Amines and Heterocycles Amines are organic derivatives of ammonia Amines contain a nitrogen atom with a lone pair of electrons Amines are basic and nucleophilic Amines occur widely in both plants and animals

18.1 Naming Amines Amines can be either alkyl-substituted (alkylamines) or aryl-substituted (arylamines) Amines are classified depending on the number of organic substituents attached to nitrogen: Primary (RNH2) One organic substituent such as methylamine (CH3NH2) Secondary (R2NH) Two organic substituents such as dimethylamine [(CH3)2NH] Tertiary (R3N) Three organic substituents such as trimethylamine [(CH3)3N]

Naming Amines Quaternary ammonium salts Nitrogen containing compounds with four organic (R) groups attached to the nitrogen atom Nitrogen carries a formal positive charge

Naming Amines Primary amines are named in the IUPAC system in several ways For simple amines the suffix –amine is added to the name of the alkyl substituent Aniline is an aryl amine The suffix –amine can by used in place of the final –e in the name of the parent compound

Naming Amines Complex amines with more than one functional group are named by considering the –NH2 as an amino substituent on the parent molecule

Naming Amines Symmetrical secondary and tertiary amines are named by adding the prefix di- or tri- to the alkyl group

Naming Amines Unsymmetrically substituted secondary and tertiary amines are named as N-substituted primary amines Largest alkyl group is chosen as the parent name Other alkyl groups are considered N-substituents on the parent N because they are attached to nitrogen

Naming Amines Heterocyclic amines Compounds in which the nitrogen atom occurs as part of a ring Each different heterocyclic ring system has its own parent name The heterocyclic nitrogen atom is always numbered as position 1

18.2 Properties of Amines Nitrogen atom in alkylamines is sp3-hybridized Three substituents occupy the three corners of a tetrahedron and the lone pair of electrons occupies the fourth corner Bond angles are close to 109°

Properties of Amines Nitrogen with three different substituents is chiral Chiral amines cannot be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion Inversion occurs by momentary rehybridization of nitrogen atom to planar, sp2 geometry, to give planar intermediate Rehybridization of planar intermediate occurs giving the tetrahedral, sp3 geometry Barrier to inversion is about 25 kJ/mol

Properties of Amines Alkylamines are starting materials for insecticides and pharmaceuticals Labetalol is a b-blocker used for the treatment of high blood pressure Prepared by SN2 reaction of an epoxide with a primary amine

Properties of Amines Amines with fewer than five carbons are generally water-soluble Amines form hydrogen bonds and are highly associated H-bonding results in higher boiling points than alkanes of similar molecular weights Amines possess characteristic odors

18.3 Basicity of Amines Chemistry of amines dominated by the lone pair of electrons on nitrogen Lone pair makes amines both basic and nucleophilic Electrostatic potential surface of trimethylamine shows in red the region where the nonbonding electrons of nitrogen are located

Basicity of Amines Amines are much stronger bases than alcohols and ethers Base strength measured by basicity constant, Kb

Basicity of Amines Kb values are not often used Basicity of the amine is commonly measured by determining the acidity of its conjugate acid

Basicity of Amines Weaker base: Smaller pKa for ammonium ion Stronger base: Larger pKa for ammonium ion

Basicity of Amines Amides (RCONH2) are nonbasic Amides do not undergo substantial protonation when treated with acids Amides are poor nucleophiles Nitrogen lone-pair electrons are stabilized through orbital overlap with the carbonyl group

Basicity of Amines Primary and secondary amines are very weak acids N-H proton can be removed by a sufficiently strong base Diisopropylamine (pKa ≈ 40) reacts with butyllithium to yield lithium diisopropylamide (LDA)

18.4 Basicity of Arylamines Aryl amines are generally less basic than alkylamines Nitrogen lone-pair electrons are delocalized by interaction with the aromatic ring p electron system and less available for bonding to H+

Basicity of Arylamines Arylamines have a larger positive DG° for protonation and are therefore less basic than alkylamines, primarily because of resonance stabilization of the ground state Nitrogen lone-pair electron density is delocalized in the amine but the charge is localized in the corresponding ammonium ion

Basicity of Arylamines Electron-donating substituents which increase the reactivity for an aromatic ring toward electrophilic substitution also increase the basicity of the aryl amine Electron-withdrawing substituents which decrease ring reactivity toward electrophilic substitution also decrease arylamine basicity

18.5 Biological Amines and the Henderson- Hasselbalch Equation Amines exist essentially 100% in their protonated conjugate acid forms at physiological pH of 7.3 Use Henderson-Hasselbalch equation to determine relative concentrations of amines and their conjugate acids

Biological Amines and the Henderson-Hasselbalch Equation For a 0.0010 M solution of methylamine at pH = 7.3 pKa of methylammonium ion = 10.64

Biological Amines and the Henderson-Hasselbalch Equation Cellular amines are written in their protonated forms Amino acids shown in their ammonium carboxylate form to reflect their structures at physiological pH

