Chapter 19
Amines
19-01

Labeled
Title
 Examples of Biologically Active Amines
Caption
 Figure 19-1 Examples of some biologically active amines.
Notes
 The amine group is present in a large number of drugs and medicines.
Keywords
 amine, biological activity
19-02

Labeled
Title
 Alkaloids
Caption
 Figure 19-2 Some representative alkaloids
Notes
 Many drugs of addiction are alkaloids.
Keywords
 alkaloids
19-02-15

Labeled
Title
 Structure of Amines
Caption
 Ammonia has a slightly distorted tetrahedral shape, with a lone pair of non-bonding electrons occupying one of the tetrahedral positions. This geometry is represented by sp3 hybridization of nitrogen, with the bulky lone pair compressing the H-N-H bond angles to 107o from the "ideal" sp3 bond angle of 109.5o.
Notes
 Trimethylamine has angles of 108o.
Keywords
 ammonia, distorted, tetrahedral, trimethylamine
19-03

Labeled
Title
 Interconversion of Chiral Amines
Caption
 Figure 19-3 Nitrogen inversion interconverts the two enantiomers of a simple chiral amine. The transition state is a planar, sp2 hybrid structure with the lone pair in a p orbital.
Notes
 Resolution of amines is difficult because nitrogen inversion interconverts the enantiomers.
Keywords
 inversion, enantiomers, interconversion
19-03-01UN

Labeled
Title
 Chiral Amines
Caption
 Amines whose chirality stems from the presence of chiral carbon atoms.
Notes
 Inversion of the nitrogen is not relevant because it will not affect the chiral carbon.
Keywords
 chiral carbon
19-03-02UN

Labeled
Title
 Chiral Amines
Caption
 Quaternary ammonium salts with chiral nitrogen atoms. Inversion of configuration is not possible because there is no lone pair to undergo nitrogen inversion.
Notes
 The nitrogen must have 4 different groups around it to be chiral.
Keywords
 quaternary ammonium salt, chiral nitrogen
19-03-03UN

Labeled
Title
 Chiral Amines
Caption
 Amines that cannot attain the sp2 hybrid transition state for nitrogen inversion.
Notes
 Amines involved in small sized rings cannot invert.
Keywords
 inversion, transition state, chiral
19-03-04UN

Labeled
Title
 Physical Properties of Amines
Caption
 Amines are strongly polar because the large dipole moment of the lone pair of electrons adds to the dipole moments of the C-N and H-N bonds.
Notes
 The N-H hydrogen bond is weaker than the O-H hydrogen bond, therefore amines have lower boiling points than alcohols of similar molecular weight.
Keywords
 hydrogen bonds, dipole moment
19-03-06UN

Labeled
Title
 Reactivity of Amines
Caption
 An amine is a nucleophile (a Lewis base) because its lone pair of non-bonding electrons can form with an electrophile. An amine can also acts as a Bronsted-Lowry base by accepting a proton from a proton acid.
Notes
 When an amine acts as a nucleophile, a N-C bond is formed. When it acts as a base, a N-H bond is formed.
Keywords
 nucleophile, electrophile, Lewis base
19-04

Labeled
Title
 Potential-Energy Diagram of the Base Dissociation of an Amine
Caption
 Figure 19-4 Potential energy diagram of the base-dissociation reaction of an amine.
Notes
 Alkyl groups stabilize the ammonium ion, making the amine a stronger base. Primary, secondary, and tertiary amines, however, show similar basicities due to solvation effects.
Keywords
 ammonium ion, solvation effect
19-04-01UN

Labeled
Title
 Alkyl Group Stabilization of Amines
Caption
 Alkyl groups are electron-donating toward cations and methylamine has a methyl group to stabilize the positive charge on nitrogen. This stabilization lowers the potential energy of the methylammonium cation, making methylamine a stronger base than ammonia.
Notes
 Simple alkylamines tend to be stronger bases than ammonia.
Keywords
 stabilization, methylammonia
19-05

