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Organic Chemistry
Table of Contents
Unit 24 Overview: Amines and Heterocycles
24.1 Naming Amines
24.2 Structure and Properties of Amines
24.3 Basicity of Amines
24.4 Basicity of Arylamines
24.5 Biological Amines and the Henderson–Hasselbalch Equation
24.6 Synthesis of Amines
24.7 Reactions of Amines
24.8 Reactions of Arylamines
24.9 Heterocyclic Amines
24.10 Spectroscopy of Amines

Amine synthesis is a crucial skill in organic chemistry, involving various methods to create these nitrogen-containing compounds. From reduction techniques to nucleophilic substitutions, each approach offers unique advantages for crafting different types of amines.

Reductive amination stands out as a versatile two-step process, converting aldehydes or ketones into amines. This method, along with SN2 reactions and Gabriel synthesis, provides organic chemists with a robust toolkit for synthesizing primary, secondary, and tertiary amines.

Synthesis of Amines

Reduction methods for amine synthesis

  • Nitriles reduced to primary amines using LiAlH4 or catalytic hydrogenation
    • LiAlH4 reduction proceeds through an imine intermediate which is hydrolyzed to form the primary amine (propionitrile to propylamine)
    • Catalytic hydrogenation reduces nitrile using H2 gas and a metal catalyst like Raney Ni or Pd/C (benzonitrile to benzylamine)
  • Amides reduced to amines with one less carbon atom using LiAlH4
    • Reduction proceeds through a tetrahedral intermediate which collapses to an aldehyde and is further reduced to the amine (acetamide to ethylamine)
  • Nitro compounds reduced to amines through various methods
    • LiAlH4 reduction proceeds through nitroso and hydroxylamine intermediates before yielding the amine (nitrobenzene to aniline)
    • Catalytic hydrogenation reduces nitro compound using H2 gas and a metal catalyst such as Pd/C or Pt (4-nitroanisole to 4-methoxyaniline)
    • Dissolving metal reduction uses a metal like Fe or Sn in an acidic medium such as HCl or acetic acid (3-nitrotoluene to 3-methylaniline)

SN2 and Gabriel synthesis techniques

  • SN2 reactions (nucleophilic substitution) convert alkyl halides to primary amines using a nucleophilic nitrogen source followed by reduction
    • NaN3 method treats alkyl halide with NaN3 to form an alkyl azide which is reduced using LiAlH4 or catalytic hydrogenation (1-bromobutane to butylamine)
    • Potassium phthalimide method treats alkyl halide with potassium phthalimide to form an N-alkylphthalimide which is hydrolyzed using hydrazine or acid/base (benzyl bromide to benzylamine)
  • Gabriel synthesis prepares primary amines from alkyl halides using potassium phthalimide
    1. Alkyl halide treated with potassium phthalimide to form an N-alkylphthalimide (ethyl bromide to N-ethylphthalimide)
    2. N-alkylphthalimide hydrolyzed using hydrazine or acid/base to yield the primary amine (N-ethylphthalimide to ethylamine)
    • Phthalimide group acts as a protecting group for the amine during alkylation and is easily removed during hydrolysis

Reductive amination process

  • Two-step process for converting aldehydes or ketones into amines
    • Step 1: Formation of an imine intermediate
      1. Aldehyde or ketone treated with an amine (primary or secondary) in the presence of an acid catalyst to form an imine (acetone and methylamine to form an imine)
      2. Reaction proceeds through a tetrahedral carbinolamine intermediate which dehydrates to form the imine
    • Step 2: Reduction of the imine to the amine
      • Imine reduced using a reducing agent such as NaBH4, NaBH3CN, or catalytic hydrogenation (imine reduced to isopropylmethylamine)
      • Reduction converts the C=N double bond of the imine to a C-N single bond yielding the final amine product
  • Versatile method for synthesizing various types of amines
    • Primary amines synthesized by using ammonia as the amine source (formaldehyde and ammonia to methylamine)
    • Secondary amines synthesized by using a primary amine as the amine source (acetaldehyde and methylamine to ethylmethylamine)
    • Tertiary amines synthesized by using a secondary amine as the amine source although this may lead to a mixture of products due to over-alkylation (propionaldehyde and dimethylamine to ethyldimethylamine and methylpropylamine)

