What is protonation



DEFINITION:Amines are organic derivatives of ammonia, in which one, two, or all three ofthe hydrogens of ammonia are replaced by organic groups. Compounds RNH­2are called primary amines, R2NH secondary amines, and R3Nare tertiary amines.


q     ImportantNote: The designation of amines as primary,secondary, and tertiary is differentfrom the usage of these terms in connection with alcohols and alkyl halides. Inthese latter two cases there is only one organic group (R), so that the termsare used to designate the type of carbon to which the alcohol or halidefunction is attached.


q     Consequently, tertiarybutylamine is a primary amine, but tertiary butyl alcohol is classed as a tertiary alcohol.


q     Similarly, dipropylamineis a secondary amine, even though the R groups attached to nitrogen areprimary.


NOMENCLATURE:  Thereare two valid systems for naming amines. One system is used for naming relatively simple amines, i.e., moleculesin which there are no other functional groups than the amine function and thecompound is named as an amine, while the other is more flexible for namingmolecules in which there are functional groups other than amines or in whichthere is considerable molecular complexity, so that it is convenient to use theamino functional group as a substituent.


SimpleAmines.Simple amines are named according to the number ofcarbons in the longest continuous chain (or ring) of carbon atoms present in any of the R groups attachedto nitrogen. Numbering, of course,must begin with the carbon immediately attached to the amine function. Afteridentifying the main chain, the amine is named as a derivative of the alkane(or cycloalkane) having the appropriate number of carbon atoms by deleting theterminal –e of the alkane and replacing it with the suffix –amine. For example CH­3NH2 , thesimplest amine, is named methanamine.The common name for this very simple amine is methylamine (no separators between methyl and amine).


The secondary amine which has one methyl group and one ethyl groupattached to nitrogen is named N-methylethanamine (the two carbon chain is usedas the main chain in preference to the one carbon chain). Note the usage of theletter N to designate that the methyl substitutent is attached to nitrogen. Ifone R group is methyl, a second is ethyl, and a third is propyl, the aminewould be named N-ethyl-N-methylpropanamine. Note the alphabetic criterion forarranging the methyl and ethyl sequence.


More ComplexAmines. The substituent name of the–NH2 is amino.The (CH3)2N- substituent is, e.g., N,N-dimethylamino. Thename of the compound

H2N-CH­2CH2CH2OHis therefore 3-amino1-butanol.




Basicity.You willrecall that the nitrogen atom of ammonia is sp3 hybridized and there is an unshared pair of electrons in the fourth tetrahedral orbital. This makes ammoniaa base and a nucleophile. Becausenitrogen is less electronegative than oxygen, ammonia is a much strongerbase than water and also a much better nucleophile. Amines, which are merely organic derivatives ofammonia, are also tetrahedrally hybridized and are comparably basic andnucleophilic to ammonia. You might recall that amines are completelyneutralized (protonated) by carboxylic acids.


            Thebasicity of amines is often discussed indirectly in terms of the acidity of their respectiveconjugate acids. Recall that theconjugate acid of a weak base (e.g. like water) is a strong acid (likehydronium ion), while the conjugate acid of a strong base (like hydroxide ion)is a weak acid (like water). The concept of pKa has already been developed as a measure of theacidity of Bronsted acids, and we will also see that a corresponding concept, pKb can be used as a measure of the basicity of bases andthat these two quantities are very closely related. Consider the acid dissociation, in dilute aqueoussolution, of ammonia and a representative primary, secondary, and tertiaryamine:


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


q     We 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.


q     Note also that the alkylstabilizing effect is purely inductive! [By looking at possible resonance structures, see if you can see whythere is no hyperconjugative resonance stabilization by the alkyl group.


q     Notice 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.


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


q     The 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.


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


q     The definition of pKbis shown below:


q     The 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.


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


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


q     The 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.


q     Note 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.


q     Since 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.


q     However, 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.


q     Please 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.





