Chapter 19: Amines
399 Introduction (19-1) Amines are abundant in nature. There are many natural products with the amino group in their structures that you know. Can you name these compounds (common names)?
400 Physical Properties
Amines are basic (pH ~ 9-11). Since they can hydrogen bond with each other, boiling point is somewhat high, but not as high as alcohols since H-bonding is not as strong.
401 Effect of HH--BondBond on Boiling Point
402 Synthesis of Amines (review)
• Reduction of Nitriles (19-21)
Nitriles can be produced by S N2 reaction of alkyl halides. Reduction produces the corresponding amines.
403 • Reduction of Amides (19-20) Amides can also be reduced to the
corresponding amines using LiAlH 4.
404 Reduction of Aromatic Nitro Group (19-21)
Aromatic nitro (NO 2) group can be reduced to the corresponding amine under two different set of conditions. Non-aromatic nitro group are not reactive.
405 New Synthesis of Amines
• SN2 reaction with Alkyl Halides (19-12) This is not a good method to make amines, because the resulting product is more reactive than the original nucleophile due to the inductive effect.
406 • SN2 reaction of Azide ion/reduction (19-21) This is a much better way to make amines
via the S N2 reaction. Reduction of the alkyl azide that is formed yields the amine.
407 Gabriel Synthesis (19-21)
This second indirect method involves the S N2 reaction of an imide followed by its hydrolysis generating 1 o amines. The first step is a
simple S N2 reaction: deprotonation of the nitrogen, followed by nucleophilic attack. The hydrolysis can be either acid or base catalyzed.
408 BaseBase--catalyzedcatalyzed hydrolysis of the alkyl imide.
409 An alternative second step is to react the alkylated phthalimide with hydrazine generating the very stable phthalimide hydrazide and a primary amine.
410 Practice Question
Complete the following reactions.
O 1) EtO- N H 2) CH2=CHCH2Br 3) NaOH/H O, O 2
O 1) EtO-
N H 2) I
O + 3) H3O , 4) NaOH/H2O,
411 Reductive Amination (19-19) We have seen in chapter 18 that amines react with ketones and aldehydes to give imines and enamines. It is possible to reduce these compounds as they are formed, hence producing substituted amines. ◦ The intermediate can be an imine, enamine or oxime.
◦ A reducing agent is necessary, either H 2/catalyst or a borohydride reagent, or LiAlH 4 are commonly used.
412 413 Hofmann Rearrangement (19-21) Primary amide react with bromine under basic condition to produce amines via a rearrangement reaction. The reaction is limited to primary amide. Secondary and tertiary do not give the reaction.
O NaOH NH2 + CO2 NH2 Br2/H2O
O NaOH no reaction NH Br2/H2O
414 Mechanism of Hofmann Rearrangement
415 Practice Question Complete the following reactions. NaOH NH2 Br /H O O 2 2 H N NaOH
Br2 / H2O
416 Reactions of Amines (Review)
Acylation (19-13)
Amines react with acid chlorides and anhydrides to give amides.
417 Imine and Enamine Formations (19-10) Reaction with aldehydes and ketones give either imines (with 1 o amines) or enamines (with 2 o amines).
418 New Reactions of Amines Hofmann Elimination (19-15) Reaction of quaternary ammonium salt in the presence of a base gives alkenes following the Hofmann elimination mechanism. The least substituted alkene is produced, hence the name: Hofmann product .
419 The reaction is a three step process.
420 If the ammonium salt has more than one βββ-hydrogen, the least substituted will be removed. This is due to the stability of the anion like transition state of the elimination.
421 Practice Question How would you prepare the following compounds from the identified starting material?
422 Oxidation/Cope Elimination (19-16) Amines can be oxidized with hydrogen peroxide (or a peracid) to other nitrogen containing compounds that also possess oxygen in their structure. The oxidation level of nitrogen containing compounds follow the trend below:
423 All amines can be oxidized: ◦ 1o amines can be oxidized all the way to the nitro function
◦ 2o and 3 o amines give either the hydroxylamine or the tertiary amine oxide R R R R [O] RN [O] RN+ R R NH RN OH O- R 2o amine hydroxylamine 3o amine amine oxide
424 The Cope elimination reaction takes place when the tertiary amine oxide is heated. An alkene and hydroxylamine are produced.
425 This process is very similar to the Hofmann elimination seen before, but is internal to the molecule. Once again, the least substituted alkene is produced (the Hofmann product). The deprotonation takes place at the βββ-carbon.
426 The entire reaction process can be summarized by the reaction:
427 Practice Question
What are the products of the following reactions?
H2O2 N
H2O2
N
428 NH2 Reactions of Aryl Amines
Halogenation (19-11) We have seen in the first semester that the amino group is amongst the strongest activator in aromatic substitution. In fact, it is so strong, that most reactions of aromatic amines do not require the activation of the electrophile.
429 430 Reactions of Arenediazonium Salts (19-18) A very important reaction in aromatic chemistry since this represents is a nucleophilic substitution where the aromatic system is now the electrophile. The reaction uses the aromatic amine to form a diazonium salt that will be attack by nucleophiles.
431 The diazonium salt can be formed from an the aromatic amine by treatment with
nitrous acid (HNO 2).
432 Mechanism of Diazonium ion Formation
433 A large variety of nucleophiles can now displace N 2 and give nucleophilic aromatic substitutions.
434 When a copper (I) salt is reacted with the diazonium ion, the reaction is known as the Sandmeyer reaction .
435 Iodo and fluoro benzenes can also be prepared using different nucleophiles.
436 Phenols can be formed by addition of aqueous acid.
437 Treatment with hypophosphorus acid
(H 3PO 2) provide the benzene derivative
438 Practice Question
Complete the following reactions.
439