogen has no remaining N-H bonds and therefore cannot be alkylated further. Subsequent hydrolysis or hydrazinolysis (treatment with hydrazine) liberates the free primary amine. The limitation is that only primary amines can be produced, and only methyl and primary alkyl halides are compatible with the SN2 step.
Reduction of nitro groups is the most common route to aromatic amines. Treatment of a nitroaromatic compound with H2/Pd, Sn/HCl, or Fe/HCl gives the corresponding aniline. This transformation is typically paired with electrophilic aromatic nitration to install the nitrogen on the ring.
Reduction of amides with LiAlH4 provides excellent control over amine class: primary amides give primary amines, secondary amides give secondary amines, and tertiary amides give tertiary amines. Reduction of nitriles with LiAlH4 or H2/Ni also gives primary amines, and since nitriles are easily made by SN2 displacement with NaCN, this provides a one-carbon homologation route to amines.
Reductive amination is the most versatile method for amine synthesis. An aldehyde or ketone reacts with an amine to form an imine (or iminium ion), which is then reduced in situ to the amine. Sodium cyanoborohydride (NaBH3CN) or sodium triacetoxyborohydride (NaBH(OAc)3) are the preferred reducing agents because they selectively reduce imines and iminium ions without reducing the starting carbonyl at the mildly acidic pH of the reaction. This method can produce primary, secondary, or tertiary amines depending on the amine starting material and is widely used in pharmaceutical synthesis.
<image>Comparison of three amine synthesis methods. Method 1 (Gabriel synthesis): potassium phthalimide reacts with benzyl bromide via SN2, then hydrazinolysis releases benzylamine and phthalhydrazide. Method 2 (Reduction of nitro compounds): nitrobenzene is reduced with H2/Pd to give aniline. Method 3 (Reductive amination): cyclohexanone reacts with methylamine to form an imine intermediate, which is then reduced with NaBH3CN to give N-methylcyclohexylamine. Each method shows the starting materials, conditions, intermediates, and products.</image>
VI. Hofmann Rearrangement
The Hofmann rearrangement converts a primary amide to a primary amine with one fewer carbon. Treatment of RCONH2 with Br2 and NaOH initiates a sequence in which the amide nitrogen is first deprotonated and then brominated to give an N-bromoamide. A second deprotonation generates an anion that undergoes a 1,2-rearrangement: the alkyl group migrates from carbon to nitrogen with simultaneous loss of bromide, producing an isocyanate (R-N=C=O). The isocyanate is rapidly hydrolyzed by water to a carbamic acid, which spontaneously loses CO2 to give the primary amine. The migrating group retains its stereochemical configuration throughout the rearrangement. The net effect is the conversion of RCONH2 to RNH2 with loss of one carbon as CO2.