SYNTHESIS OFALIPHATIC AMINES (Aliphatic means thegroups attached to nitrogen are alkyl or cycloalkyl, but not aromatic as in thecase of aniline).


q     Since amines are fairly basic functional groups, it stands to reason that they arealso fairly nucleophilic.


q     Since amines are far morebasic than any oxygenated functional group such as an alcohol or an ether orketone, they are also expected to be, and are, much more nucleophilic than this oxygenated functionalities. Consequently,they can be used effectively as nucleophiles in SN2 reactions withalkyl halides. This also applies to ammonia, the inorganic parent of organic amines.


q     Using ammonia as anucleophile in a reaction with an appropriate (methyl, primary, or secondary)alkyl halide in an SN2 reaction to prepare primary amines does work,but it requires a huge excess of ammonia, because the product primary amine is also reactive toward thealkyl halide. This would produce asecondary amine, and then even further reaction with alkyl halide would give atertiary amine. Thus, a mixture of primary, secondary, and tertiary amineswould be generated unless ammonia is used in large excess.


q     When ammonia is presentin large excess (e.g., at least 10 fold) over the alkyl halide, the alkylhalide has much more ammonia to react with than it does the amine.




q     It should be noticedthat the initially formed product is an alkylammonium cation, which can not actas a nucleophile (no unshared electron pair), so it could not react, itself,with alkyl bromide to give a dialkylamine.


q     However, in the presenceof ammonia, the proton transfer shown below, which produces the free alkylamine (which is a nucleophile and can react with alkyl bromide to give a secondary amine)and the parent ammonium ion is quite rapid (remember: proton transfer from oneelectronegative atom to another is very fast).




q     An alternative route forforming amines---specifically and exclusively primary amines--- is to employanother nitrogen nucleophile which is readily available, the azide anion. This reacts readily with an alkyl halide to give anorganic azide, which can be reduced with lithium aluminum hydride to theprimary amine. We will not look into the specific mechanism of this latterreduction reaction.



q     This strategy worksbecause the azide anion is a strong nucleophile, but the neutral organic azideis a very weak nucleophile (recall that hydroxide anion is a strongnucleophile, but its neutral conjugate acid, water, is a very weaknucleophile). Therefore, the organic azide, once formed, is unable to reactwith the alkyl halide. The result is that we do not have to use an excess ofthe  nucleophile to get exclusivelythe primary amine.


q     We want to note that thecyanide anion (which is a carbon type nucleophile which contains nitrogen) is astrong nucleophile which can readily react with alkyl halides to produceorganic cyanides, which are called nitriles. These nitriles can also be reduced with lithiumaluminum hydride to the primary amine. In this case, the primary amine has oneadditional carbon atom than is contained in the alkyl halide.


q     Amides can also bereduced in the same way as nitriles.





q     Many arylamines can besynthesized by first installing a nitro function (another nitrogen-containing functionality which iseasily introduced onto an aromatic ring, as you know) and then reducing it tothe amino function.


q     Aniline (which isessentially phenylamine) is the simplest aromatic amine. It can be synthesizedas shown below.




q     As an amine, aniline(and its related arylamines) are basic.


q     However, it is muchless basic than typical alkyl amines.Replacing an alkyl group by a phenyl or other aryl group greatly diminishes thebasicity of the amine function.


q     Note that the pK­a­of the anilinium ion (the conjugate acid of aniline) is 4.6, whereas that ofmethylamine is 10.7. This means, of course,that the anilinium ion is  a one-millionfold stronger acid than the methylaminium ion.Correspondingly, this means that aniline is a weaker base than methylamine, bya factor of a million!





q     Recall thatstabilization of the reactant side of the equation tends to diminish acidity(because the hydronium ion is on the right hand side of the equation), whilestabilization of the product side tends to increase acidity.


q     Aniline is ratherstrongly stabilized by resonance, whereas the anilinium ion is not. Theresonance structures for aniline are shown below, where it is shown that thering becomes electron rich, with partial negative charge (carbanion character)at the ortho and para positions, while the nitrogen tends to become electrondeficient (partial positive charge).



q     This 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:


q     This 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).


q     So 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).


q     Finally, 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.



PYRIDINE. Pyridine is an aromatic amine, but in a verydifferent sense from aniline. Pyridine is essentially benzene with one of theCH groups of benzene replace by a N atom.


q     Note below that theunshared electron pair in pyridine is in the trigonal plane, perpendicular tothe pi system consisting of overlapping pz AO’s, so theunshared pair is not a part of the aromatic system, but is independent of it.


q      Pyridine, like aniline, is much lessbasic than typical aliphatic amines,but for a very different reason: the unshared pair is in an sp2 AO,which as you recall is much lower in energy than the electron pair of aliphaticamines, which is in an sp3 AO. Therefore, pyridine is less easilyprotonated than typical aliphatic amines such as piperidine. The pKaof pyridine is 5.25.


q     Interestingly, thepyridinium ion (the conjugate acid) remains aromatic, because when the unsharedpair bond to a proton, the C-H bond is in the trigonal plane, and doesn’tremove any electrons from the pi electron system, which remains a  6 pi electron system, like benzene.





