Preparation of Amines

The alkylation of ammonia, Gabriel synthesis, reduction of nitriles, reduction of amides, reduction of nitrocompounds, and reductive amination of aldehydes and ketones are methods commonly used for preparing amines.

Alkylation of ammonia

The reaction of ammonia with an alkyl halide leads to the formation of a primary amine. The primary amine that is formed can also react with the alkyl halide, which leads to a disubstituted amine that can further react to form a trisubstituted amine. Therefore, the alkylation of ammonia leads to a mixture of products.

Reduction of alkylazides

You can best prepare a primary amine from its alkylazide by reduction or by the Gabriel synthesis.



In the Gabriel synthesis, potassium phthalimide is reacted with an alkyl halide to produce an N-alkyl phthalimide. This N-alkyl phthalimide can be hydrolyzed by aqueous acids or bases into the primary amine.

Reduction of nitriles

Nitriles can be reduced by lithium aluminum hydride (LiAIH₄) to primary amines.

Reduction of amides

Amides yield primary amines on reduction by lithium aluminum hydride, while N-substituted and N, N-disubstituted amides produce secondary and tertiary amines, respectively.



Because amides are easily prepared, their reduction is a preferred method for making all classes of amines.

Reduction of nitrocompounds

Aromatic amines are normally prepared by reduction of the corresponding aromatic nitrocompound.

Reductive amination of aldehydes and ketones

Aldehydes or ketones can be reduced by catalytic or chemical reductions in the presence of ammonia or primary or secondary amines, producing primary, secondary, or tertiary amines.
The reaction of a ketone with ammonia, followed by catalytic reduction or reduction by sodium cyanoborohydride, produces a 1° amine.



N-substituted amines are produced by reaction of ketones with primary amines, followed by reduction.



N,N-disubstituted amines can be produced by reaction of 2° amines with ketones followed by reduction

Introduction to Amines

Amines are aliphatic and aromatic derivatives of ammonia. Amines, like ammonia, are weak bases (K_b = 10⁻⁴ to 10⁻⁶). This basicity is due to the unshared electron pair on the nitrogen atom.

Classification and nomenclature of amines

Amines are classified as primary, secondary, or tertiary based upon the number of carbon-containing groups that are attached to the nitrogen atom. Those amine compounds that have only one group attached to the nitrogen atom are primary, while those with two or three groups attached to the nitrogen atom are secondary and tertiary, respectively.



In the common system, you name amines by naming the group or groups attached to the nitrogen atom and adding the word amine.



In the IUPAC System, apply the following rules to name amines:

1. Pick out the longest continuous chain of carbon atoms. The parent name comes from the alkane of the same number of carbons.
   
2. Change the -e of the alkane to “amine.”
   
3. Locate and name any substituents, keeping in mind that the chain is numbered away from the amine group. Substituents, which are attached to the nitrogen atom instead of the carbon of the chain, are designated by a capital N.
   

Aromatic amines belong to specific families, which act as parent molecules. For example, an amino group (—NH₂) attached to benzene produces the parent compound aniline.

Basicity of amines

Amines are basic because they possess a pair of unshared electrons, which they can share with other atoms. These unshared electrons create an electron density around the nitrogen atom. The greater the electron density, the more basic the molecule. Groups that donate or supply electrons will increase the basicity of amines while groups that decrease the electron density around the nitrogen decrease the basicity of the molecule. For alkyl halides in the gas phase, the order of base strength is given below:

(CH3)3 N > (CH3)2NH > CH3NH2 > NH3 most least basic basic

However, in aqueous solutions, the order of basicity changes.

(CH3)2 NH > CH3NH2 > (CH3)3N > NH3 most least basic basic

The differences in the basicity order in the gas phase and aqueous solutions are the result of solvation effects. Amines in water solution exist as ammonium ions.



In water, the ammonium salts of primary and secondary amines undergo solvation effects (due to hydrogen bonding) to a much greater degree than ammonium salts of tertiary amines. These solvation effects increase the electron density on the amine nitrogen to a greater degree than the inductive effect of alkyl groups.

Arylamines are weaker bases than cyclohexylamines because of resonance. Aniline, a typical arylamine, exhibits the resonance structures shown in Figure 1 .

