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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 R R R R R R primary secondary tertiary 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” ethyl isopropyl amine o IUPAC names Find the longest carbon chain with the nitrogen attached. 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. 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. - - 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. hexane phenol dipropyl amine phenol phenol decanoic acid dipropyl amine dipropyl amine decanoic acid diethyl ether diethyl ether diethyl ether diethyl ether HCl NaHCO3 dipropyl ammonium Cl NaOH decanoate decanoate phenoxide H2O o Here’s an example with draining in between. Remember that he can change up when you drain, which would change the answer. hexane phenol dipropyl amine phenol decanoic acid decanoic acid diethyl ether diethyl ether 1)HCl 2) Drain phenol diethyl ether 1)NaHCO3 diethyl ether NaOH 2) Drain phenoxide H2O 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? NH2 CH3Cl NH2 AlCl3 H3C All the electrophilic aromatic substitution conditions were acidic, so the nitrogen would become positive, and thus now a meta-director. _ AlCl3 NH2 +NH 2 CH3Cl AlCl3 You need to protect the –NH2, often by acylating it. NH2 H3O+ H2SO4 HO3S HO3S That said, when aniline is not protonated, it is a strong ortho-, paradirecting activator. In fact, it’s so active that you can halogenate without the metal Lewis-acid catalyst. NH2 Br2 Alkylation of amines by alkyl halides o Just SN2 followed by deprotonation. NH2 NH2 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 NH3 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. H3O+ HNO3 H2SO4 NO2 Formation of sulfonamides o Just like Acylation, but with sulfonyl chlorides Is it me, or did all the colors make this one exciting? NO2 Hofmann Elimination o An E2-like reaction where 4° nitrogen is the leaving group, and you get the lesssubstituted alkene. First, excess of an alkyl halide (usually CH3X) is added to give quaternary ammonium salt. excess CH3I NH2 Then, a strong base abstracts a proton to give a carbanion intermediate. _ -OH This carbanion intermediate explains why you get the anti-Zaitsev product with Hoffman elimination. Elimination occurs to expel the amine, giving an alkene product. _ 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 HNO2 Reaction of HNO2 with aryl amines HNO2 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. HBF4 CuCl CuBr KI CN CuCN H2O heat H3PO2 or ethanol o Now we can do even more synthesis! ? Step 1: CH3Cl AlCl3 Step 2: HNO3 H2SO4 NO2 Step 3: Sn/HCL NH2 NO2 Step 4: AlCl3 NH2 Step 5: AlCl3 Step 6: H3O+ NH2 Step 7: HNO2 N2+ NH2 Step 8: ethanol N2+ 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. - OH o The anion is a good nucleophile (but weak base) which performs an S N2 on a suitable alkyl halide or tosylate. o Hydrolysis gives you the amine H3O+ 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. N3 LiAlH4 N3- Nitriles are also reduced to the amine by the same conditions. H2 CN Pt 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 LiAlH4 Hoffman rearrangement o 1° amide + bromine or chlorine in base → amine where the whole carbonyl is gone. Br2 - OH o You are not responsible for the mechanism.