Additional Amine Synthesis Methods

  • Reduction of other nitrogen-containing compounds
    • Oximes, hydrazones, and enamines can be reduced to amines using various reducing agents
    • Hydrogenation of these compounds often yields primary amines
  • Alkylation of ammonia or primary amines
    • Direct alkylation can lead to mixtures of primary, secondary, and tertiary amines
    • Careful control of reaction conditions and stoichiometry is necessary to minimize over-alkylation

Key Terms to Review (44)

Imide: Imides are organic compounds characterized by two acyl groups bound to the same nitrogen atom, often derived from the condensation of an amine with two carboxylic acids or their derivatives. They are a crucial class of compounds in the synthesis of amines, offering both stability and reactivity for further chemical transformations.
Nucleophilic substitution reactions: Nucleophilic substitution reactions are a class of chemical reactions in organic chemistry where an electron-rich nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms to replace a leaving group. The reaction is characterized by the substitution of a nucleophile for a leaving group, which can occur via different mechanisms (SN1 or SN2).
Enamines: Enamines are organic compounds formed by the reaction between a secondary amine and an aldehyde or ketone, characterized by the presence of a nitrogen atom connected to a carbon-carbon double bond. They are the result of nucleophilic addition of amines to carbonyl compounds followed by dehydration.
Curtius rearrangement: The Curtius rearrangement is a chemical reaction where an acyl azide is heated to generate an isocyanate, which can subsequently be converted into a primary amine with the addition of water or other nucleophiles. It serves as an important method for the synthesis of amines from carboxylic acids.
Gabriel amine synthesis: Gabriel amine synthesis is a method used in organic chemistry to produce primary amines from primary alkyl halides through the use of phthalimide as a nitrogen source. The process involves nucleophilic substitution followed by deprotection of the phthalimide to release the primary amine.
Azide synthesis: Azide synthesis is a chemical process used to introduce azide groups (-N3) into molecules, often as a step towards creating amines. This method can involve various strategies, including substitution reactions where an azide ion replaces a leaving group in an organic compound.
Hofmann rearrangement: Hofmann rearrangement is a chemical reaction that converts primary amides into primary amines with one fewer carbon atom, using bromine and a base. This process involves the rearrangement of the molecular structure and elimination of a carbon unit in the form of carbon dioxide.
Reductive amination: Reductive amination is a chemical process that combines an aldehyde or ketone with an amine in the presence of a reducing agent to form a substituted amine. This method is widely used for synthesizing primary, secondary, and tertiary amines from simpler organic molecules.
Heat of hydrogenation: The heat of hydrogenation is the amount of energy released when a double bond in an alkene reacts with hydrogen gas to form a single bond, turning it into an alkane. This process is exothermic, indicating that energy is given off during the conversion.
Amines: Amines are a class of organic compounds derived from ammonia (NH3) by the replacement of one or more hydrogen atoms with alkyl or aryl groups. They are characterized by the presence of a nitrogen atom with a lone pair of electrons, giving them basic properties and the ability to act as nucleophiles in chemical reactions.
Hydrogenation: Hydrogenation is a chemical reaction in which hydrogen gas (H2) is added to an organic compound, typically an alkene or alkyne, to produce a more saturated compound. This process is commonly used in the food industry to convert unsaturated fats into more stable, saturated fats.
Nucleophilic Substitution: Nucleophilic substitution is a fundamental organic reaction where a nucleophile (a species that donates electrons) replaces a leaving group attached to a carbon atom, resulting in the formation of a new carbon-nucleophile bond. This process is central to many organic transformations and is particularly relevant in the context of alkyl halides, alcohols, carboxylic acids, and amines.
Alkyl Halides: Alkyl halides are organic compounds that consist of an alkyl group (a hydrocarbon chain) bonded to a halogen atom (fluorine, chlorine, bromine, or iodine). They are widely used in organic synthesis and have various applications in chemistry and biology.
