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Questions and Answers
Which statement about the pKa values of ammonium ions is correct?
Which statement about the pKa values of ammonium ions is correct?
Amines are stronger bases than alcohols, ethers, or water.
Amines are stronger bases than alcohols, ethers, or water.
True
What is the suffix used for naming simple amines?
What is the suffix used for naming simple amines?
-amine
The bond angles in amines are close to ____ degrees due to their sp3 hybridization.
The bond angles in amines are close to ____ degrees due to their sp3 hybridization.
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Match the following amine types with their classifications:
Match the following amine types with their classifications:
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Which of the following pairs are both classified as secondary amines?
Which of the following pairs are both classified as secondary amines?
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Amines can form hydrogen bonds which contribute to increasing their boiling points.
Amines can form hydrogen bonds which contribute to increasing their boiling points.
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In the context of amines, what does the term 'chirality' imply?
In the context of amines, what does the term 'chirality' imply?
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Amines react with acids to form _____-base salts.
Amines react with acids to form _____-base salts.
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Which of the following options best describes the basicity of substituted arylamines compared to simple amines?
Which of the following options best describes the basicity of substituted arylamines compared to simple amines?
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What is the typical pKa range for most simple alkylammonium ions?
What is the typical pKa range for most simple alkylammonium ions?
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Aryl amines are more basic than alkyl amines.
Aryl amines are more basic than alkyl amines.
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What type of substituents increase the basicity of arylamines?
What type of substituents increase the basicity of arylamines?
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Amides (RCONH2) are generally _______ proton acceptors.
Amides (RCONH2) are generally _______ proton acceptors.
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Match the amine synthesis methods with their descriptions:
Match the amine synthesis methods with their descriptions:
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How does the Henderson-Hasselbalch Equation relate to amines?
How does the Henderson-Hasselbalch Equation relate to amines?
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Primary, secondary, and tertiary amines exhibit different reactivities during alkylation.
Primary, secondary, and tertiary amines exhibit different reactivities during alkylation.
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Name one common reducing agent used in reductive amination.
Name one common reducing agent used in reductive amination.
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In the Curtius rearrangement, an acyl azide prepares a primary amine via migration of ______.
In the Curtius rearrangement, an acyl azide prepares a primary amine via migration of ______.
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Which of the following amines can be synthesized using the Gabriel synthesis method?
Which of the following amines can be synthesized using the Gabriel synthesis method?
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The basicity of arylamines increases when an electron-withdrawing group is attached.
The basicity of arylamines increases when an electron-withdrawing group is attached.
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What effect does the presence of an aromatic ring have on the basicity of arylamines?
What effect does the presence of an aromatic ring have on the basicity of arylamines?
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The reaction of arenediazonium salts with CuCl or CuBr yields __________.
The reaction of arenediazonium salts with CuCl or CuBr yields __________.
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Which spectroscopic method can indicate the presence of N-H bonds in amines?
Which spectroscopic method can indicate the presence of N-H bonds in amines?
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Study Notes
Amines and Heterocycles
- Amines are organic derivatives of ammonia (NH₃).
- Nitrogen atoms in amines have lone electron pairs, making them both basic and nucleophilic.
- Amines are found in plants and animals.
Why this Chapter?
- Amines and carbonyl compounds are abundant and have complex chemistry.
- Many pharmaceutical agents contain amine functional groups.
Naming Amines
- Amines can be alkyl-substituted or aryl-substituted.
- Amines are classified as primary (1°), secondary (2°), or tertiary (3°) based on the number of alkyl groups attached to the nitrogen atom.
Quaternary Ammonium Ions
- A nitrogen atom with four attached groups is positively charged.
- Compounds with these ions are quaternary ammonium salts.
IUPAC Names - Simple Amines
- The suffix "-amine" is added to the name of the alkyl substituent in simple amines.
IUPAC Names - "-amine" Suffix
- The suffix "-amine" can replace the final "-e" in the name of the parent compound.
IUPAC Names - Amines With More Than One Functional Group
- The NH₂ group is treated as an amino substituent on the parent molecule.
IUPAC Names - Multiple Alkyl Groups
- Symmetrical secondary and tertiary amines are named by adding the prefix "di-" or "tri-" to the alkyl group.