Labeled
Title
 Stabilization of Aniline
Caption
 Figure 19-5 Aniline is stabilized by the overlap of the lone pair with the aromatic ring. No such overlap is possible in the anilinium ion.
Notes
 The nitrogen of aniline has the non-bonding electrons parallel to the p orbitals of the ring so overlap can occur. The anilinium ion does not have this stabilization so its formation is not favored.
Keywords
 aniline, overlap, anilinium ion
19-05-02UN

Labeled
Title
 Hybridization Effects
Caption
 In pyridine the non-bonding electrons occupy an sp2 orbital, with greater s character and more tightly held than those in the sp3 orbital of an aliphatic amine. Pyridine's non-bonding electrons are less available for bonding to a proton.
Notes
 Pyridine is less basic than aliphatic amines, but it is more basic than pyrrole because it does not lose its aromaticity on protonation.
Keywords
 pyridine, aliphatic amines, pyrrole
19-05-05UN

Labeled
Title
 Solubility of Amines
Caption
 Most amines containing more than six carbons are relatively insoluble in water. In dilute aqueous acid, the amines form their corresponding ammonium salts, and they dissolve. When the solution is made alkaline, the free amine is regenerated.
Notes
 The purified free amine either precipitates out of solution, or it is extracted into an organic solvent.
Keywords
 alkaline, free amine, precipitation, extraction
19-06

Labeled
Title
 Solubility of Amines and Ammonium Salts
Caption
 Most amines containing more than six carbon atoms are relatively insoluble in water. In dilute aqueous acid, these amines form their corresponding ammonium salts, and they dissolve. Formation of a soluble salt is one of the characteristics functional group tests for amines.
Notes
 A free amine can be converted into its ammonium salt by treatment with acid. The ammonium salt is soluble in water. Treating the ammonium salt with basic solutions will convert it back into the free amine.
Keywords
 free amine, ammonium salt
19-06-03UN

Labeled
Title
 Cocaine
Caption
 Cocaine is usually smugled and "snorted" as the hydrochloride salt. Treating cocaine hydrochloride with sodium hydroxide and extracting it into ether converts it back to the volatile "free-base" for smoking.
Notes
 Cocaine is usually found as the hydrochloride salt because it is a solid and can be easily handled. Neutralizing cocaine hydrochloride converts it into the free-base which is more volatile.
Keywords
 cocaine, free-base
19-07

Labeled
Title
 Phase Transfer Catalyst
Caption
 The quaternary ammonium ion forms and ion pair with hydroxide ion, allowing hydroxide to transfer into the organic phase (a solution of cyclohexene in chloroform). In the organic phase hydroxide is more reactive than in the aqueous phase because it is stripped of its solvating water molecules. Hydroxide reacts with chloroform to give dichlorocarbene, which reacts with cyclohexene to give the cyclopropanated product.
Notes
 The hydroxyde ion is "transferred" to the organic phase by the quaternary ammonium ion, which is used as a phase-transfer catalyst.
Keywords
 quaternary ammonium ion, phase-transfer catalyst
19-08

Labeled
Title
 IR Spectrum of 1-Propanamine
Caption
 Figure 19-7 Infrared spectrum of 1-propanamine. Notice the characteristic N-H stretching absorptions at 3300 and 3400 cm-1.
Notes
 The absorption of N-H stretch appears between 3200 and 3500 cm-1. Primary amines have two N-H spikes, while there is only one N-H spike for secondary amines.
Keywords
 infrared, stretching frequency, absorption
19-09

Labeled
Title
 13C and Proton NMR Spectrum of 1-Propanamine
Caption
 13C and 1H-NMR spectra of 1-propanamine.
Notes
 Protons of an amine's a carbon atom generally absorb between d2 and d3, the exact position depending on the structure and substitution of the amine. Protons that are beta to a nitrogen atoms show a much smaller effect, usually absorbing in the range d1.1 to d1.8.
Keywords
 nuclear magnetic resonance
19-10

