Class Summary and Notes from 11/9/00, 11/14/00 and 11/16/00 - CHEM3312

Topic: Amines (Preparation and Reactions)

Related Reading

Related Problems

Summary

• SN2 Reactions of amines with alkyl halides: This reaction is best used to prepare quaternary amines (ammonium salts) because an alkylamine is a better nucleophile than ammonia, and a dialkylamine is a better nucleophile than an alkylamine... The reaction cannot be cleanly stopped, so it is best used with an excess of alkyl halide to produce the quaternary amine.
• Reduction of azides (N₃): Sodium azide is a good source of the nucleophilic azide ion. This can be used to substitute for alkyl halides (alkyl azides are no longer nucleophilic) and the product can be reduced (commonly with lithium aluminum hydride followed with water).
• Reduction of nitriles: Sodium cyanide can be used to substitute a nitrile for a leaving group. The product can then be reduced (commonly with lithium aluminum hydride followed with water). Note that since the nitrile group contains a carbon, this adds one carbon in between the alkyl group with the leaving group and the amine.
• Reduction of amides: Amides can be reduced (again with lithium aluminum hydride) to form amines.
• Gabriel synthesis: The Gabriel synthesis uses the conjugate base of phthalimide (shown below) as a nitrogen nucleophile to displace a leaving group. The conjugate base is much more nucleophilic than phthalimide itself so the reaction stops cleanly after the addition of one alkyl group. The phthalimide can then be hydrolyzed in aqueous base to free the amine.
  
• Reductive amination: This process combines a reaction you've seen before - the nucleophilic attack of an amine at a carbonyl carbon - with reduction to remove the oxygen. An amine is mixed with a carbonyl compound in the presence of H₂ and a metal catalyst. This results in the amine taking the place of the carbonyl group. This reaction can be used to prepare primary, secondary or tertiary amines. It is especially useful when different alkyl groups are needed on the nitrogen. (the reaction will be run several times, each time adding one of the desired alkyl groups)
• Arylamines are prepared by the reduction of nitrobenzenes. Several sets of reduction conditions are effective. (H₂ with Pt, or Fe and HCl)

Aliphatic amines are able to react:

1. as bases
2. as nucleophiles (mentioned above reaction with alkyl halides and discussed reacting with acid halides in chapter 21)
3. as precursors to leaving groups: The Hofmann Elimination reaction
   Note that neutral amines would have to become negative if they were to act as leaving groups. This is an even more unstable leaving group than hydroxide. The first step in turning an amine into a good leaving group is to let it react with an excess of methyl iodide to give the quaternary ammonium salt. This will then be neutral if it is pushed off as a leaving group. A base (Ag₂O is a source of hydroxide ion and is traditionally used in this reaction) can then cause an elimination. The use of a large ammonium as the leaving group results in the LESS substituted alkene as the major product. This is unlike eliminations that use smaller leaving groups (such as a halide).

1. as substrates in electrophilic aromatic substitution. Two important considerations:
   1. The -NH₂ group is highly activating and multiply-substituted products are common
   2. The -NH₂ group forms a complex with some of the catalysts used (such as AlCl₃ or FeCl₃ and will prevent reactions using those catalysts
   These problems can be avoided by converting the arylamine into an arylamide (using reactions described in chapter 21), doing the desired electrophilic aromatic substitution, and then converting the amide back to an amine (by hydrolysis as described in chapter 21).
2. by conversion to diazonium salts (note that other amines can be converted to diazonium salts but the diazonium will usually decompose by loss of N₂). The diazonium is the central structure in the following diagram.
   
   nucleophiles that can be used in diazonium replacement:

   nucleophile	HCl and CuCl	HBr and CuBr	NaI	KCN and CuCN	H3O+	H3PO2
   exact replacement	Cl	Br	I	CN	OH	H

Problems Discussed In Class

Results of Class Discussion

• The first thing to note about the desired product is that it appears to be the product of a diazonium coupling reaction. The diazonium coupling reaction requires that the diazonium react with an ACTIVATED ring. This helps decide the final step in the synthesis. The diazonium must start on the same ring as the sulfonamide as that is a deactivating group and will not couple if the diazonium is on the other ring. Here is the final step in the synthesis:
  
• This leaves us with two separate products that we will need to synthesize from benzene.
• Synthesis of the diazonium: The two substituents are para to each other. The sulfonamide is a deactivating substituent (because the sulfur has a partial positive charge) and will be a meta director. This substituent therefore cannot be put on first. Start the synthesis of this piece from benzene, and add the sulfonate when there is an ortho, para directing substituent (the amine in this case) in place. The final important note is that the diazonium should be formed before converting the sulfonyl chloride to the sulfonamide (otherwise the nitrogen on the sulfur will also be converted to the diazonium, which we would like to avoid). Here is the synthesis of the diazonium fragment:
  
• Synthesis of the diamine: An aryl amine is generated by reduction of a nitrobenzene. The amine is an o,p directing substituent whereas the nitro is a meta-directing substituent. The reduction should therefore be performed after the second nitro group is in place. Here is one possible synthesis of the diamine:
  
  

Special Notes

1. Make sure to review electrophilic aromatic substitution (from last semester)
2. Note that HNO₃ is used to put an NO₂ group on an aromatic ring and HNO₂ is used to convert an amine into a diazonium. These two reagents are NOT interchangeable!

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