- The largest alkyl group is the parent name.
Common Names of Heterocyclic Amines
- If nitrogen is part of a ring, the compound is heterocyclic.
- Each ring system has its own parent name.
Properties of Amines
- Bonding to nitrogen is similar to that in ammonia (N is sp³ hybridized).
- C-N-C bond angles are close to 109° tetrahedral value.
Chirality Is Possible (But Not Observed)
- Amines with three different substituents on nitrogen are chiral in principle.
- However, molecules readily interconvert via pyramidal inversion, making them nonchiral in practice.
Amines Form H-Bonds
- Amines with fewer than five carbons are water-soluble.
- Primary and secondary amines have higher boiling points than tertiary amines due to hydrogen bonding.
Basicity of Amines
- The lone pair of electrons on nitrogen in amines makes them basic and nucleophilic.
- Amines react with acids to form acid-base salts.
- Amines react with electrophiles.
Relative Basicity
- Amines are stronger bases than alcohols, ethers, or water.
- Amines establish an equilibrium with water that protonates the amine and produces hydroxide.
- Basicity of amines can be measured by looking at the acidity of the corresponding ammonium ion (high pKa → weaker acid and stronger conjugate base).
- The equilibrium reaction for amine basicity is: RNH₂ + H₂O <=> RNH₃⁺ + OH⁻
Synthesis of Amines
- Arylamines are made through nitration of an aromatic compound, then reducing the nitro group.
- Reduction by catalytic hydrogenation over platinum (Pt) is suitable if other groups are not reduced.
- Iron (Fe), zinc (Zn), tin (Sn), and tin(IV) chloride (SnCl₄) are effective reducing agents in acidic solutions.
SN2 Reactions of Alkyl Halides
- Ammonia and other amines are good nucleophiles in SN2 reactions.
Uncontrolled Multiple Alkylation
- Primary, secondary, and tertiary amines have similar reactivity.
- The initially formed monoalkylated compound undergoes further reaction to yield a mixture of products.
Selective Preparation of Primary Amines: The Azide Synthesis
- Azide ion (N₃⁻) displaces halide ions from primary or secondary alkyl halides to form alkyl azides (RN₃).
- Alkyl azides are not nucleophilic but are explosive.
- Reduction of alkyl azides produces primary amines.
Gabriel Synthesis of Primary Amines
- A phthalimide alkylation is a method to produce primary amines from alkyl halides.
- N-H in imides (CONHCO) can be removed by KOH followed by alkylation and hydrolysis.
Reductive Amination of Aldehydes and Ketones
- Treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent (e.g., H₂/catalyst, NaBH₄) yields primary, secondary, or tertiary amines, depending on the starting amine.
Reductive Amination Is Versatile
- The reactant ammonia, primary or secondary amine yields the corresponding primary, secondary, or tertiary amine respectively via a reductive amination pathway.
Mechanism of Reductive Amination
- Ammonia adds to the ketone carbonyl group to create a carbinolamine intermediate.
- The carbinolamine then loses water to generate an imine.
- The imine is further reduced by NaBH₄ or H₂/metal catalyst to produce the corresponding amine product.
Reducing Step
- Sodium cyanoborohydride (NaBH₃CN) reduces C=N bonds but not C=O bonds.
- It is stable in water.
Hofmann and Curtius Rearrangements
- Carboxylic acid derivatives can be converted to primary amines.
- The Hofmann rearrangement loses one carbon atom.
- The Curtius rearrangement also loses one carbon atom.
Hofmann Rearrangement
- RCONH₂ reacts with Br₂ and base produces high yields of arylamines and alkylamines.
- Refer to figure 24.5 for the mechanism.
Curtius Rearrangement
- Heating an acyl azide (derived from acid chloride) leads to rearrangement with simultaneous loss of a leaving group.
Reactions of Amines
- Alkylation and acylation reactions have been presented in prior sections.
Hofmann Elimination
- Amines are converted into alkenes.
- NH₂ is a poor leaving group, so it's converted to an alkylammonium ion, which is a good leaving group.
Silver Oxide Is Used for the Elimination Step
- Exchanges hydroxide ion for iodide ion in the quaternary ammonium salt.