Labeled
Title
 Mass Spectrum of Butyl Propyl Amine
Caption
 Figure 19-9 Mass spectrum of butyl propylamine. The base peak corresponds to a cleavage in the butyl group, giving a propyl radical and a resonance-stabilized iminium ion.
Notes
 Breaking the a,b C-C bond forms the iminium ion.
Keywords
 base peak, iminium, resonance
19-11

Labeled
Title
 Activation of Benzene by the Amino Group
Caption
 Figure 19-10 The amino group is a strong activator and ortho, para-director. The non-bonding electrons on nitrogen stabilize the s complex when attack occurs at the ortho and para positions.
Notes
 The nitrogen can use its non-bonding electrons to stabilize the positive charge of the sigma complex.
Keywords
 sigma complex, activator, ortho, para
19-11-03UN

Labeled
Title
 Electrophilic Aromatic Substitution of Pyridine
Caption
 The non-bonding electrons of nitrogen are perpendicular to the p system and cannot stabilize the positively charged intermediate. When pyridine does react it gives substitution at the 3-position, analogous to the meta substitution shown by deactivated benzene derivatives.
Notes
 Attack at the 2-position would have an unfavorable resonance structure in which the positive charge is localized on the nitrogen. Substitution at the 2-position is not observed.
Keywords
 electrophilic aromatic substitution, pyridine, meta
19-11-06UN

Labeled
Title
 Nucleophilic Aromatic Substitution of Pyridine
Caption
 Pyridine is deactivated toward electrophilic attack but it is activated toward attack by electron-rich nucleophiles: nucleophilic aromatic substitution. If there is a good leaving group at either the 2-position or the 4-position, a nucleophile can attack and displace the leaving group.
Notes
 Attack at the 2-position or 4-position gives a favorable resonance structure in which the negative charge is on the nitrogen. Attack at the 3-position does not have the negative charge on the nitrogen so substitution at the 3-position is not observed.
Keywords
 nucleophilic aromatic substitution
19-11-07UN

Labeled
Title
 Alkylation of Amines by Alkyl Halides
Caption
 Amines react with primary alkyl halides to give alkylated ammonium halides.
Notes
 Polyalkylation is a problem when alkylating amines through this method.
Keywords
 ammonim halide, polyalkylation
19-11-10UN

Labeled
Title
 Acylation of Amines
Caption
 Primary and secondary amines react with acid halides to form amides.
Notes
 The nitrogen of the amine will attack the carbonyl carbon and displace the chloride.
Keywords
 acid halides, acylation, amide
19-11-11UN

Labeled
Title
 Mechanism of Acylation of Amines
Caption
 The acid chloride is more reactive than a ketone or aldehyde because the electronegative chlorine atom draws electron density away from the carbonyl carbon, making it more electrophilic.
Notes
 The nitrogen of the amine attacks the carbonyl carbon forming a tetrahedral intermediate. Displacement of chloride and deprotonation gives the amide as the final product.
Keywords
 acid chloride, tetrahedral intermediate, amide
19-11-20UN

Labeled
Title
 Synthesis of Sulfonamides
Caption
 A primary or secondary amine attacks a sulfonyl chloride and displaces chloride ion to give an amide. Amides of sulfonic acids are called sulfonamides.
Notes
 Sulfa drugs are a class of sulfonamides used as antibacterial agents.
Keywords
 sulfonyl chloride, sulfonic acid, sulfonamide
19-11-24UN

Labeled
Title
 The Hofmann Elimination
Caption
 An amino group can be converted into a good leaving group by exhaustive elimination: conversion to a quaternary ammonium salt that can leave as a neutral amine. Exhaustive methylation is usually accomplished using methyl iodide.
Notes
 After exhaustive methylation, the ammonium salt is treated with silver oxide and water to convert it to the hydroxide salt. Upon heating elimination takes place producing an alkene. When more than one alkene can form, the least highly substituted alkene will be the major product (Hofmann product).
Keywords
 exhaustive elimination, silver oxide, Hofmann product
19-11-26UN