Catalytic Hydrogenation: Catalytic hydrogenation is a chemical process where hydrogen gas is used to reduce unsaturated organic compounds, such as alkenes, aromatic rings, and carbonyl groups, in the presence of a metal catalyst. This reaction allows for the selective and controlled addition of hydrogen to these functional groups, leading to the formation of new, more saturated compounds.
Reduction: Reduction is a chemical process that involves the gain of electrons by a molecule or atom, resulting in a decrease in its oxidation state. This term is particularly important in the context of various organic chemistry reactions and transformations.
Dissolving Metal Reduction: Dissolving metal reduction, also known as metal-ammonia reduction, is a type of chemical reaction where a metal, typically an alkali metal like sodium or lithium, is dissolved in liquid ammonia to form a reducing agent. This reducing agent can then be used to selectively reduce certain functional groups, such as alkynes or nitro groups, in organic synthesis.
Pd/C: Pd/C, or palladium on carbon, is a heterogeneous catalyst commonly used in organic chemistry reactions, particularly in the reduction of alkynes and the synthesis of amines. It consists of palladium metal dispersed on a porous carbon support, which enhances the catalytic activity and stability of the palladium.
SN2 Reactions: SN2 reactions, or bimolecular nucleophilic substitution reactions, are a type of organic reaction where a nucleophile attacks the backside of a carbon atom bearing a good leaving group, resulting in the inversion of stereochemistry at that carbon center.
Amides: Amides are a class of organic compounds that contain a carbonyl group (C=O) bonded to a nitrogen atom. They are derived from carboxylic acids and can be considered the result of replacing the hydroxyl group (-OH) of a carboxylic acid with an amino group (-NH2). Amides are important functional groups in many organic molecules, including proteins, and play a crucial role in various chemical reactions and processes.
Protecting Groups: Protecting groups are chemical moieties that are temporarily attached to reactive functional groups, such as alcohols and amines, to prevent them from participating in unwanted reactions during a synthetic sequence. These groups are then selectively removed at a later stage to reveal the original functional group, allowing for further transformations.
Tetrahedral Intermediate: A tetrahedral intermediate is a key reaction step that occurs in many organic chemistry reactions, where a trigonal planar carbonyl carbon temporarily becomes a tetrahedral carbon with four bonded atoms. This transient intermediate is crucial for understanding the mechanisms of various nucleophilic addition and substitution reactions.
LiAlH4: LiAlH4, also known as lithium aluminum hydride, is a powerful reducing agent commonly used in organic chemistry reactions. It is particularly useful in the context of nucleophilic addition reactions of aldehydes and ketones, the chemistry of esters and amides, as well as the synthesis of amines.
NaBH4: NaBH4, or sodium borohydride, is a powerful reducing agent commonly used in organic chemistry reactions to reduce carbonyl compounds, such as aldehydes and ketones, to alcohols. This versatile reagent is particularly useful in the context of nucleophilic addition reactions, aldol condensations, and the synthesis of amines.
Hydroxylamine: Hydroxylamine is a compound with the chemical formula NH2OH, consisting of an amino group (NH2) bonded to a hydroxyl group (OH). It is an important intermediate in various organic reactions, particularly in the context of nucleophilic addition of amines and the synthesis of amines.
Carbinolamine: A carbinolamine is an intermediate species formed during the nucleophilic addition of an amine to an aldehyde or ketone. It is a key step in the formation of imines and enamines, and is also involved in the synthesis of amines.
Hydrazine: Hydrazine is a colorless, flammable liquid with a distinctive ammonia-like odor. It is a highly reactive and reducing compound that finds applications in various chemical reactions and processes, particularly in the context of nucleophilic addition reactions and the synthesis of amines.
Nitriles: Nitriles are organic compounds containing a cyano (-C≡N) functional group, which consists of a carbon atom triple-bonded to a nitrogen atom. Nitriles are important intermediates in the synthesis of various nitrogen-containing compounds, including amines, which are key building blocks in organic chemistry.
Imine: An imine is a functional group that consists of a carbon-nitrogen double bond, where the nitrogen is connected to a hydrogen atom and an organic substituent. Imines are important intermediates in organic synthesis and are found in various biological processes.
