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20.5: Synthesis of Primary Amines

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May 30, 2020
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- 20.4: Synthesis of Amines
- 20.6: Reactions of Amines

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Preparation of Primary Amines

Although direct alkylation of ammonia by alkyl halides leads to 1º-amines, alternative procedures are preferred in many cases. 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.

Nitrogen Reactant	Carbon Reactant	1st Reaction Type	Initial Product	2nd Reaction Conditions	2nd Reaction Type	Final Product
N₃^(–)	RCH₂-X or R₂CH-X	S_N2	RCH₂-N₃ or R₂CH-N₃	LiAlH₄ or 4 H₂ & Pd	Hydrogenolysis	RCH₂-NH₂ or R₂CH-NH₂
C₆H₅C₂O₂NH / OH^-	RCH₂-X or R₂CH-X	S_N2	RCH₂-NC₂O₂C₆H₅ or R₂CH-NC₂O₂C₆H₅	NaOH / heat	Hydrogenolysis	RCH₂-NH₂ or R₂CH-NH₂
CN^(–)	RCH₂-X or R₂CH-X	S_N2	RCH₂-CN or R₂CH-CN	LiAlH₄	Reduction	RCH₂-CH₂NH₂ or R₂CH-CH₂NH₂
NH₃	RCH=O or R₂C=O	Addition / Elimination	RCH=NH or R₂C=NH	H₂ & Ni or NaBH₃CN	Reduction	RCH₂-NH₂ or R₂CH-NH₂
NH₃	RCOX	Addition / Elimination	RCO-NH₂	LiAlH₄	Reduction	RCH₂-NH₂
NH₂CONH₂ (urea)	R₃C⁽⁺⁾	S_N1	R₃C-NHCONH₂	NaOH soln.	Hydrolysis	R₃C-NH₂

A specific example of each general class is provided in the diagram below. In the first two, an anionic nitrogen species undergoes an S_N2 reaction with a modestly electrophilic alkyl halide reactant. For example #2, the Gabriel synthesis is shown. The alkaline conditions deprotonate phthalmide to create a strong nucleophile for S_N2 reactions with alkyl halides. Example #3 also starts with an S_N2 reaction of cyanide with an alkyl halide following by reduction of the cyano group to form a primary amine that extends the carbon system of the alkyl halide by a methylene group (CH₂). In all three of these methods 3º-alkyl halides cannot be used because the major reaction path is an E2 elimination.

The methods illustrated by examples #4 and #5 proceed by the reaction of ammonia, or equivalent nitrogen nucleophiles, with the electrophilic carbon of a carbonyl group. A full discussion of carbonyl chemistry is presented in an independent chapter, but for present purposes it is sufficient to recognize that the C=O double bond is polarized so that the carbon atom is electrophilic. Nucleophilic 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. The reaction of ammonia with aldehydes or ketones occurs by a reversible addition-elimination pathway to give imines (compounds having a C=N function). These intermediates are not usually isolated, but are reduced as they are formed (i.e. in situ). Acid chlorides react with ammonia to give amides, also by an addition-elimination path, and these are reduced to amines by LiAlH₄.

The 6th example is a specialized procedure for bonding an amino group to a 3º-alkyl group (none of the previous methods accomplishes this). 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. The resulting 3º-alkyl-substituted urea is then hydrolyzed to give the amine. One important method of preparing 1º-amines, especially aryl amines, uses a reverse strategy. Here a strongly electrophilic nitrogen species (NO₂⁽⁺⁾) bonds to a nucleophilic carbon compound. This nitration reaction gives a nitro group that can be reduced to a 1º-amine by any of several reduction procedures.

Hofmann rearrangement

Hofmann rearrangement, also known as Hofmann degradation and not to be confused with Hofmann elimination, is the reaction of a primary amide with a halogen (chlorine or bromine) in strongly basic (sodium or potassium hydroxide) aqueous medium, which converts the amide to a primary amine. For example:

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Mechanism:

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Curtius Rearrangement

The Curtius rearrangement involves an acyl azide.

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The mechanism of the Curtius rearrangement involves the migration of an -R group form the carbonyl carbon to the the neighboring nitrogen.

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Reduction of Nitro Groups

Several methods for reducing nitro groups to amines are known. These include catalytic hydrogenation (H₂ + catalyst), zinc or tin in dilute mineral acid, and sodium sulfide in ammonium hydroxide solution. The procedures described above are sufficient for most case

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Reduction of Nitriles

Nitriles can be converted to primary amines by reaction with lithium aluminum hydride. During this reaction the hydride nucleophile reacts with the electrophilic carbon in the nitrile to form an imine anion. Once stabilized by a Lewis acid-base complexation the imine salt can accept a second hydride to form a dianion. The dianion can then be converted to an amine by addition of water.

Exercise

9. Complete the reaction map below to build reaction patterns for multiple step synthesis.

ch 20 sect 5 exercise solution updated.png

Answer

ch 20 sect 5 exercise solution.png

Preparation of Primary Amines

Hofmann rearrangement

Curtius Rearrangement

Reduction of Nitro Groups

Reduction of Nitriles

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