Labeled
Title
 Hofmann Product
Caption
 In the Hofmann elimination, however, the product is commonly the least highly substituted alkene. We often classify an elimination as giving mostly the Saytzeff product (the most highly substituted alkene) or the Hofmann product (the least highly substituted product).
Notes
 In the Hofmann elimination, the hydroxide ion abstracts a proton from the least substituted carbon. The product is the least highly substituted alkene.
Keywords
 Hofmann elimination, Saytzeff product
19-12

Labeled
Title
 Hofmann Elimination of 2-Butanamine
Caption
 Figure 19-12 Hofmann elimination of 2-butanamine. The most stable conformation of the C2-C3 bond has no proton on the C3 in an anti relationship to the leaving group Along the C1-C2 bond, however, any staggered conformation has an anti relationship between a proton and the leaving group.
Notes
 The proton being abstracted has to be anti to the leaving group.
Keywords
 Hofmann elimination, staggered conformation
19-13-005UN

Labeled
Title
 Oxidation Products of an Amine
Caption
 Some oxidation states of amines and their oxidation products.
Notes
 Amines can be oxidized easily with hydrogen peroxide or MCPBA. They can also be oxidized by air.
Keywords
 amine, imine, ammonium salt, hydroxylamine, amine oxide, nitro compound
19-13-008UN

Labeled
Title
 Preparation of Amine Oxides
Caption
 Tertiary amines are oxidized to amine oxides, often in good yields. Either H2O2 or MCPBA may be used for this oxidation.
Notes
 The amine oxide has a positive charge on the nitrogen.
Keywords
 amine oxide, MCPBA
19-13-009UN

Labeled
Title
 Cope Elimination
Caption
 Because of the positive charge on the nitrogen, the amine oxide may undergo a Cope elimination much like the Hofmann elimination of a quaternary ammonium salt. The amine oxide acts as its own base through a cyclic transition state, so a strong base is not needed.
Notes
 The oxygen of the oxide abstracts a proton forming an alkene. Unlike the Hofmann elimination, the Cope elimination requires the proton and the leaving group to be syn.
Keywords
 Cope elimination, amine oxide
19-13-014UN

Labeled
Title
 Reaction of Amines with Nitrous Acid
Caption
 In an acidic solution, nitrous acid may protonate and lose water to give the nitrosonium ion, NO2+. The nitrosonium ion appears to be the reactive intermediate in most reactions of amines with nitrous acid.
Notes
 The nitrosonium ion is stabilized by two resonance structures in which the positive charge is shared by both, the nitrogen and the oxygen atoms.
Keywords
 nitrous acid, nitrosonium ion
19-13-015UN

Labeled
Title
 Formation of Diazonium Salts
Caption
 Primary amines react with nitrous acid, via the nitrosonium ion, to give diazonium cations. This procedure is called diazotization of an amine.
Notes
 The amine attacks the nitrosonium ion and forms a N-nitrosoamine. Proton transfer, followed by protonation and loss of water gives the diazonium cation.
Keywords
 nitrosonium ion, diazonium cations, diazotization, N-nitrosoamine
19-13-016UN

Labeled
Title
 Formation of Diazonium Salts
Caption
 A proton transfer (a tautomerism) from nitrogen to oxygen forms a hydroxyl group and a second N-N bond. Protonation of the hydroxyl group, followed by loss of water, gives the diazonium cation.
Notes
 Proton transfer, followed by protonation and loss of water gives the diazonium cation.
Keywords
 nitrosonium ion, diazonium cations, diazotization, N-nitrosoamine
19-13-021UN