Reactions ofAmines.


  1. The Hoffmann Elimination Reaction. Recall that alkyl halides (except fluorides) and alcohols (in the presence of acid) can undergo elimination reactions to give alkenes. In both of these systems, good leaving groups are present, thus permitting an E2 elimination (or in some cases an E1 elimination). In the case of halides, the chloride, bromide, and iodide ions are good leaving groups. Recall that good leaving groups are weak bases. In the case of alcohols, the hydroxide ion, being a strong base, is a poor leaving group, but in acidic solution, when protonated, a good leaving group is generated (water). What about amines. If we should want to perform an elimination reaction on an amine to convert this functionality to an alkene function, could we do it? And how could we do it?


q     First, we note that theamide ion (NH2--) is even more strongly basic than ahydroxide anion, so it would be an atrocious leaving group.


q     What about using acid,as in the case of alcohols, to generate a better leaving group? In the simplestcase, this would be ammonia (NH3), which is not too strong a base (albeitmore basic than water or a halide ion).


q     In acidic solution, wewould not have a very good base to abstract the beta proton, we would have tosettle for water as the base. The question is, is ammonia a good enough leavinggroup to effectively leave when the weak base water is the best base available.It is not! The difference betweenthe eliminations of alcohols and amines in acidic solution is the poorerleaving group ability of ammonia than that of water (remember, ammonia is a stronger base; therefore apoorer leaving group.)


q     What is the solution tothis apparent dilemma? Essentially, convert the ammonium ion function to afunctional group which will allow the use of a strong base, like hydroxideanion. Since the amide ion is such a terrible leaving group, it would stillhave to be converted to the ammonium form, so that the leaving group couldbe a neutral amine. This canonly be done if all of the acidic protons of the ammonium ion are removed andreplace by alkyl groups, specifically methyl groups.


q     Since amines are prettydecent nucleophiles, as well as bases, they can react with alkyl halides in anSN2 displacement, as shown below.



q     The primary amine isfirst converted to a secondary amine function, the secondary amine to atertiary amine, and finally this reacts with a third molecule of methyl iodideto give the quaternary ammonium salt. At this point, there are no more acidicprotons, so base can be employed in an E2 reaction.


q     This is usually done byfirst reacting the quaternary ammonium iodide, which is initially formed to aquaternary ammonium hydroxide, by treatment with silver oxide (giving insolublesilver iodide). At this point we have a good base and a reasonable leavinggroup. Heating this ionic compound up to arount eighty degrees usually succeedsin effecting elimination of trimethylamine.




TransitionState for the Hoffmann Elimination Reaction.


q     Like all E2 reactions,this reaction is concerted.


q     We would like, then, todevelop a transition state model for the reaction, so we can rationalize and/ormake predictions of such things as selectivity (especially regioselectivity).


q     We do this in the usualway, using canonical structures for the reactant and the product, but also fora non-reactant and non-product-like structure (an “X” structure).






q     Note that when wederived the TS model for the elimination of HX from an organic halide by a basesuch as hydroxide ion, for simplicity we used only the reactant and product-like structures, so we only wereable to see the alkene character of the TS. Fortunately, it is the alkenecharacter which is dominant in theeliminations of alkyl halides.


q     However, somecarbanion character is also present in that type of elimination, and in allsuch eliminations. The importance of including the more complete treatmentwhich reveals the carbanion character in the present instance (eliminationswhere the leaving group is an amine) is that it is now the carbanion characterwhich is dominant over alkene character, resulting in a sharp change in theregiochemical selectivity.



q     Recall that theelimination of alkyl halides tended to favor the more highly substitutedalkene which is the more stablealkene. We called that Saytzeffregiochemistry.


q     In the Hoffmanelimination reactions of alkylammonium hydroxides, the less stable alkene is favored, fundamentally as a result of morefavorable carbanion character. This kind of regiochemistry is called Hoffmannregiochemistry.


q     For example, in theelimination of the quaternary ammonium salt shown below, 1-butene is verystrongly favored over the 2-butenes, even though the alkene character in the TSwould tend to favor the latter.





q     The TS models for thetwo competing TS’s are shown below:



q     The TS leading to1-butene is favored, because it has primaryCbcarbanion character, while that leading to 2-butene has secondarycarbanion character.


