A to Z Directory – Virginia Commonwealth University



Chapter 19 – Amines

• Nomenclature

o Classification of amines

▪ Amines are classified as 1°, 2°, or 3° based on how many R groups are attached to the nitrogen

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▪ When there are four R groups attached to a nitrogen, it is called a quaternary ammonium salt.

o Common names

▪ Say the alkyl groups attached and then say “amine”

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o IUPAC names

▪ Find the longest carbon chain with the nitrogen attached.

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▪ Name that as the parent, remove the –e, and replace it with amine

• Heptane → 3-heptanamine

▪ Whatever else is on the nitrogen is named as a substituent, with N as the locant.

N-methyl-3-heptanamine

▪ If the amine is not the high-priority group, then the nitrogen is named as an amino substituent.

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5-amino-N-methyl-2-heptanol

• Structure of amines

o Trigonal pyramidal

o Chirality

▪ Amines can be chiral, but the lone pair flips from side to side of the nitrogen, changing them from R to S.

▪ There are two times when chirality is locked.

• Quaternary ammonium salts

• Sometimes sterics can prevent the lone pair from flipping.

• Physical properties

o Strongly polar

o Can hydrogen-bond if they are 1° or 2°

▪ Remember that the hydrogen bonding of nitrogen is not as strong as that with oxygen, so boiling points will be lower than similarly sized alcohols.

o Small amines will be water-soluble. Larger ones will not.

• Basicity of amines

o The pKb of ammonia is 4.74.

o Amines are slightly stronger bases because the alkyl groups are electron donating groups, as we have seen in previous chapters.

▪ Amines have pKb’s around 3-4.

▪ Aniline has a pKb around 10 because the lone pair is conjugated with the aromatic system.

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▪ Pyridine also has a pKb around 10, because the lone pair is less available in the sp2 orbital than it would be in a sp3 orbital.

▪ Pyrrole is even less basic, with a pKb around 16, because its lone pair is involved in aromaticity.

o EDGs will increase basicity, while EWGs will decrease basicity.

o My weird way of thinking about basicity:

▪ The lone pair of a base is like teeth that want to bite a proton.

▪ The bigger the teeth, the stronger the base.

▪ EDGs make the teeth bigger, EWGs suck the teeth back into the gums.

▪ When the teeth are involved with aromaticity, that’s like they’re already chewing something, so they’re not available to bite a proton.

• This is why pyrrole has a pKb around 15.

▪ When the teeth are in sp2 orbitals, they are held closer in to the mouth, and aren’t as available.

• This is why pyridine has a pKb of 8.75

• Amine salts and extraction

o By protonating an amine, you make it more water-soluble.

o Mr. Baker likes to ask questions about what would be left in the organic or aqueous layer after adding either an acid or base.

▪ If on a test or quiz he doesn’t specifically say that you drain off the aqueous phase, make sure to ask.

▪ Below, you are not draining in between.

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o Here’s an example with draining in between. Remember that he can change up when you drain, which would change the answer.

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• Phase transfer catalysts

o Large 4° ammonium salts are somewhat soluble in both organic and aqueous phases. As such, they can move ionic reagents into the organic phase so that they can react.

o Crown ethers also make good phase transfer catalysts.

• Substitution of aniline

o In chapter 17 we said that NH2 was a strong ortho-, para-director, but is it?

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▪ All the electrophilic aromatic substitution conditions were acidic, so the nitrogen would become positive, and thus now a meta-director.

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• You need to protect the –NH2, often by acylating it.

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▪ That said, when aniline is not protonated, it is a strong ortho-, para-directing activator.

• In fact, it’s so active that you can halogenate without the metal Lewis-acid catalyst.

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• Alkylation of amines by alkyl halides

o Just SN2 followed by deprotonation.

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o The problem with this reaction is that it’s difficult to control how many alkyl groups add.

▪ This works if you want a 4° ammonium salt.

▪ This also works if you add excess ammonia, so that you get one addition.

• Acylation of amines by acid chlorides

o This is a nucleophilic substitution at the carbonyl

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o The acid chloride is more reactive than ketones and aldehydes, and amines are not nucleophilic enough to add to the amide formed in the substitution.

o Acylating aniline is a way to maintain the ortho-, para-directingness of the –NH2 and the acyl group is easily removed by acid hydrolysis.

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• Formation of sulfonamides

o Just like Acylation, but with sulfonyl chlorides

▪ Is it me, or did all the colors make this one exciting?

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• Hofmann Elimination

o An E2-like reaction where 4° nitrogen is the leaving group, and you get the less-substituted alkene.

▪ First, excess of an alkyl halide (usually CH3X) is added to give quaternary ammonium salt.

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▪ Then, a strong base abstracts a proton to give a carbanion intermediate.

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• This carbanion intermediate explains why you get the anti-Zaitsev product with Hoffman elimination.

▪ Elimination occurs to expel the amine, giving an alkene product.

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o Sometimes Ag2O (aq) is the base used.

▪ It generates O2-, to a small extent.

• This is the conjugate base of hydroxide. Yikes!

▪ But remember that because it’s aqueous, it just deprotonates the water, forming hydroxide.

• You cannot have a base stronger than hydroxide in an aqueous environment.

o For those of you going on to take inorganic, you’ll see that this is called “solvent leveling.”

• Diazonium salts

o Formation

▪ Reaction of HNO2 (nitrous acid) with 1° alkyl amines

• Often formed in situ with NaNO2 with HCl

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▪ Reaction of HNO2 with aryl amines

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• The last step of the N2 gas falling off doesn’t happen because the aryl cation would be unstable.

o Reactions of aryl diazonium salts

▪ You don’t need to know any mechanisms here.

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o Now we can do even more synthesis!

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• Step 1:

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• Step 2:

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• Step 3:

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• Step 4:

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• Step 5:

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• Step 6:

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• Step 7:

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• Step 8:

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• Synthesis of amines by acylation-reduction

o Just what it sounds like

o Acylate

o LiAlH4 completely chops off the oxygen of an amide instead of reducing the carbonyl to an alcohol

• Gabriel synthesis – always makes 1° amines

o Phthalimide is deprotonated by a strong base

▪ The pKa is 8.3.

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o The anion is a good nucleophile (but weak base) which performs an SN2 on a suitable alkyl halide or tosylate.

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o Hydrolysis gives you the amine

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• Reduction of azides and nitriles

o Once an azide has been used as a nucleophile in an SN2 reaction, it can be reduced to the amine by either LiAlH4 or catalytic hydrogenation.

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Nitriles are also reduced to the amine by the same conditions.

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▪ Be sure not to lose a carbon here.

• Reduction of nitro groups to NH2

o LiAlH4

o Catalytic hydrogenation

o Fe, Zn, or Sn in acid

• Removing the oxygen from amides to form amines

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• Hoffman rearrangement

o 1° amide + bromine or chlorine in base → amine where the whole carbonyl is gone.

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o You are not responsible for the mechanism.

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