The fundamental principle. .A base and a nucleophile, ammonia is created as a result.As nitrogen is less electronegative than oxygen, ammonia is stronger than water as a base, and it's also a stronger nucleophile.It should be noted that amino acids are also tetrahedrally hybridized, similar in basic properties and nucleophilic to ammonia.Carboxylic acids can neutralize (protonate) amines completely. It is often suggested that amino acids are acidic by referring to their respective conjugate acids.Conjugate acid of a weak base (e.g. like water) is a strong acid (like potassium ion), while conjugate acid of a strong base (e.g. like hydroxide ion) is a weak acid (like water).There is already an established concept of pKa as a measure of the acidity of Bronsted acids, and we will see that a corresponding concept, pKb, can be used to measure the basicity of bases and that these two quantities are closely related.

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qNote that the strongestacid (least positive pKa) is ammonia. This means that ammonia is theweakest base of the four bases.

qWe can easily understandthis because alkyl groups are electron donating (EDG), so they stabilize the positively chargeammonium ions, i.e., the methyl ammonium ion is more stable than the parentammonium ion because the alkyl group stabilizes the positive charge on theattached nitrogen atom.

qNote also that the alkylstabilizing effect is purely inductive! no hyperconjugative resonance stabilization by the alkyl group.

qNotice that the secondalkyl group, in the dimethylammonium ion, has only a very slight effect, while the third group (in the trimethylammonium ion)causes an increase in acidity(decrease in basicity) relative to the dimethylammonium ion. Of course, thetrimethylammonium ion is still lessacidic than ammonia.

qAll of the amines aremore basic than ammonia, but primaryand secondary amines are the most basic.

qThe effect of the thirdalkyl group is another instance of steric inhibition of solvation. The presence of three alkyl groups sharply diminishesthe ability of the solvent to stabilize the corresponding ammonium ion, thuscausing a reversal in the tendency of the alkyl groups to decrease acidity andincrease basicity.

qPlease note therelationship between pKb and pKa is pKa + pKb= 14 in water.

qThe definition of pKbis shown below:

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qThe pKb’sof ammonia, methyl amine, dimethylamine, and trimethyl amine are therefore,respectively, 4.74, 3.34, 3.27. and 4.19. Note that, in terms of pK­­b,the strongest bases have the least positive values of pKb, just aswas the case for acidity in its relationship to pKa’s.

ACIDITY AS ABASIS FOR SEPARATING AMINES FROM ORGANICS HAVING OTHER FUNCTIONALITIES. Aminesare the most basic class of organiccompounds. They are virtually theonly organic compounds which are substantially basic in aqueous solution andwhich are completely protonated by dilute solutions of strong acids. Uponprotonation, of course, the form salts of the alkyl ammonium ions, which arewater soluble (if the R groups arenot too large). Consequently, amines can be separated from other classes oforganic compounds like halides, ethers, alcohols, and ketone (as well asalkanes, alkenes and alkynes, of course), by a simple extraction technique.

qThe solution of themixture of organic compounds dissolved in an organic solvent such as ether istreated with dilute aqueous acid (careful: exothermic).

qThe amine is protonatedand goes into the aqueous solution as an ammonium salt, while otherfunctionalities such as ketones remain in the organic phase.

qThe phases are separated(separatory funnel), and the non-amine organic compounds are obtained from theether phase (drying and evaporation of the ether), while the amine is obtainedfrom the aqueous solution by adding more ether and making the aqueous solutionalkaline, which liberates the amine, this dissolving in the ether phase. Afterdrying and evaporation, the amine is obtained.

qNote that this would ofcourse not work if the ketone or alcohol has only 1-4 carbons, because analcohol or ketone having such few carbons would have substantial watersolubility.

ACIDITY OFAMINES. Note thatprimary and secondary amines, likeammonia have protic hydrogens and therefore possess a degree of acidity (unliketertiary amines, which have no acidic hydrogen). We have previously seen thatammonia has a pKa value of about 38, and is a very weak acid.Primary and secondary amines have pKa’s of very similarmagnitude. Consequently, such amines are much more basic (pKb about4) than they are acidic (pKa 38), so that their aqueous solutions are rather strongly alkaline.

qSince amines are onlyvery weakly acidic, their conjugate bases, RNH- or R2NH­-­are very strong bases!! We have seenthat they are strong enough bases to be able to generate enolates of ketonesquantitatively.

