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AMINES

Nitrogen inversion : interconverts the two enantiomers of a simple chiral amine.


The transition state is a planar, structure with the lone pair in a sp2 hybrid p orbital.

Although most simple amines cannot be resolved into enantiomers, several types of chiral amines can be resolved
Quaternary ammonium salts with asymmetric nitrogen atoms
Amines that cannot attain the sp2 hybrid transition state for nitrogen inversion( a small ring).

Physical Properties of Amines


Because nitrogen is less electronegative than oxygen, the N-H bond is less polar than the O-H bond. Therefore, amines form weaker hydrogen bonds
than do alcohols of similar molecular weights. Primary and secondary amines have boiling points that are lower than those of alcohols, yet higher than
those of ethers of similar molecular weights.

Effects on Amine Basicity


for any conjugate acidbase pair , pKa + pKb = 14

The pKa of RNH+3 is the pH at which half of the molecules are protonated. At lower (more acidic) pH, the amine is mostly protonated RNH+3 . At
higher (more basic) pH, the amine is mostly deprotonated (RNH2).

Substitution by Alkyl Groups


We might expect secondary amines to be stronger bases than primary amines (correct),and tertiary amines to be the strongest bases of all (incorrect).
The actual situationis more complicated because of solvation effects secondary alkylamines are slightly stronger bases than primary or tertiary
alkylamines.

Salts of Amines
Protonation of an amine gives an amine salt. The amine salt is composed of two typesof ions: the protonated amine cation (an ammonium ion)
and the anion derived from the acid.
Amine salts are ionic, high-melting, nonvolatile solids. They are much more soluble in water than the parent amines, and they are only slightly
soluble in nonpolar organic solvents

The basicity of an amine can be used for purification.

Electrophilic Aromatic Substitution of Arylamines


The following reactions show halogenation of aniline derivatives, which occurs readily without a catalyst( no lewis acid required). If an excess of the
reagent is used, all the unsubstituted positions ortho and para to the amino group become substituted

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NOTE: Strongly acidic reagents protonate the amino group, giving an ammonium salt that bears a full positive charge. The NH3 group is strongly
deactivating and meta-allowing

Electrophilic Aromatic Substitution of Pyridine


Deactivation results from the electron-withdrawing effect of the electronegative nitrogen atom and its lone pair cannot stabilize the positively charged
intermediate. When pyridine react, it gives substitution at the 3-position, analogous to the meta substitution

Nucleophilic Aromatic Substitution of Pyridine


it is activated toward nucleophilic aromatic substitution. If there is a good leaving group at either the 2-position or the 4-position, a nucleophile can
attack and displace the leaving group

Alkylation of Amines by Alkyl Halides


Amines react with primary alkyl halides to give alkylated ammonium halides. Alkylation proceeds by the SN2 mechanism
The disadvantage of direct alkylation lies in stopping it at the desired stage because nucleophilicity of tertiary > secondary> primary .

Alkylation of amines can give good yields of the desired alkylated products in two types of reactions:

1) Exhaustive alkylation to the tetraalkylammonium salt


A mild base ( NaHCO3 or dilute NaOH) is added to deprotonate the intermediate alkylated amines and to neutralize the HX formed

2) Reaction with a large excess of ammonia

Acylation of Amines by Acid Chlorides

The acid chloride is more reactive than a ketone or an aldehyde.


The amide produced in this reaction usually does not undergo further acylation. Amide sare stabilized by a resonance . As a result, amides are
much less basic and less nucleophilic than amines
The diminished basicity of amides can be used to advantage in electrophilic aromatic substitutions. For example, if the amino group of aniline is
acetylated to give acetanilide, the resulting amide is still activating and ortho, para-directing. Unlike aniline, however, acetanilide may be treated
with acidic

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with acidic

Amines as Leaving Groups: The Hofmann Elimination


An amino group can be converted to a good leaving group by exhaustive methylation,which converts it to a quaternary ammonium salt that can
leave as a neutral amine.Exhaustive methylation is usually accomplished using methyl iodide.
Elimination of the quaternary ammonium salt generally takes place by the E2 mechanism,which requires a strong base. To provide the base, the
quaternary ammonium iodide is converted to the hydroxide salt by treatment with silver oxide.

Problem-solving Hint
The key to solving Hofmannelimination problems is to find allpossible ways the compound caneliminate. Then, the one that gives
the least substituted alkene is probably favored

Oxidation of Amines; The Cope Elimination


Amines are notoriously easy to oxidize. Most amines are oxidized by common oxidants such as permanganate, and peroxyacids.
Tertiary amines are oxidized to amine oxides. Because of the positive charge on nitrogen, the amine oxide may undergo a Cope
elimination, much like the Hofmann elimination of a quaternary ammonium salt. The amine oxide acts as its own base through a cyclic transition
state, so a strong base is not needed. The Cope elimination generally gives the same orientation as Hofmann elimination, resulting in the leastsubstituted alkene

Reactions of Amines with Nitrous Acid


Because nitrous acid is unstable, it is generated in the reaction mixture) by mixing sodium nitrite NaNO2 with cold, dilute hydrochloric acid.
In an acidic solution, nitrous acid may protonate and lose water to give the nitrosonium Ion +NO
1) Reaction with Primary Amines: Formation of Diazonium Salts

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Because of the many competing reaction pathways, alkanediazoniums alts usually decompose to give complex mixtures of products. Therefore,
the diazotization of primary alkylamines is not widely used for synthesis

2) Reaction with Secondary Amines: Formation of N-Nitrosoamines

Secondary N-nitrosoamines are stable under the reaction conditions because they do not have the NH proton needed for the tautomerism.

Reactions of Arenediazonium Salts


In contrast to alkanediazonium salts, arenediazonium salts are relatively stable in aqueous solutions .

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Synthesis of Amines by Reductive Amination


Reductive amination is a two-step procedure. First we form an imine or oxime derivative of a ketone or aldehyde, and then reduce it to the amine

Primary Amines

Secondary Amines

Tertiary Amines
The reducing agent mustreduce the iminium salt, but it must not reduce the carbonyl group of the ketone or Aldehyde becz Iminium salts are
frequently unstable, so they are rarely isolated

Synthesis of Amines by AcylationReduction


Acylation of the starting amine by an acid chloride gives an amide, which is much less nucleophilic and unlikely to over-acylate (Section 19-12).
Reduction of the amide by lithium aluminum hydride LiAlH4 gives the corresponding amine

Gabriel Synthesis

Formation and Reduction of Azides


Azide ion -N3 is an excellent nucleophile that displaces leaving groups from unhindered primary and secondary alkyl halides and tosylates.

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Azide ion also reacts with a variety of other electrophiles

Formation and Reduction of Nitriles


Like the azide ion, cyanide ion is a Good SN2 nucleophile;

Reduction of Nitro Compounds


Both aromatic and aliphatic nitro groups are easily reduced to amino groups.

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