Nomenclature for amines Chapter 20 Common names are widely used, named as alkylamines Systematic (IUPAC) nomenclature replaces the -e of the corresponding parent alkane with -amine Amines Simple secondary and tertiary amines are named by designating the organic groups separately in front of the word amine In systematic nomenclature, the smaller groups on the amine nitrogen are designated as substituents and given the locant N Aryl amines In IUPAC nomenclature the substitutent -NH 2 is called the amino group N H 2 C HO Cl N O 2 3-chloro-4-nitroaniline N (C H 3) 2 p-dimethylaminobenzaldehyde 1
The important heterocyclic amines have common names In IUPAC nomenclature the prefixes aza-, diaza- and triazaare used to indicate that nitrogen has replaced carbon in the corresponding hydrocarbon Heterocyclic Amines The nitrogen is assigned position 1 and the ring is numbered to give the lowest overall set of locants to the heteroatoms DNA base pairs are a purine with a pyrimidine Physical Properties and Structure of Amines Primary and secondary amines can form hydrogen bonds to each other and water Tertiary amines cannot hydrogen bond to each other but can form hydrogen bonds to hydrogen bond donors such as water Tertiary amines have lower boiling points than primary or secondary amines of comparable molecular weights Low molecular weight amines tend to be water soluble whether they are primary, secondary or tertiary Amines smell fishy (or worse) 2
Structure of Amines = sp 3 hybridized Organophosphorus analogs can be resolved The unshared electron pair around nitrogen - along with the three groups results in a tetrahedral geometry The shape of the amine itself is trigonal pyramidal.. P CH3 Chiral: racemizes at 200 o C It is usually impossible to resolve amine enantiomersthat are chiral at nitrogen because they interconvert rapidly Nitrogen inversionof the unshared electron pair Quaternary ammonium salts can be resolved into enantiomers Nitrogen inversion not possible with 4 substituents Basicity of Amines Amines are weak bases Relative basicitydefined by pk a of its conjugate acid The more basic the amine, the higher the pk a of its conjugate acid In the gas phase, basicityin the family of methylamines increases with increasing methyl substitution More alkyl substitution = more stabilization of the alkylaminium ion Primary alkyl amines are more basic than ammonia An alkyl group helps to stabilize the alkylaminium ion In aqueous solution, trimethylamine is less basic than dimethyl- or methylamine Solvation of the ion becomes important The trimethylaminium ion is solvated less well than the dimethylaminium ion, which has two hydrogen atoms for hydrogen bonding 3
Arylamines are weaker bases than the corresponding nonaromatic cyclohexylamines Greater resonance stabilization of aniline than its anilinium ion means a larger DH o for protonation, as compared with DH o for protonation of an amine that is not aromatic The unshared electron pair on nitrogen of an arylamine is delocalized to the ortho and para positions of the ring Lone pair is less available for protonation, i.e., it is less basic Less resonance stablization available to the anilinium ion Basicity of Heterocyclic Amines Nonaromaticheterocyclic amines have comparable basicity to acyclic counterparts Amines versus Amides Amides are much less basic than amines The pk a of a protonated amide is typically about zero 1. Amide is stabilized by resonance and protonated amide is not Aromatic heterocyclic amines (in aqueous solution) are much weaker bases than nonaromatic amines 2. The nitrogen lone pair is delocalized to the carbonyl oxygen Amides are actually protonated at the oxygen atom Allows resonance stabilization of the positive charge 4
Aminium Salts and Quaternary Ammonium Salts Protonation of amines with acids leads to aminium salts Aminium salts are formed from 1 o, 2 o or 3 o amines An aminium ion bears at least one hydrogen Quaternary ammonium halides are not basic because they do not have an unshared electron pair on nitrogen and are not acidic because they have no H to donate Quaternary ammonium hydroxides are very basic because they contain the very strong base hydroxide Quaternary ammonium salts have four groups on the nitrogen The nitrogen atom is positively charged but has no hydrogen atom These ions can be soluble in water because they are charged They can also be soluble in organic solvents if alkyl groups are larger Phase Transfer Catalysis (Solomons, p.504) General problem: anionic nucleophiles tend to be soluble in water, but not organic solvents Purple benzene?? Herriott and Picker, Journal of the American Chemical Society, 97, 2345 (1975) Herriott, Journal of Chemical Education, 54, 229 (1977) Q + = (Bu) 4 N + 5
Solubility of Amines in Aqueous Acid Most aminiumsalts are water soluble Amines in soluble in water usually dissolve in dilute aqueous acid Amines as Resolving Agents A chiral amines can be used to resolve a racemic mixture of carboxylic acids by formation of diastereomeric salts Diastereomers = different physical properties (solubility, m.p.) Acidification of the separated diastereomeric salts gives the resolved carboxylic acids Used as a chemical test to distinguish amines Extraction : water-insoluble amines can be separated from other water-insoluble organic compounds The amine is extracted into aqueous acid The amine is recovered by making the solution basic and extracting the amine into an organic solvent Amides are not basic and are not soluble in aqueous acids Preparation of Amines Nucleophilic Substitution Reactions Alkylation of Ammonia with an alkyl halide Initial aminiumsalt is treated with base to give the primary amine The method is limited because multiple alkylations usually occur Using an excess of ammonia helps to minimize multiple alkylations 6
Amines via Nucleophilic Substitution Reactions Amines via Nucleophilic Substitution Reactions Gabriel Synthesis Alkylation of Azide Ion followed by Reduction A primary amine is prepared more efficiently by reaction of azide anion with an alkyl halide and subsequent reduction of the alkylazide to the amine Primary amines can also be made cleanly by the Gabriel Synthesis First step in the Gabriel synthesis is alkylation of potassium phthalimide Reaction of the N-alkylphthalimide with hydrazine in boiling ethanol gives the primary amine Preparation of Aromatic Amines by Reduction of Nitro Compounds Amines through Reductive Amination Aldehydes and ketones react with ammonia, primary or secondary amines to yield imines or iminium ions These are then be reduced to alkylated amines Useful way to introduce an amino group on a benzene ring: 1. Nitration [H ] 2. Reduction 7
The reduction can be accomplished using catalytic hydrogenation or a hydride reducing reagent NaBH 3 CN and LiBH 3 CN are especially effective in reductive aminations (milder; added sequentially, but one pot) Amines through Reduction of Nitriles, Oximes, and Amides Reduction of nitriles or oximes yield primary amines Reduction of amides can yield primary, secondary or tertiary amines Reduction can be accomplished by dissolving metal reduction, catalytic hydrogenation, or LiAlH 4 Reductive amination can be used for monoalkylation of an amine Acylation the amine with an acid chloride Reduction of the resulting amide 8
Primary Amines by the Hofmann and Curtius Rearrangements An unsubstituted amide can be converted with bromine in base to a primary amine by formal loss of the amide carbonyl The N-bromo amide losses a second proton and then a bromide ion, and rearranges to an isocyanate The initial steps of the mechanism result in N-bromination of the amide Isocyanates readily hydrolyzed to a carbamate and lose CO2 to yield the primary amine Converts a carboxylic acid to an amine with one fewer carbons The Curtius rearrangement occurs similarly through the intermediacy of an acyl azide The acyl azide is obtained from an acid chloride with sodium azide Rearrangement of the acyl azide occurs with loss of N 2, a very stable leaving group In the last step, the isocyanate is hydrolyzed by adding water CO 2H CO2NH2 Br 2 NaOH NH2 9