CHAPTER 21: AMINES
DEFINITION: Amines are organic derivatives of ammonia, in which one, two, or all three of the hydrogens of ammonia are replaced by organic groups. Compounds RNH2 are called primary amines, R2NH secondary amines, and R3N are tertiary amines.
q Important Note: The designation of amines as primary, secondary, and tertiary is different from the usage of these terms in connection with alcohols and alkyl halides. In these latter two cases there is only one organic group (R), so that the terms are used to designate the type of carbon to which the alcohol or halide function is attached.
q Consequently, tertiary butylamine is a primary amine, but tertiary butyl alcohol is classed as a tertiary alcohol.
q Similarly, dipropylamine is a secondary amine, even though the R groups attached to nitrogen are primary.
NOMENCLATURE: There are two valid systems for naming amines. One system is used for naming relatively simple amines, i.e., molecules in which there are no other functional groups than the amine function and the compound is named as an amine, while the other is more flexible for naming molecules in which there are functional groups other than amines or in which there is considerable molecular complexity, so that it is convenient to use the amino functional group as a substituent.
Simple Amines. Simple amines are named according to the number of carbons in the longest continuous chain (or ring) of carbon atoms present in any of the R groups attached to nitrogen. Numbering, of course, must begin with the carbon immediately attached to the amine function. After identifying the main chain, the amine is named as a derivative of the alkane (or cycloalkane) having the appropriate number of carbon atoms by deleting the terminal –e of the alkane and replacing it with the suffix –amine. For example CH3NH2 , the simplest 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 group attached to nitrogen is named N-methylethanamine (the two carbon chain is used as the main chain in preference to the one carbon chain). Note the usage of the letter N to designate that the methyl substitutent is attached to nitrogen. If one R group is methyl, a second is ethyl, and a third is propyl, the amine would be named N-ethyl-N-methylpropanamine. Note the alphabetic criterion for arranging the methyl and ethyl sequence.
More Complex Amines. The substituent name of the –NH2 is amino. The (CH3)2N- substituent is, e.g., N,N-dimethylamino. The name of the compound
H2N-CH2CH2CH2OH is therefore 3-amino1-butanol.
Basicity. You will recall that the nitrogen atom of ammonia is sp3 hybridized and there is an unshared pair of electrons in the fourth tetrahedral orbital. This makes ammonia a base and a nucleophile. Because nitrogen is less electronegative than oxygen, ammonia is a much stronger base than water and also a much better nucleophile. Amines, which are merely organic derivatives of ammonia, are also tetrahedrally hybridized and are comparably basic and nucleophilic to ammonia. You might recall that amines are completely neutralized (protonated) by carboxylic acids.
The basicity of amines is often discussed indirectly in terms of the acidity of their respective conjugate acids. Recall that the conjugate acid of a weak base (e.g. like water) is a strong acid (like hydronium 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 the acidity of Bronsted acids, and we will also see that a corresponding concept, pKb can be used as a measure of the basicity of bases and that these two quantities are very closely related. Consider the acid dissociation, in dilute aqueous solution, of ammonia and a representative primary, secondary, and tertiary amine:
q Note that the strongest acid (least positive pKa) is ammonia. This means that ammonia is the weakest base of the four bases.
q We can easily understand this because alkyl groups are electron donating (EDG), so they stabilize the positively charge ammonium ions, i.e., the methyl ammonium ion is more stable than the parent ammonium ion because the alkyl group stabilizes the positive charge on the attached nitrogen atom.
q Note also that the alkyl stabilizing effect is purely inductive! [By looking at possible resonance structures, see if you can see why there is no hyperconjugative resonance stabilization by the alkyl group.
q Notice that the second alkyl 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, the trimethylammonium ion is still less acidic than ammonia.
q All of the amines are more basic than ammonia, but primary and secondary amines are the most basic.
q The effect of the third alkyl group is another instance of steric inhibition of solvation. The presence of three alkyl groups sharply diminishes the ability of the solvent to stabilize the corresponding ammonium ion, thus causing a reversal in the tendency of the alkyl groups to decrease acidity and increase basicity.
q Please note the relationship between pKb and pKa is pKa + pKb = 14 in water.
q The definition of pKb is shown below:
q The pKb’s of 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 as was the case for acidity in its relationship to pKa’s.