CHIRALITY OFNITROGEN. It isinteresting to note that, since the nitrogen atom of amines is tetrahedral,such a nitrogen can be a stereocenter if it has three different R groupsattached. By definition, the fourth group is an electron pair, so that all fourgroups are different.

qHowever, it is observedthat when chiral amines are generated, they very rapidly undergo anumbrella-like inversion to generate the corresponding enantiomer, quickly racemizingthe amine. Certain amines, for which this inversion is especially difficult,can be prepared and are relatively stable as a single enantiomer.

qPlease note, however,that if a fourth different R groups is added in the context of a tetraalkylammonium ion, this kind of inversion is prevented, and such quaternary ammoniumions can be chiral and stable as a single enantiomer.

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It is logical to conclude that since amines are quite basic functional groups, they are also quite nucleophilic. As amines have far greater basicity than oxygenated functional groups like alcohols or ethers, they are also expected to be more nucleophilic than these oxygenated functionalities.As a consequence, they are useful as nucleophiles in reactions involving alkyl halides.In a similar way, ammonia, a chemical compound derived from inorganic matter, is also a parent. .Further reaction with alkyl halide would result in a secondary amine, and a third reaction with the alkyl halide would result in a tertiary amine.If excessive ammonia is used, it would result in a mix of primary, secondary, and tertiary amines. There is a much greater amount of ammonia to react with for the alkylhalide when there is an excess of ammonia (e.g., ten times) than amine.

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In addition to amines being readily available, it is possible to make them with another nitrogen nucleophile, the azide anion, which is also readily available. .The mechanism for this latterreduction will not be discussed in this document.

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It works because the azide anion is a strong nucleophile, but the neutral organic azide is very weak (recall that the hydroxide anion is a strong nucleophile, but its neutral conjugate acid, water, is very weak).As a result, the organic azide cannot react with the alkyl halide once it has been formed.We do not have to use an excess of the nucleophile to get exclusively the primary amine. .A primary amine can also be formed from these nitriles using lithium aluminum hydride.Unlike the alkyl halide, the primary amine contains one more carbon atom.

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qAmides can also bereduced in the same way as nitriles.

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ANILINEAND ARYLAMINES.

In summary. As a result, the cyanide anion (which is a carbon nucleophile containing nitrogen) is a strong nucleophile and readily reacts with alkyl halides to produce organic cyanides, also known as nitriles. In essence, aniline (phenylamine) is the simplest aromatic amine.The synthesis for it is shown below.

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The basic. An aniline(and its related arylamines) is a basic amine. However, it is much less basic than typical alkyl amines. Replacing an alkyl group with a phenyl or another aryl group greatly diminishes the basicity of amines. Note that the pKa of anilinium is 4.6 while that of methylamine is 10.7.

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THETHEORETICAL BASIS FOR THE DIMINISHED BASICITY OF ANILINE

Stabilization of the reactant side tends to diminish acidity (since the hydronium ion is on the right hand side of the equation), while stabilization of the product side tends to increase acidity. As amines are relatively basic functional groups, it stands to reason they are also rather nucleophilic.

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qThis resonance ordelocalization stabilization is possible because the unshared pair of electronson nitrogen are in conjugation with (able to directly overlap with) the 2p AOon the directly attached ring carbon. These electrons are then delocalizedaround the ring on to the positions indicated. See the indicated overlap in theorbital picture shown below:

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qThis conjugation is onlypossible when the orbital external to the ring is in the benzylic-type position(that is, on an atom directly attached to the ring).

qSo the reactant isresonance stabilized in the case of aniline, but of course not in the case ofmethylamine, which does not have a p type orbital available to overlap with. Thismakes aniline much more stable thermodynamically than methylamine or anyalkylamine, and thus much less readily protonated (weaker base).

qFinally, theanilinium ion (the conjugate acid of aniline) lacks this conjugated system,because the nitrogen atom is positively charged (highly electron deficient) andthus it cannot contribute any electrons to the ring. Of course it could notaccept electrons from the ring because it doesn’t have any vacantorbitals to use for such acceptance (this would violate the octet rule). Notethat the resonance structure on the right, below, is not a valid resonancestructure.

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The Pyridine.Unlike aniline, pyridine also functions as an aromatic amine.Pyridine is essentially benzene with one of the CH groups replaced by a N atom. The acidity of amines is often indirectly discussed in terms of their respective conjugate acids. Conjugate acids of weak bases (like water) are strong acids (like hydrogen ions), while conjugate acids of strong bases (like hydroxide ions) are weak acids (like water). .Therefore, pyridine is harder to protonate than piperidine and other typical aliphatic amines. Pyridine's pKa is 5.25.