Labeled
Title
 Reactions of Arenediazonium Salts
Caption
 Arenediazonium salts are formed by diazotizing a primary aromatic ring. Primary aromatic amines are commonly prepared by nitrating an aromatic ring, then reducing the nitro group to an amino group. In effect, by forming and diazotizing and amine, an activated aromatic position can be converted into a wide variety of functional groups.
Notes
 Once the diazonium ion is formed it can be easily replaced by other functional groups.
Keywords
 arenediazonium salts, diazonium ion
19-13-023UN

Labeled
Title
 Hydrolysis of the Diazonium Group
Caption
 Hydrolysis takes place when a solution of an arenediazonium salt is strongly acidified (usually by adding H2SO4) and warmed.
Notes
 The hydroxyl group of water replaces N2, forming a phenol.
Keywords
 hydrolysis, arenediazonium salt
19-13-024UN

Labeled
Title
 The Sandmeyer Reaction
Caption
 Copper(I) salts (cuprous salts) have a special affinity for diazonium salts. Cuprous chloride, cuprous bromide, and cuprous cyanide react with arenediazonium salts to give aryl chlorides, aryl bromides, and aryl cyanides.
Notes
 The Sandmeyer reaction (using cuprous cyanide) is an excellent way of attaching another carbon substituent to an aromatic ring.
Keywords
 cuprous salts, Sandmeyer reaction, diazonium salts
19-13-025UN

Labeled
Title
 Synthesis of Aryl Fluorides
Caption
 When an arenediazonium salt is treated with fluoroboric acid (HBF4), the diazonium fluoroborate precipitates out of solution. If the precipitate is filtered and then heated, it decomposes to give the aryl fluoride.
Notes
 Diazonium salts are explosive so this reaction needs to be carried out with extreme care.
Keywords
 arenediazonium salt, aryl fluorides, fluoroboric acid, diazonium fluoroborate
19-13-026UN

Labeled
Title
 Synthesis of Aryl Iodides
Caption
 Aryl iodides are formed by treating arenediazonium salts with potassium iodide. This is one of the best methods for the synthesis of iodobenzene derivatives.
Notes
Keywords
 aryl iodides, arenediazonium salts
19-13-027UN

Labeled
Title
 Deamination of Anilines
Caption
 Hypophosphorous acid (H3PO2) reacts with arediazonium salts, replacing the diazonium group with a hydrogen.
Notes
 The amino group can be used to activate the ring and take advantage of its directing abilities.
Keywords
 hypophosphorous acid, deamination
19-13-030UN

Labeled
Title
 Diazo Coupling
Caption
 Arenediazonium ions act as weak electrophiles in electrophilic aromatic substitutions. The products have the structure Ar-N=N-Ar, containing the -N=N- azo linkage. For this reason the products are called azo compounds, and the reaction is called diazo coupling.
Notes
 The reaction needs strongly activated rings to react with the arenediazonium salt.
Keywords
 azo linkage, diazo coupling
19-13-048UN

Labeled
Title
 Reductive Amination: Synthesis of Primary Amines
Caption
 Primary amines result from the condensation of hydroxylamine (zero alkyl) groups) with a ketone or an aldehyde, followed by reduction of the oxime. This is a convenient reaction because most oximes are stable, easily isolated compounds.
Notes
 LiAlH4 or NaBH3CN can be used to reduce the oxime.
Keywords
 hydroxylamine, oxime
19-13-049UN

Labeled
Title
 Reductive Amination: Synthesis of Secondary Amines
Caption
 Condensation of a ketone or an aldehyde with a primary amine forms an N-substituted imine (a Schiff base). Reduction of the N-substituted imine gives a secondary amine.
Notes
 LiAlH4 or NaBH3CN can be used to reduce the imine.
Keywords
 imine
19-13-050UN

Labeled
Title
 Reductive Amination: Synthesis of Tertiary Amines
Caption
 Condensation of a ketone or an aldehyde with a secondary amine gives an iminium salt. Iminium salts are frequently unstable so they are rarely isolated. A reducing agent in the solution reduces the iminium salt to a tertiary amine
Notes
 The iminium salt is in equilibrium with the ketone or aldehyde. Using NaBH3CN is best because it will selectively reduce the iminium salt and not the carbonyl group.
Keywords
 iminium salt
19-13-056UN