18.6 Synthesis of Amines Reduction of Nitriles, Amides and Nitro Compounds Nitriles and amides are reduced by LiAlH4 into amines SN2 displacement with CN- followed by LiAlH4 reduction of the nitrile converts a primary alkyl halide into a primary alkylamine having one more carbon Carboxylic amides, formed from the reaction of the corresponding acid chloride with ammonia, are reduced with LiAlH4 into amines with the same number of carbons

Synthesis of Amines Arylamines are usually prepared by nitration of an aromatic starting material, followed by reduction of the nitro group Reduction is accomplished by several methods

Synthesis of Amines SN2 Reaction of Alkyl Halides Ammonia and other amines are good nucleophiles in SN2 reactions Alkylamines are synthesized most simply by SN2 alkylation of ammonia or an alkylamine with an alkyl halide

Synthesis of Amines Alkylations of ammonia and alkylamines often yield mixtures of products

Synthesis of Amines Reductive Amination of Aldehydes and Ketones Amines can be synthesized in a single step from aldehydes or ketones with ammonia in the presence of a reducing agent Synthesis called a reductive amination

Synthesis of Amines Mechanism of reductive amination Imine intermediate is formed by dehydration of the carbinolamine from the initial nucleophilic addition reaction C=N bond of imine is then reduced

Synthesis of Amines Ammonia, primary amines, and secondary amines can all be used in reductive amination yielding primary, secondary, and tertiary amines, respectively

Synthesis of Amines Reductive aminations occur in biological pathways Biosynthesis of amino acid proline Glutamate 5-semialdehyde undergoes internal imine formation to give 1-pyrrolinium-5-carboxylate 1-pyrrolinium-5-carboxylate is reduced by nucleophilic addition of hydride ion by NADH

Worked Example 18.1 Using a Reductive Amination Reaction How might you prepare N-methyl-2-phenylethylamine using a reductive amination reaction?

Worked Example 18.1 Using a Reductive Amination Reaction 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 there are two combinations that can lead to the product: Phenylacetaldehyde plus methylamine Formaldehyde plus 2-phenylethylamine In general, it’s usually better to choose the combination with the simple amine component – methylamine in this case – and to use an excess of that amine as reactant

Worked Example 18.1 Using a Reductive Amination Reaction Solution

18.7 Reactions of Amines Alkylation and Acylation Primary and secondary (not tertiary) amines can be acylated by reaction with acid chlorides or acid anhydrides to yield amides

Reactions of Amines Hofmann Elimination Amines can be converted into alkenes by an elimination reaction NH2- is a poor leaving group and must be converted into a better leaving group Hofmann elimination Amine is methylated with excess iodomethane to produce a quaternary ammonium salt Quaternary ammonium salt undergoes elimination upon heating with silver oxide

Reactions of Amines Silver oxide exchanges hydroxide ion for iodide ion in the quaternary salt Elimination is E2 and non-Zaitsev

Reactions of Amines Major product is the less highly substituted alkene Base abstracts hydrogen from least hindered position due to the sterically bulky trialkylamine leaving group

Reactions of Amines Biological eliminations analogous to the Hofmann elimination occur frequently In the biosynthesis of nucleic acids adenylosuccinate undergoes elimination of a positively charged nitrogen to give fumarate plus adenosine monophosphate

Worked Example 18.2 Predicting the Product of a Hofmann Elimination What product would you expect from Hofmann elimination or the following amine?

Worked Example 18.2 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 least highly substituted double bond. Look at the reactant and identify the positions from which elimination might occur (the positions two carbons removed from nitrogen). Carry out the elimination using the most accessible hydrogen. In the present instance, the primary (1o) position is the most accessible and leads to the least highly substituted alkene, ethylene.

Worked Example 18.2 Predicting the Product of a Hofmann Elimination Solution

Reactions of Amines Electrophilic Aromatic Substitution Amino substituents are strongly activating, ortho- and para-directing groups in electrophilic aromatic substitution Often give polysubstituted products Aryl amines do not undergo Friedel-Crafts reactions due to the acid-base reaction between the nonbonding electrons of the amino group and the AlCl3 catalyst

Reactions of Amines Amido- substituted (-NHCOR) benzenes are less strongly activated because the nitrogen lone-pair electrons are delocalized by neighboring carbonyl group

Reactions of Amines Sulfa drugs are prepared by chlorosulfonation of acetanilide Reaction of p-(N-acetylamino)benzenesulfonyl chloride with ammonia gives a sulfonamide Nitrogen of amide group is less basic that nitrogen of aryl amines Amide can be hydrolyzed in presence of sulfonamide group

18.8 Heterocyclic Amines Heterocyclic amines are common in biological systems Most heterocycles have the same chemistry as their open-chain counterparts

