Amines

Introduction to Amines Amines are derivatives of ammonia Amines are designated as primary, secondary, or tertiary

Examples of Amines There are hundreds of examples of amines found in natural products

Introduction to Amines Some naturally occurring amines take part in neurochemistry

Introduction to Amines The trigonal pyramidal nitrogen atom of an amine carries a partial negative charge on its lone pair Act as base or nucleophile

Amines are stronger bases than alcohols, ethers, or water Solubility can be increased following protonation of amine. Amines establish an equilibrium with water; amine is protonated, producing hydroxide Higher pKa of the corresponding ammonium ion (RNH 3 + ) → weaker acid and stronger conjugate base. Relative Basicity

Review: Nomenclature of Amines There are multiple methods for naming 1° amines 1.Name the alkyl group ending in “yl” followed by the word, amine

Review: Nomenclature of Amines There are multiple methods for naming 1° amines 2.Find the carbon parent chain, and use the suffix, amine

Review: Nomenclature of Amines There are multiple methods for naming 1° amines 3.Use the term, amino, for the group as a side group

Review: Nomenclature of Amines There are multiple methods for naming 1° amines 4.If the amine is directly attached to an aromatic ring, it may be called aniline

Review: Nomenclature of Amines There are multiple methods for naming 2° amines 1.Name the alkyl groups ending in “yl” followed by the word, amine

Review: Nomenclature of Amines There are multiple methods for naming 2° amines 2.Find the carbon parent chain, and use the suffix, amine. Smaller groups attached to the amine should be named as alkyl groups with the N-locant

Properties of Amines The N atom in typical amines is sp 3 hybridized The angles are 108 degrees. The C-N bond lengths are 147 pm, which is slightly shorter than C-C bonds.

An amine with three different substituents on nitrogen is chiral (in principle but not in practice) : the lone pair of electrons is the fourth substituent Most amines that have 3 different substituents on N cannot be resolved because the molecules interconvert by pyramidal inversion Chirality Is Possible (But Not Observed)

Amines with fewer than five carbons are water-soluble Primary and secondary amines form hydrogen bonds, increasing their boiling points Amines Form H-Bonds

Properties of Amines Many small molar mass amines stink!!! These are both produced from the degradation of amino acids, and responsible for the odor of putrefying flesh. This is why zombies are unpleasant party guests!

Review: Preparation of Amines

Preparation of Amines via substitution

Azide ion, N 3  displaces a halide ion from 1°or 2°alkyl halide to give an alkyl azide, RN 3 Alkyl azides are not nucleophilic (but they are explosive) Reduction gives the primary amine Selective Preparation of Primary Amines: Azide Synthesis

Preparation of Amines via Substitution Reactions: Gabriel Synthesis of 1° amines The Gabriel synthesis produces primary amines via potassium phthalimide

Preparation of Amines via Reductive Amination Ketones and aldehydes can be converted to imines, and if a reducing agent is present, the imine can be reduced in situ to form an amine

Ammonia, primary amines, and secondary amines yield primary, secondary, and tertiary amines, respectively Reductive Amination Is Versatile

Mechanism of Reductive Amination

Sodium cyanoborohydride, NaBH 3 CN, reduces C=N but not C=O Stable in water Mechanism of Reductive Amination: Reducing Step

Acylation of Amines Amines can attack acyl chlorides Polysubstitution is not observed. An acyl group can act as a protecting group. An acyl group can help to limit the reactivity of amines in Electrophilic Aromatic Substitution reactions

Acylation of Amines Aromatic amines cannot undergo Friedel Crafts directly as addition of AlCl 3 deactivates ring

Acylation of Amines To achieve ring alkylation, first the amine must be acylated

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement Hofmann and Curtius Rearrangements

Converts amines into alkenes NH 2  is very a poor leaving group so it is converted to an alkylammonium ion, which is a good leaving group The less substituted (less stable) product is observed as the base must abstract a hydrogen from the most sterically accessible, least hindered position Hofmann Elimination

Reactions of Aryldiazonium Ions Alkyl diazonium salts are extremely reactive (potentially explosive) because of the excellent N 2 leaving group Aryl diazonium salts are a bit more stable and synthetically versatile

Reactions of Aryldiazonium Ions Treatment with a copper salt yields an aryl halide or nitrile

Reactions of Aryldiazonium Ions There are many other diazonium salt substitutions Using this synthesis, amines can be used as a directing group and subsequently replaced with a –H atom

Arenediazonium salts undergo a coupling reaction with activated aromatic rings, such as phenols and arylamines The electrophilic diazonium ion reacts with the electron- rich ring of a phenol or arylamine Usually occurs at the para position but goes ortho if para is blocked Diazonium Coupling Reactions

Azo-coupled products have extended  conjugation that lead to low energy electronic transitions that occur in visible light Produce brightly colored dyes Azo Dyes

A heterocycle is a cyclic compound that contains atoms of two or more elements in its ring, usually C along with N, O, or S Heterocyclic Amines

Pyrole is an amine and a conjugated diene Is also aromatic Pyrole and Imidazole

Nitrogen Heterocycles Imidazole is another simple heterocycle that is aromatic. Histamine contains an imidazole ring

Nitrogen Heterocycles Pyridine is a six-membered heterocycle The lone pair on N in pyridine is not necessary to achieve 4n+2 pi electrons Pyridine is significantly less basic than typical alkyl amines.

Spectroscopy of Amines Amines generally give broad IR peaks between cm -1 that are less intense than O-H stretching – Recall that 1° amines give two N-H stretch IR signals (symmetric and asymmetric stretching) – 2° amines give one N-H stretch IR signal – 3° amines do not give N-H stretching signals – 3° amines can give a N-H stretching signal if treated with an acid like H-Cl. Protonated amines show an ammonium band in the range 2200 to 3000 cm  1

Examples of Infrared Spectra

NMR Spectroscopy of Amines N-H protons generally appear between 0.5 and 5.0 ppm in the 1 H NMR – Solvent, concentration, and temperature can affect the chemical shift Because N-H protons are generally exchanged at a faster rate than the NMR timescale, N-H protons generally give broad signals with no splitting If a deuterated solvent is used, N-H proton peaks disappear completely.

Hydrogens on C next to N absorb at lower field than alkane hydrogens N-CH 3 gives a sharp three-H singlet at  2.2 to  2.6 Chemical Shift Effects

13 C NMR Carbons next to amine N are slightly deshielded - about 20 ppm downfield from where they would absorb in an alkane

A compound with an odd number of nitrogen atoms has an odd-numbered molecular weight and a corresponding parent ion Alkylamines cleave at the C–C bond nearest the nitrogen to yield an alkyl radical and a nitrogen- containing cation Mass Spectrometry

The two main modes of a cleavage give fragment ions at m/z = 58 and m/z = 72. Mass Spectrum of Ethylpropylamine