Amines

Amines are nitrogen-based compounds. Just as water is related to alcohols which are related to ethers, etc., amines follow a similar pattern: R O O O O R R R H R R H H Water Alcohol Ether Trialkyloxonium salt (unstable, quite rare) R R N R R R R H R R H H R Primary Secondary ammonia Tertiary Quaternary amine amine amine ammonium salt (stable & very common) There are of course major differences between the way oxygen-based compounds and nitrogen-based compounds react. The main thing to remember is that amines have a very active lone pair - they are much more basic, and much more nucleophilic than alcohols or ethers. One thing amines do have in common with alcohols hydrogen bonds. Amines form GREAT hydrogen bonds. Massive supramolecular networks have been constructed based on nitrogen hydrogen bonding in compounds like: O H H (dashed lines = hydrogen bonds) N N H N N O H H N N N H H Let me re-emphasize that if not for hydrogen bondage, we would all fall apart into little pools of disorganized sludge (sorta the way I feel on Monday mornings...) Amides: Recall that amides are not particularly reactive. The carbonyl group of an amide is significantly less reactive than that of any other carbonyl compound, for the simple fact that this resonance predominates: H N H N H N R N H N H N

Result: The nitrogen in an amide is essentially NONBASIC and NON-NUCLEOPHILIC, and the carbonyl carbon is ONLY MARGINALLY ELECTROPHILIC. Remember also how amides are prepared - reaction of an acid chloride with ammonia or just about any other primary or secondary amine Synthesis

Yeah, you knew you couldn't get away with it for long. There are a LOT of ways to make amines, some of which youve already seen. Here is a review of new and old: The most obvious way to prepare amines is by the alkylation of ammonia (or other amine) with an alkyl halide. Unfortunately, it is VERY difficult to stop at mono-alkylated product; mixtures are obtained (as shown from the attempted preparation of ethylamine), and ORGANIC CHEMISTS HATE MIXTURES!!!!:
H N + H H N + N + N

Br

+ NH3

The only time you can simply mix an alkyl halide and an amine is when you are trying to make a quaternary salt (which we occasionally do in order to make a big organic molecule more water-soluble): Big Ugly Organic Molecule Water Insoluble Br Big Ugly Organic Molecule Br

Charged (ionic) compound Water Soluble!

But how do we make normal amines? You already know of several methods. The reduction of amides and nitriles with LiAlH4, for example: O R or NH2 LiAlH4 R NH2

R C N There are some other methods that are particularly good for making primary amines: The Azide Synthesis, and the Gabriel Synthesis. The azide synthesis takes advantage of the fact that azides are great nucleophiles, and can be easily converted (again, by LAH reduction) to amines. Heres the scheme: 1) LiAlH4 NaN3 R N N N R Br R NH2 EtOH 2) H2O This scheme works quite well with just about any primary or secondary amine. The Gabriel synthesis is a much older method, but works just as well. This method uses a sort of protected ammonia, and relies on blocking two of the reactive sites on ammonia leading to mono-alkylation. Removal of the protecting groups leads to the primary amine:
O O N H O KOH O N K O R Br O N R O KOH + R NH 2 O OO-

Succinamide is deprotonated with a decent base to yield the stabilized anion. This anion can then react with a primary or secondary alkyl halide, to lead to the substituted succinamide. Deprotection with concentrated base gives the amine and phthalate.

A very useful method for the preparation of amines from ketones and aldehydes is called reductive amination. It is often simplest to think of this as the formation of an imine, followed by hydrogenation (although your text gives a very good example of what really happens). This method can be used to prepare primary, secondary AND tertiary amines. Here are a few examples: O RNH2 R R' O NH2 R

N R'

R
H2 / cat. R

NH R' OH

NH + HO Reductive amination is a very mild and versatile method for preparing amines (especially secondary amines). Rearrangements Okay, this is where everybody gets lost. It is possible, under the correct conditions, to get a rearrangement to occur which turns an amide (or amide-like molecule) into an amine. These methods are quite general for the preparation of primary amines, and partiuclarly good for the preparation of vinyl, aryl and tertiary amines (which cannot be formed by the azide or Gabriel methods!). These rearrangements are the Hofmann and the Curtius rearrangements, and they both proceed through a similar mechanism - basically, the rearrangement of a deprotonated amide with a good leaving group: O H2O L.G. NH2 + CO2 N C O R N R R Now lets look at each of these reactions more specifically. The Curtius rearrangement requires you to start with an acid chloride. Addition of sodazide (NaN3) leads to the acyl-azide. This rearranges thermally (the leaving group being nitrogen [N2]) to an unstable intermediate isocyanate (thats what we call the NCO group), which decomposes to give the amine and CO2. Heres a real live example:
O OH SOCl2 O Cl NaN3 O N N N N C O O

H2 / Pt EtOH

ON C O H H proton transfer H N C

H O O H NH + CO2 H2O

H NH 2

The Hofmann rearrangement proceeds by nearly the same mechanism. The main difference is that you start with an amide, which is then brominated on nitrogen . . . heres the same example, using a Hofmann

O N

H H

O KOH Br2 OH H N Br Br

O N

OH H Br

O N Br N C O

Again, we get the same isocyanate intermediate, which decomposes to the amine by the same pathway. These rearrangements are the best way to make amines from delicate substrates. Phase Transfer Catalysis One of the cool things about quaternary ammonium salts is that they can be used to carry all sorts of negatively charged species into apolar (hydrophobic) regions. Whether it is to carry base into chloroform (as your book says), or polyphosphates through a lipid membrane, well talk a bit about this in class ( I wouldnt want to encourage anyone to skip lecture, now, would I....)