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Analyses of amino acids. Because alkyl groups are electron donating (EDG), they stabilize the positively charged ammonium ions. For example, the methyl ammonium ion is more stable than the parent ammonium ion because the alkyl group stabilizes the positive charge on the nitrogen atom attached to it. The alkylstabilizing effect is strictly inductive as well! Resonance stabilization by the alkyl group was not hyperconjugative.Notice that the second alkyl group in dimethylammonium ion has only a very slight effect, whereas the third group in trimethylammonium ion causes an increase in acidity (a decrease in basicity) compared to dimethylammonium ion. In any case, trimethylammonium ions are less acidic than ammonia.Although all amines are more basic than ammonia, primary and secondary amines are more basic.Another example of steric inhibition of solvation occurs with the effect of a thirdalkyl group. By forming three alkyl groups, the solvent can no longer stabilize the corresponding ammonium ion, reversing the tendency of the alkyl groups to decrease acidity and increase basicity.

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. The quaternary ammonium iodide is formed by first reacting it with silver oxide (giving insoluble silver iodide) to yield aquaternary ammonium hydroxide.We have a good basis and a reasonable departure group.By heating this ionic compound to approximately 80 degrees, trimethylamine is often effectively removed from the system.

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The transition state for the Hoffmann Elimination Reaction. As with all E2 reactions, this is a concerted reaction. Pyridine, like aniline, is much more basic than typical aliphatic amines, but for a very different reason: the unshared electron pair is in an AOsp2 configuration, which, as you know, is much lower in energy than the electron pair of aliphatic acids, which is in an AOsp3. The Pyridinium ion (conjugate acid) can remain aromatic, because when bonded to a proton in the trigonal plane, the CH bond does not displace any of the electrons from the pi electron system, which remains 6 pi electrons like Benzene.

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ALKENE AND CARBANION CHARACTERS IN THE TSSFOR Elimination reactions. .Fortunately, it's the alkene character which dominates the halide elimination. In modern chemistry, aniline (which is essentially phenylamine) is the simplest aromatic amine.Here's how to make it. .qThese reactions are called Saytzeff reactions. Hoffman reactions of alkylammonium hydroxides favor the more stable alkenes, largely due to their more favorable carbanion character.Hoffmannregiochemistry is this type of regiochemistry. It can be seen in the example shown below that 1-butene is strongly preferable to the 2-butenes, despite the alkene nature of the TS.

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qThe TS models for thetwo competing TS’s are shown below:

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In the case of TS as a model for eliminating a halide from an organic structure by a base such as a hydroxide ion, for simplicity, we examined only the reactant and product-like structures, so we could only discern the alkene character.The alkenecharacter is dominant in alkyl halides' elutions. It should be noted that the TS leading to 1-butene has primary carbanion character, while those leading to either of the 2-butenes have secondary carbanion character. The elimination of alkyl halides tends to favor less substituted alkenes, which is a more stable alkene. When Hoffman elimination reactions are performed on alkylammonium hydroxides, the less stable alkene is favored, fundamentally because carbanion properties are more favorable.Hoffmannregiochemistry is a type of regiochemistry of this kind.Similarly, in the elimination of the quaternary ammonium salt shown below, 1-butene is stronglyfavored over the 2-butenes, although the alkene character of the TS actually favors the latter.IRONIONS AND THEIR REACTIONS.Diazonium salts can be readily formed from all primary amines by nitrous acid. Diazonium ions are extremely unstable in aliphatic R groups, rapidly decaying to carbocations which undergo reaction with any nucleophile present (such as water).

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.A positive charge on nitrogen is inherently not very favorable (electronegative atom), but resonance stabilization allows this ions to form. If, however, the Rgroup is alkyl, diazonium ions can readily decompose via SN1, with dinitrogen as the leaving group. It should be noted that nitrogen is such an extremely thermodynamically stable molecule that it is perhaps the best leaving group of all.

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.After the diazonium ion is generated, the aryldiazonium ions can be used in reactions with substances. This is performed by first reacting quaternary ammonium iodide with silver oxide to produce aquaternary ammonium hydroxide (which then becomes insoluble silver iodide).In this point, we have a strong base and a reasonable leavinggroup.

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Azole compounds In this reaction, we are seeing a concerted reaction.It is one of their main uses in electrophilic aromatic substitution reactions. .In contrast, they react with amines that have powerful electron-donating functions.For example, N,N-dimethylaniline easily reacts with aryl diazonium ions, as follows:

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An azo compound is the end result of this reaction. As an amine, aniline (and related arylamines) are basic. However, it is much less basic than typical alkyl amines. Replacing an alkyl group with a phenyl or another aryl group greatly diminishes the basicity of amines.

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The aminogroup can be converted into a chloro, bromo, iodo, or nitrile function (or even reduced to hydrogen if an appropriate reducing agent is used). You may recall that arylhalides do not undergo SN1 or SN2 substitutions because the double bond in the aryl halogen has too much strength to easily break.SN1 substitution reactions can take place when the potent leaving group is dinitrogen.