Orientation in Hofmann Elimination
- The least substituted alkene is predominantly formed in Hofmann elimination due to steric hindrance. Base must abstract the less hindered hydrogen.
Steric Effects Control the Orientation
- The steric bulk of the leaving group directs the base to abstract a hydrogen from the less hindered position. The more highly substituted alkene is usually formed from an elimination of an alkyl halide.
Reactions of Arylamines
- Amino substituents are strongly activating and ortho/para directing in electrophilic aromatic substitution.
- Reactions can be controlled by converting to an amide.
Arylamines Are Not Useful for Friedel-Crafts Reactions
- The amino group forms a Lewis acid-base complex with the AlCl₃, preventing further reaction.
- Use the amide analog for the Friedel-Crafts Reaction.
Diazonium Salts: The Sandmeyer Reaction
- Primary arylamines react with HNO₂ to form stable arenediazonium salts.
Uses of Arenediazonium Salts
- The N₂ group can be replaced by a nucleophile.
Preparation of Aryl Halides
- Reaction of an arenediazonium salt with CuCl or CuBr gives aryl halides (Sandmeyer Reaction).
- Aryl iodides form from reaction with NaI without copper(I) salt.
Aryl Nitriles and Carboxylic Acids
- Arenediazonium salt and CuCN yields nitrile.
- Nitriles can be hydrolyzed to ArCOOH.
Formation of Phenols (ArOH)
- From reaction of the arenediazonium salt with copper(I) oxide in an aqueous solution of copper(II) nitrate produces a phenol.
Reduction to a Hydrocarbon
- Treatment of a diazonium salt with hypophosphorous acid (H₃PO₂) reduces the diazonium to a hydrocarbon group.
Mechanism of Diazonium Replacement
- Through radical pathways rather than polar/ionic pathways.
Diazonium Coupling Reactions
- Arenediazonium salts undergo a coupling reaction with activated aromatic rings (e.g., phenols, arylamines) to produce azo compounds.
How Diazonium Coupling Occurs
- Electrophilic diazonium ion reacts with the electron-rich ring of a phenol or arylamine.
- Usually occurs at the para position, but may go ortho if para is blocked.
Azo Dyes
- Azo-coupled products have an extended conjugation that allows low energy electronic transitions that form visible light dyes.
Heterocycles
- A heterocycle is a cyclic compound that contains two or more elements in its ring, typically C, and N, O, or S.
Pyrole and Imidazole
- Pyrole is an amine and a conjugated diene, but its chemical properties aren't consistent with either structural feature.
Chemistry of Pyrole
- Electrophilic substitutions occur at C₂ next to the N.
- Stable intermediate cation has three resonance forms.
- At C₃, only two resonance forms.
Polycyclic Heterocycles
- Polycyclic heterocycles include quinoline, isoquinoline, indole, and purine.
- Examples are quinine, tryptophan, and adenine.
Spectroscopy of Amines - Infrared
- Characteristic N-H stretching absorptions are in the 3300 to 3500 cm⁻¹ region.
- Amine absorption bands are sharper and less intense than hydroxyl bands.
- Protonated amines show an ammonium band in the 2200 to 3000 cm⁻¹ region.
Nuclear Magnetic Resonance Spectroscopy
- N-H hydrogens, having broad signals without clear-cut coupling to neighboring C-H hydrogens.
- D₂O exchange of N-D for N-H occurs, eliminating the N-H signal.
Chemical Shift Effects
- Hydrogens on C next to N absorb at a lower field than alkane hydrogens.
- N-CH₃ gives a sharp three-H singlet at 2.2 to 2.6 ppm.
13C NMR
- Carbons next to amine N have a slightly deshielded (~20 ppm) chemical shift compared to the same carbons in alkanes.
Mass Spectrometry
- Compounds with an odd number of nitrogen atoms have an odd-numbered molecular weight.
- Alkylamines cleave at the C-C bond nearest the nitrogen to yield an alkyl radical and a nitrogen-containing cation.
Mass Spectrum of N-Ethylpropylamine
- Cleavage in the mass spectrum of N-ethylpropylamine yields fragment ions at m/z 58 and m/z 72.
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