q     Carbanions aredestabilized by alkyl groups (remember that alkyl groups are electron donatinggroups; they stabilize positive charge, but destabilize negative charge. Theorder of carbanion stability is: methyl more stable than primary than secondary than tertiary.


q     Note that the TSleading to 1-butene has primary carbanion character, while that leading toeither of the 2-butenes has secondary carbanion character.


q     The ratio of 1- to2-butenes is approximately 90:10.

q     Finally, we raisethe question of why the drastic change in the relative amounts of carbanion andalkene character in the two types of elimination (alkyl halides andalkylammonium salts). Note that of the three canonical structures for the TS,the one which gives rise to alkene character is the last one (in our drawingabove). The structure will be of lower energy and contribute more when theleaving group is of lower energy (in this structure the leaving group hasleft.). That is, the better the leaving group the more alkene characterthere is in the TS.  Since chloride (or bromide or iodide)ions are better leaving groups than trimethylamine, the alkyl halideeliminations have much more alkene character than do the alkylammonium ioneliminations.


q     Interesting thatfluoride ion, the worst of the halogen leaving groups, tends to giveregiochemical preferences which are more like those of the alkylammonium ions,i.e., favoring the less substituted, less stable, alkene.



            Allprimary amines are readily converted by nitrous acid to diazonium salts. In thecase of aliphatic R groups, the diazonium ions are extremely unstable, rapidlydecomposing to give carbocations which undergo reaction with whatevernucleophiles may be present (such as water). The reason this especially highlevel of reactivity is that dinitrogen, being thermodynamically highly stable,is an outstanding leaving group. [Recall, again, good leaving groups are weakbases, and nitrogen is a really poor base] 



q     Note that the positivecharge in the diazonium ion is delocalized, i.e., it is shared by both nitrogens. Positive charge on nitrogen is inherently not veryfavorable (electronegative atom), but resonance stabilization makes this ionstable enough to form.


q     However, when the Rgroup is alkyl, these diazonium ions readily decompose via an SN1mechanism, with dinitrogen as the leaving group.


q     Note that becausenitrogen is such a thermodynamically stable molecule, it is perhaps the verybest leaving group of all. Even whenthese diazonium ions are formed at ice bath temperatures, they lose nitrogenextremely quickly, forming a carbocation, which then reacts with availablenucleophiles (e.g., solvent or chloride ion).



q     However, when R is anaryl group, such as phenyl, the diazonium ion is moderately stable at aboutzero degrees centigrade, but whenwarmed up to room temperature it rapidly decomposes en route to roomtemperature. This permits the use of the aryldiazonium ions in reactions withsubstances supplied after the diazonium ion is generated.


q     Aryldiazonium ions aremore stable than alkyldiazonium ions because the Ar-N bond is partially double,as shown in the resonance structure below, which is an additional smallcontributor over the main two resonance structures written previously. In otherwords, the pi system of the N-N pi bond overlaps with the pi system of thebenzene ring, providing delocalization of the positive charge onto the orthoand para positions of the benzene ring.





 Azo Compounds


q     Aryldiazonium ions areelectron deficient and therefore are electrophilic. However, they are relatively mild (not highly reactive, but very selective) electrophiles, because of their resonancestabilization.


q     One of their main usesin in electrophilic aromatic substitution reactions. As very mild and selectiveelectrophiles, they do not react with benzene or toluene or even anisole (methoxybenzene—normallyconsidered a highly reactive aromatic). They do, however, reactive witharomatics which have the powerfully electron donating amine function. Inparticular, N,N-dimethylaniline reacts readily with aryl diazonium ions as shownbelow:




q     The final product ofthis reaction is generically called an azo comound.


q     Azo compounds are highlycolored compounds and are frequently used as dyes for textiles.


The Sandmeyer Reaction


         Another common use for aryldiazonium ions is in thetransformation of the amino group of aniline or a derivative of aniline toother functionality such as a halide or a nitrile function. This involves theaddition of an appropriate salt containing the desired nucleophile to the cold,aqueous solution containing the diazonium ion and the allowing the temperatureto ascend to room temperature. In this way, the diazonium ion decomposes to thearyl carbocation, which then reacts with the appropriate nucleophile.


q     In this way, the aminogroup can be converted to a chloro, bromo, iodo, or nitrile function (or even reduced to hydrogen by using anappropriate reducing agent).


q     You may recall that arylhalides do not under either SN1 or SN2 substitutionbecause the aryl halogen bond has double bond character and is too strong toeasily break. However, when the potent leaving group is dinitrogen, evenaryl systems can undergo an SN1 substitution reaction.