Reactions of Amines. A general equation for such electrophilic substitution of nitrogen is:. A list of some electrophiles that are known to react with amines is shown here. In each case the electrophilic atom or site is colored red. It is instructive to examine these nitrogen substitution reactions, using the common alkyl halide class of electrophiles.
The hydrogen bromide produced in the reaction combines with some of the excess ammonia, giving ammonium bromide as a by-product. It follows that simple amines should also be more nucleophilic than their alcohol or ether equivalents. If, for example, we wish to carry out an S N 2 reaction of an alcohol with an alkyl halide to produce an ether the Williamson synthesis , it is necessary to convert the weakly nucleophilic alcohol to its more nucleophilic conjugate base for the reaction to occur.
In contrast, amines react with alkyl halides directly to give N-alkylated products. Since this reaction produces HBr as a co-product, hydrobromide salts of the alkylated amine or unreacted starting amine in equilibrium will also be formed. If a ratio of amine to alkylating agent is used, as in the above equation, the HX issue is solved, but another problem arises.
Both the starting amine and the product amine are nucleophiles. Consequently, once the reaction has started, the product amine competes with the starting material in the later stages of alkylation, and some higher alkylated products are also formed.
Another electrophilic reagent, benzenesulfonyl chloride, reacts with amines in a fashion that provides a useful test for distinguishing primary, secondary and tertiary amines the Hinsberg test. Because of the heterogeneous nature of this system, the rate at which the sulfonyl chloride reagent is hydrolyzed to its sulfonate salt in the absence of amines is relatively slow.
These methods require two steps, but they provide pure product, usually in good yield. The general strategy is to first form a carbon-nitrogen bond by reacting a nitrogen nucleophile with a carbon electrophile. The following table lists several general examples of this strategy in the rough order of decreasing nucleophilicity of the nitrogen reagent.
In the second step, extraneous nitrogen substituents that may have facilitated this bonding are removed to give the amine product. A specific example of each general class is provided in the diagram below. In the first two, an anionic nitrogen species undergoes an S N 2 reaction with a modestly electrophilic alkyl halide reactant. For example 2 an acidic phthalimide derivative of ammonia has been substituted for the sulfonamide analog listed in the table.
The principle is the same for the two cases, as will be noted later. Example 3 is similar in nature, but extends the carbon system by a methylene group CH 2. The methods illustrated by examples 4 and 5 proceed by attack of ammonia, or equivalent nitrogen nucleophiles, at the electrophilic carbon of a carbonyl group. Nucleophile addition to aldehydes and ketones is often catalyzed by acids. Acid halides and anhydrides are even more electrophilic, and do not normally require catalysts to react with nucleophiles.
These intermediates are not usually isolated, but are reduced as they are formed i. Acid chlorides react with ammonia to give amides, also by an addition-elimination path, and these are reduced to amines by LiAlH 4.
Since a carbocation is the electrophilic species, rather poorly nucleophilic nitrogen reactants can be used. Urea, the diamide of carbonic acid, fits this requirement nicely. To learn about this useful procedure Click Here. Examples showing the application of these methods to the preparation of specific amines are shown in the following diagram. The sulfonamide procedure used in the first example is similar in concept to the phthalimide example 2 presented in the previous diagram.
In both cases the acidity of the nitrogen reactant ammonia or amine is greatly enhanced by conversion to an imide or sulfonamide derivative. Finally, the activating group is removed by hydrolysis phthalimide or reductive cleavage sulfonamide to give the desired amine. A weak acid catalyst is necessary for imine formation, which takes place by amine addition to the carbonyl group, giving a 1-aminoalcohol intermediate, followed by loss of water.
The imine or enamine intermediates are normally not isolated, but are immediately reduced to the amine product. To see an animated mechanism for imine formation.
Another general method for preparing all classes of amines makes use of amide intermediates, easily made from ammonia or amines by reaction with carboxylic acid chlorides or anhydrides. These stable compounds may be isolated, identified and stored prior to the final reduction. The Leuckart Reaction A useful variant of the reductive amination method uses formic acid or formate salts as reductants.
To see examples of this procedure Click Here. Practice Problems The following problems review many aspects of amine chemistry. The first three questions concern the nomenclature of amines. 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 —NH 2 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:. The differences in the basicity order in the gas phase and aqueous solutions are the result of solvation effects.
Since alcohols are much stronger acids than amines, their conjugate bases are weaker than amine bases, and fill the gap in base strength between amines and amide salts. Pyridine is commonly used as an acid scavenger in reactions that produce mineral acid co-products. Barton's base is a strong, poorly-nucleophilic, neutral base that serves in cases where electrophilic substitution of other amine bases is a problem.
The alkoxides are stronger bases that are often used in the corresponding alcohol as solvent, or for greater reactivity in DMSO. Finally, the two amide bases see widespread use in generating enolate bases from carbonyl compounds and other weak carbon acids. In addition to acting as a base, 1 o and 2 o amines can act as very weak acids. Their N-H proton can be removed if they are reacted with a strong enough base. LDA is a very strong base and is commonly used to create enolate ions by deprotonating an alpha-hydrogen from carbonyl compounds Section The 4-methylbenzylammonium ion has a pKa of 9.
Which is more basic? What's the pKb for each compound? The butylammonium is more basic. The pKb for butylammonium is 3. Steven Farmer Sonoma State University. Objectives After completing this section, you should be able to account for the basicity and nucleophilicity of amines.
Key Terms Make certain that you can define, and use in context, the key term below. Study Notes The lone pair of electrons on the nitrogen atom of amines makes these compounds not only basic, but also good nucleophiles. Basicity of nitrogen groups In this section we consider the relative basicity of amines. Inductive Effects in Nitrogen Basicity Alkyl groups donate electrons to the more electronegative nitrogen.
Compound pK a NH 3 9. Comparing the Basicity of Alkylamines to Amides The nitrogen atom is strongly basic when it is in an amine, but not significantly basic when it is part of an amide group. Amine Extraction in the Laboratory Extraction is often employed in organic chemistry to purify compounds.
Important Reagent Bases The significance of all these acid-base relationships to practical organic chemistry lies in the need for organic bases of varying strength, as reagents tailored to the requirements of specific reactions. Exercises Q
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