Gabriel Synthesis: The Gabriel synthesis is a chemical reaction used to synthesize primary amines from phthalimide and an alkyl or aryl halide. It is a versatile method for the preparation of a wide range of primary amines, which are important building blocks in organic chemistry and have applications in the synthesis of various compounds, including amides, amino acids, and pharmaceuticals.
Primary Amines: Primary amines are organic compounds containing a nitrogen atom bonded to two hydrogen atoms and one alkyl or aryl group. They are a class of amines that play a crucial role in various organic chemistry topics, including the chemistry of amides, the structure and properties of amines, the synthesis of amines, the reactions of amines, and the spectroscopy of amines.
Alkylation: Alkylation is the process of introducing an alkyl group (a hydrocarbon chain) into a molecule, typically through the reaction of a nucleophile with an alkyl halide or other alkylating agent. This versatile reaction is employed in various organic chemistry contexts, including the formation of new carbon-carbon bonds, the synthesis of more complex molecules, and the modification of existing functional groups.
NaN3: NaN3, or sodium azide, is an inorganic compound with the chemical formula NaN3. It is a colorless, crystalline solid that is commonly used as a precursor in the synthesis of amines, as well as in various other applications such as in the production of airbags and as a preservative.
N-alkylphthalimide: N-alkylphthalimide is an organic compound consisting of a phthalimide group with an alkyl substituent attached to the nitrogen atom. It is an important intermediate in the synthesis of primary amines, a key class of organic compounds.
Reductive Amination: Reductive amination is a chemical reaction that involves the condensation of an aldehyde or ketone with an amine, followed by the reduction of the resulting imine or enamine intermediate to form a secondary or tertiary amine. This reaction is particularly useful in the synthesis of amines, including amino acids.
Imine Intermediate: An imine intermediate is a key reactive species that forms during the synthesis of amines, where a carbonyl compound (aldehyde or ketone) reacts with a primary amine to create an imine (Schiff base) as a transient intermediate. This imine intermediate is then further transformed to yield the final amine product.
Tertiary Amines: Tertiary amines are a class of organic compounds where a nitrogen atom is bonded to three alkyl or aryl groups. They are an important subgroup of amines, which are organic compounds containing a nitrogen atom with a lone pair of electrons.
Nitro Compounds: Nitro compounds are organic compounds that contain one or more nitro groups (-NO2) attached to a carbon atom. These compounds are important intermediates in the synthesis of various nitrogen-containing organic molecules, particularly amines.
Nitroso: The nitroso group (-N=O) is a functional group consisting of a nitrogen atom double-bonded to an oxygen atom. It is an important intermediate in the synthesis of various nitrogen-containing organic compounds, particularly amines.
Alkyl Azide: An alkyl azide is a functional group consisting of an alkyl chain (a hydrocarbon chain) attached to an azide group (-N=N=N). Alkyl azides are important intermediates in organic synthesis, particularly in the synthesis of amines through the Curtius rearrangement.
Potassium Phthalimide: Potassium phthalimide is an important organic compound used in the synthesis of amines. It is the potassium salt of phthalimide, which is derived from phthalic anhydride and acts as a protecting group for primary amines in various organic reactions.
NaBH3CN: NaBH3CN, or sodium cyanoborohydride, is a reducing agent commonly used in organic chemistry for the synthesis of amines from imines or other nitrogen-containing functional groups. It is an important reagent in the context of the topics covered in Section 24.6 Synthesis of Amines.
Raney Ni: Raney Ni is a heterogeneous catalyst composed of nickel that is commonly used in organic synthesis, particularly for the hydrogenation of various functional groups. It is a versatile and effective tool for the reduction of organic compounds.
Reduction Methods: Reduction methods refer to the various techniques used to convert functional groups, such as carbonyl groups, into more reduced forms. These methods are particularly important in the synthesis of amines, as they allow for the selective reduction of precursor compounds to form the desired amine products.
Secondary Amines: Secondary amines are a class of organic compounds that contain a nitrogen atom bonded to two alkyl or aryl groups. They are characterized by the presence of two carbon-nitrogen bonds, distinguishing them from primary amines which have one carbon-nitrogen bond and tertiary amines which have three carbon-nitrogen bonds.