Figure 1

As structures b through e in Figure 1 show, delocalization of the unshared electron pair occurs throughout the ring, making these electrons less available for reaction. As a result of this electron delocalization, the molecule becomes less basic

Heterocyclic Aromatic Compounds

A heterocyclic compound is an organic compound in which one or more of the carbon atoms in the backbone of the molecule has been replaced by an atom other than carbon. Typical hetero atoms include nitrogen, oxygen, and sulfur.

9 Hückel's Rule

In 1931, Erich Hückel postulated that monocyclic (single ring) planar compounds that contained carbon atoms with unhybridized atomic p orbitals would possess a closed bond shell of delocalized π electrons if the number of π electrons in the molecule fit a value of 4 n + 2 where n equaled any whole number. Because a closed bond shell of π electrons defines an aromatic system, you can use Hückel's Rule to predict the aromaticity of a compound. For example, the benzene molecule, which has 3 π bonds or 6 π electrons, is aromatic.

Benzene

In 1834, Eilhardt Mitscherlich conducted vapor density measurements on benzene. Based on data from these experiments, he determined the molecular formula of benzene to be C₆H₆. This formula suggested that the benzene molecule should possess four modes of unsaturation because the saturated alkane with six carbon atoms would have a formula of C₆H₁₄. These unsaturations could exist as double bonds, a ring formation, or a combination of both.

Introduction to Aromatic Compounds

Aromatic compounds are a class of hydrocarbons that possess much greater stability than their conjugated unsaturated system suggests. The simplest example of this class of compounds, benzene, was isolated from illuminating gas by Michael Faraday in 1825. In the years to follow, this compound and homologues were isolated by the distillation of resin gums from balsam trees. Because many of the resin gums had fragrant aromas, these compounds were often called aromatic compounds or aromatic hydrocarbons. In 1845, August Von Hofmann isolated benzene from coal tar. This isolation method remained the chief source of benzene until the 1950s. Today, most benzene is produced from petroleum.

Reactions: Alcohols

Reactions: Alcohols

Neutralization

Halide Formation

Ester formation

Oxidation

Carboxylic acid formation

Reactions: Ethers

Reactions: Ethers

Cleavage

Protonation

Reactions: Aryl Halides

Reactions: Aryl Halides

Grignard reaction

Hydrolysis

Amination

Reactions: Phenols

Reactions: Phenols

Neutralization

Ester formation

Ether formation

Halogenation

Nitration

Sulfonation

Kolbe reaction

Reactions: Alkyl Halides

Reactions: Alkyl Halides

Hydrolysis

Williamson ether synthesis

Nitrile formation

Amine formation

Alkene formation

Grignard formation

Reactions: Aromatic Compounds

Reactions: Aromatic Compounds

Halogenation

Nitration

Sulfonation

Friedel-Crafts alkylation

Friedel-Crafts acylation

Birch reduction

Reactions of Alcohols

Alcohols are capable of being converted to metal salts, alkyl halides, esters, aldehydes, ketones, and carboxylic acids.

Metal salt formation

Alcohols are only slightly weaker acids than water, with a K_a value of approximately 1 × 10⁻¹⁶. The reaction of ethanol with sodium metal (a base) produces sodium ethoxide and hydrogen gas.



This reaction is identical to the reaction of sodium metal with water.



However, the latter reaction occurs faster because of the increased acidity of water (K_a value of 1 × 10⁻¹⁵). Likewise, similar reactions occur with potassium metal.
The acidity of alcohols decreases while going from primary to secondary to tertiary. This decrease in acidity is due to two factors: an increase of electron density on the oxygen atom of the more highly-substituted alcohol, and steric hindrance (because of the alkyl groups, which inhibit solvation of the resulting alkoxide ion). Both of these situations increase the activation energy for proton removal.
The basicity of alkoxide ions increases while going from primary to tertiary. This increase in basicity occurs because the conjugate base of a weak acid is strong. The weaker the acid, the stronger the conjugate base.

Alkyl halide formation

Alcohols are converted to alkyl halides by S_N1 and S_N2 reactions with halogen acids.