Labeled
Title
 Synthesis of Amines by Acylation-Reduction
Caption
 Like reductive amination, acylation-reduction adds one alkyl group to the nitrogen atom of the starting amine. Acylation of the starting amine by an acid chloride gives an amide with no tendency toward overacylation. Reduction of the amide by LiAlH4 gives the corresponding amine.
Notes
 Depending on the amine used as the starting material we can get a primary, secondary or tertiary amine as product. Use of ammonia will give a primary amine after acylation-reduction. Reaction of a primary amine will produce a secondary amine, and reaction of a secondary amine will produce a tertiary amine after acylation-reduction.
Keywords
 reductive amination, overacylation
19-13-064UN

Labeled
Title
 The Gabriel Synthesis
Caption
 The phthalimide ion is a strong nucleophile, displacing the halide ot tosylate ion from a good SN2 substrate. Overalkylation does not occur because N-alkyl phthalimide is not nucleophilic and there are no additional acidic protons on nitrogen. Heating the N-alkyl phthalimide with hydrazine displaces the primary amine giving the very stable hydrazide of phthalimide.
Notes
 The Gabriel synthesis is a fast and easy way to make primary amines without any overalkylation by-products.
Keywords
 phthalimide, N-alkyl phthalimide
19-13-066UN

Labeled
Title
 Reduction of Azides
Caption
 Azides are easily reduced by LiAlH4 or by catalytic hydrogenation. Alkyl azides are explosive so they are reduced without purification.
Notes
 To prepare the azide, the alkyl halide or tosylate is treated with sodium azide. Primary and secondary halides or tosylates work best since this is an SN2 reaction.
Keywords
 azide
19-13-068UN

Labeled
Title
 Reduction of Nitriles
Caption
 Like the azide ion, cyanide ion is a good SN2 nucleophile; it displaces leaving groups from primary or secondary alkyl halides or tosylates. The product is a nitrile, which has no tendency to react further. Nitriles are reduced to primary amines by LiAlH4 or catalytic hydrogenation.
Notes
 Attack of the cyanide ion on a carbonyl compound followed by reduction is a convenient method to synthesize b-hydroxyamines.
Keywords
 cyanide ion, nitrile
19-13-072UN

Labeled
Title
 Reduction of Nitro Compounds
Caption
 Both aliphatic and aromatic nitro groups are easily reduced to amino groups. The most common methods are catalytic hydrogenation and acidic reduction by an active metal.
Notes
 This reduction is mostly used in the synthesis of aniline derivatives.
Keywords
 nitro compounds, active metal
19-13-074UN

Labeled
Title
 The Hofmann Rearrangement of Amides
Caption
 In the presence of strong base, primary amides react with chlorine or bromine to form shortened amines with loss of the carbonyl carbon atom. This reaction, called the Hofmann rearrangement, is used to synthesize primary and aryl amines.
Notes
 The product will have one carbon less per carbonyl than the starting material.
Keywords
 Hofmann rearrangement, amide, aryl amine
19-13-076UN

Labeled
Title
 Mechanism of the Hofmann Rearrangement: Step 1
Caption
 The first step is the replacement of on of the hydrogens on the nitrogen by a halide.
Notes
 The deprotonated amide is nucleophilic and will attack the bromine molecule forming the N -bromo amide.
Keywords
 amide, N -bromo amide
19-13-077UN

Labeled
Title
 Mechanism of the Hofmann Rearrangement: Step 2
<align="right">Caption Deprotonation of the N -bromo amide gives another resonance-stabilized anion. The deprotonated amide has a bromine atom present as a potential leaving group. In order for bromine to leave, however, the alkyl group must migrate to the nitrogen.
Notes
 This is the actual rearrangement step, giving an isocyanate intermediate.
K