Heterocyclic Amines Pyrrole and Imidazole Many unsaturated ring heterocycles exhibit unique chemistry Pyrrole is an aromatic heterocycle prepared by reacting furan with ammonia over alumina

Heterocyclic Amines Each carbon of pyrrole contributes one p electron and the sp2-hybridized nitrogen contributes two from its lone pair Pyrrole is a six p electron aromatic compound Nonbonding electrons of nitrogen are delocalized and less basic

Heterocyclic Amines Nitrogen atom in pyrrole is less electron-rich, less basic, and less nucleophilic than nitrogen atom in an aliphatic amine Carbon atoms in pyrrole are more electron-rich and more nucleophilic than typical double-bond carbons

Heterocyclic Amines Chemistry of pyrrole is similar to activated benzene rings Heterocycles are more reactive toward electrophiles than benzene rings and often require low temperatures Halogenation, nitration, sulfonation, and Friedel-Crafts acylation can all be accomplished with aromatic heterocycles

Heterocyclic Amines Electrophilic substitution normally occurs at C2 next to the nitrogen atom Substitution at C2 gives more stable intermediate with three resonance forms

Heterocyclic Amines Imidazole (a constituent of histidine) and thiazole (on which the structure of thiamin is based) are common five-membered heterocyclic amines Only the lone-pair electrons of nitrogen atoms that are not participating in the aromatic p system are basic

Heterocyclic Amines Pyridine and Pyrimidine The five carbon atoms and the sp2-hybridized nitrogen atom of pyridine contribute one p electron to the aromatic sextet The lone-pair electrons of nitrogen atom occupy an sp2 orbital in the plane of the ring Pyridine is less basic that alkylamines because the lone-pair electrons are in an sp2 orbital and are held more closely to the positively charged nucleus and thus less available for bonding

Heterocyclic Amines Pyridine undergoes electrophilic aromatic substitution reactions with great difficulty

Heterocyclic Amines Substitutions occur only slowly and usually at the C-3 of the ring Low reactivity of pyridine due to two factors: Electrophile complexes in and acid-base reaction with the ring nitrogen placing a positive charge on the ring and deactivating it toward electrophilic aromatic substitution Electron density of the ring is decreased by the inductively withdrawing electronegative nitrogen atom Pyridine has substantial dipole moment (m = 2.26 D)

Heterocyclic Amines Pyrimidine is a constituent of nucleic acids Pyrimidine is substantially less basic than pyridine due to the inductive effect of the second nitrogen atom

18.9 Fused-Ring Heterocycles Quinoline, isoquinoline, indole, and purine are common fuse-ring heterocycles Quinoline alkaloid quinine is an antimalarial drug The amino acid tryptophan is an indole derivative The purine adenine is a constituent of nucleic acids

Fused-Ring Heterocycles Quinoline and isoquinoline both undergo electrophilic substitutions less easily than benzene Reaction occurs on the benzene ring and produces a mixture of products

Fused-Ring Heterocycles Indole has a nonbasic-pyrrole-like nitrogen and undergoes electrophilic substitution more easily than benzene Substitution occurs at C3 of electron-rich pyrrole ring

Fused-Ring Heterocycles Purine has three basic, pyridine-like nitrogen atoms (1, 3, and 7) with lone-pair electrons in sp2 orbitals in the plane of the ring The remaining purine nitrogen atom (9) is non-basic and pyrrole-like with its lone-pair electrons part of the aromatic p system

18.10 Spectroscopy of Amines Infrared Spectroscopy Primary amines show a pair of bands at about 3350 and 3450 cm-1 Secondary amines show a single band at 3350 cm-1 Tertiary amines lack a N-H bond and do not absorb in this region of the IR spectrum

Spectroscopy of Amines Nuclear Magnetic Resonance Spectroscopy Amine N-H absorptions can appear over a wide range and are best identified by adding a small amount of D2O to the sample tube N-H is exchanged for N-D and the N-H signal disappears from the 1H NMR spectrum

Spectroscopy of Amines Hydrogens on the carbon next to nitrogen are deshielded because of the electron-withdrawing effect of the nitrogen Absorb at lower field than alkane hydrogens N-methyl groups are distinctive and absorb as a sharp three-hydrogen singlet at 2.2 to 2.6 d

Spectroscopy of Amines Carbons next to amine nitrogens are slightly deshielded in the 13C NMR spectrum and absorb about 20 ppm downfield from where they would otherwise absorb in an alkane of similar structure

Spectroscopy of Amines Mass Spectrometry Nitrogen rule of mass spectrometry A compound with an odd number of nitrogen atoms has an odd-numbered molecular weight Nitrogen is trivalent thus requiring an odd number of hydrogen atoms Alkylamines undergo characteristic a cleavage C-C bond nearest the nitrogen atom is broken

Spectroscopy of Amines Mass spectrum of N-ethylpropylamine has peaks at m/z = 58 and m/z = 72 corresponding to the two possible modes of a cleavage