Primary alcohols favor S_N2 substitutions while S_N1 substitutions occur mainly with tertiary alcohols.
A more efficient method of preparing alkyl halides from alcohols involves reactions with thionyl chloride (SOCl₂).



This reaction is rapid and produces few side reaction products. In addition, the sulfur dioxide and hydrogen chloride formed as byproducts are gasses and therefore easily removed from the reaction. Mechanistically, the alcohol initially reacts to form an inorganic ester.



The chloride ion produced by this reaction, acting as a nucleophile, attacks the ester in an S_N2 fashion to yield molecules of sulfur dioxide, hydrogen chloride, and an alkyl halide.



Because the reaction proceeds mainly by an S_N2 mechanism, the alkyl halide produced from an optically active alcohol will have the opposite relative configuration from the alcohol from which it was formed.



Because thionyl bromide is relatively unstable, alkyl bromides are normally prepared by reacting the alcohol with phosphorous tribromide (PBr₃).



This reaction proceeds via a two-step mechanism. In the first step, the alcohol reacts with the phosphorous tribromide.



The second step is an S_N1 or S_N2 substitution in which the bromide ion displaces the dibromophosphorous group.



In a similar manner, alkyl iodides are prepared by reacting an alcohol with phosphorous triiodide.

Ester formation

Esters are compounds that are commonly formed by the reaction of oxygen-containing acids with alcohols. The ester functional group is the
Alcohols can be converted to esters by means of the Fischer Esterification Process. In this method, an alcohol is reacted with a carboxylic acid in the presence of an inorganic acid catalyst.
Because the reaction is an equilibrium reaction, in order to receive a good yield, one of the products must be removed as it forms. Doing this drives the equilibrium to the product side.



The mechanism for this type of reaction takes place in seven steps:

1. The mechanism begins with the protonation of the acetic acid.
   
   
   
   
2. The π electrons of the carboxyl group, , migrate to pick up the positive charge.
   
   
   
   
3. The oxygen of the alcohol molecule attacks the carbocation.
   
   
   
   
4. The oxonium ion that forms loses a proton.
   
   
   
   
5. One of the hydroxyl groups is protonated to form an oxonium ion.
   
   
   
   
6. An unshared pair of electrons on another hydroxy group reestablishes the carbonyl group, with the loss of a water molecule.
   
   
   
   
7. The oxonium ion loses a proton, which leads to the production of the ester.
   
   
   
   

Alkyl sulfonate formation. Alcohols may be converted to alkyl sulfonates, which are sulfonic acid esters. These esters are formed by reacting an alcohol with an appropriate sulfonic acid. For example, methyl tosylate, a typical sulfonate, is formed by reacting methyl alcohol with tosyl chloride.



Other sulfonyl halides that form alkyl sulfonates include:



These groups are much better leaving groups than the hydroxy group because they are resonance stabilized. Alcohol molecules that are going to be reacted by S_N1 or S_N2 mechanisms are often first converted to their sulfonate esters to improve both the rate and yield of the reactions.
Formation of aldehydes and ketones. The oxidation of alcohols can lead to the formation of aldehydes and ketones. Aldehydes are formed from primary alcohols, while ketones are formed from secondary alcohols.
Because you can easily further oxidize aldehydes to carboxylic acids, you can only employ mild oxidizing agents and conditions in the formation of aldehydes. Typical mild oxidizing agents include manganese dioxide (MnO₂), Sarett-Collins reagent (CrO₃—(C₅H₅N)₂), and pyridinium chlorochromate (PCC),



Following are several examples of the oxidation of primary alcohols:



Because ketones are more resistant to further oxidation than aldehydes, you may employ stronger oxidizing agents and higher temperatures. Secondary alcohols are normally converted to ketones by reaction with potassium dichromate (K₂Cr₂O₇), potassium permanganate (KMnO₄), or chromium trioxide in acetic acid (CrO₃/CH₃COOH). Following are several examples of the oxidation of secondary alcohols:



Carboxylic acid formation. Upon oxidation with strong oxidizing agents and high temperatures, primary alcohols completely oxidize to form carboxylic acids. The common oxidizing agents used for these conversions are concentrated potassium permanganate or concentrated potassium dichromate. Following are several examples of this type of oxidatio