ACIDITY AS A BASIS FOR SEPARATING AMINES FROM ORGANICS HAVING OTHER FUNCTIONALITIES. Amines are the most basic class of organic compounds. They are virtually the only organic compounds which are substantially basic in aqueous solution and which are completely protonated by dilute solutions of strong acids. Upon protonation, of course, the form salts of the alkyl ammonium ions, which are water soluble (if the R groups are not too large). Consequently, amines can be separated from other classes of organic compounds like halides, ethers, alcohols, and ketone (as well as alkanes, alkenes and alkynes, of course), by a simple extraction technique.
q The solution of the mixture of organic compounds dissolved in an organic solvent such as ether is treated with dilute aqueous acid (careful: exothermic).
q The amine is protonated and goes into the aqueous solution as an ammonium salt, while other functionalities such as ketones remain in the organic phase.
q The phases are separated (separatory funnel), and the non-amine organic compounds are obtained from the ether phase (drying and evaporation of the ether), while the amine is obtained from the aqueous solution by adding more ether and making the aqueous solution alkaline, which liberates the amine, this dissolving in the ether phase. After drying and evaporation, the amine is obtained.
q Note that this would of course not work if the ketone or alcohol has only 1-4 carbons, because an alcohol or ketone having such few carbons would have substantial water solubility.
ACIDITY OF AMINES. Note that primary and secondary amines, like ammonia have protic hydrogens and therefore possess a degree of acidity (unlike tertiary amines, which have no acidic hydrogen). We have previously seen that ammonia has a pKa value of about 38, and is a very weak acid. Primary and secondary amines have pKa’s of very similar magnitude. Consequently, such amines are much more basic (pKb about 4) than they are acidic (pKa 38), so that their aqueous solutions are rather strongly alkaline.
q Since amines are only very weakly acidic, their conjugate bases, RNH- or R2NH- are very strong bases!! We have seen that they are strong enough bases to be able to generate enolates of ketones quantitatively.
CHIRALITY OF NITROGEN. It is interesting to note that, since the nitrogen atom of amines is tetrahedral, such a nitrogen can be a stereocenter if it has three different R groups attached. By definition, the fourth group is an electron pair, so that all four groups are different.
q However, it is observed that when chiral amines are generated, they very rapidly undergo an umbrella-like inversion to generate the corresponding enantiomer, quickly racemizing the 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 tetraalkyl ammonium ion, this kind of inversion is prevented, and such quaternary ammonium ions can be chiral and stable as a single enantiomer.
SYNTHESIS OF ALIPHATIC AMINES (Aliphatic means the groups attached to nitrogen are alkyl or cycloalkyl, but not aromatic as in the case of aniline).
q Since amines are fairly basic functional groups, it stands to reason that they are also fairly nucleophilic.
q Since amines are far more basic than any oxygenated functional group such as an alcohol or an ether or ketone, 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 with alkyl halides. This also applies to ammonia, the inorganic parent of organic amines.
q Using ammonia as a nucleophile 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 the alkyl halide. This would produce a secondary amine, and then even further reaction with alkyl halide would give a tertiary amine. Thus, a mixture of primary, secondary, and tertiary amines would be generated unless ammonia is used in large excess.
q When ammonia is present in large excess (e.g., at least 10 fold) over the alkyl halide, the alkyl halide has much more ammonia to react with than it does the amine.
q It should be noticed that the initially formed product is an alkylammonium cation, which can not act as a nucleophile (no unshared electron pair), so it could not react, itself, with alkyl bromide to give a dialkylamine.
q However, in the presence of ammonia, the proton transfer shown below, which produces the free alkyl amine (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 one electronegative atom to another is very fast).
q An alternative route for forming amines---specifically and exclusively primary amines--- is to employ another nitrogen nucleophile which is readily available, the azide anion. This reacts readily with an alkyl halide to give an organic azide, which can be reduced with lithium aluminum hydride to the primary amine. We will not look into the specific mechanism of this latter reduction reaction.
q This strategy works because the azide anion is a strong nucleophile, but the neutral organic azide is a very weak nucleophile (recall that hydroxide anion is a strong nucleophile, but its neutral conjugate acid, water, is a very weak nucleophile). Therefore, the organic azide, once formed, is unable to react with the alkyl halide. The result is that we do not have to use an excess of the nucleophile to get exclusively the primary amine.
q We want to note that the cyanide anion (which is a carbon type nucleophile which contains nitrogen) is a strong nucleophile which can readily react with alkyl halides to produce organic cyanides, which are called nitriles. These nitriles can also be reduced with lithium aluminum hydride to the primary amine. In this case, the primary amine has one additional carbon atom than is contained in the alkyl halide.
q Amides can also be reduced in the same way as nitriles.
q Many arylamines can be synthesized by first installing a nitro function (another nitrogen-containing functionality which is easily introduced onto an aromatic ring, as you know) and then reducing it to the amino function.
q Aniline (which is essentially phenylamine) is the simplest aromatic amine. It can be synthesized as shown below.
q As an amine, aniline (and its related arylamines) are basic.
q However, it is much less basic than typical alkyl amines. Replacing an alkyl group by a phenyl or other aryl group greatly diminishes the basicity of the amine function.
q Note that the pKa of the anilinium ion (the conjugate acid of aniline) is 4.6, whereas that of methylamine 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, by a factor of a million!
q Recall that stabilization of the reactant side of the equation tends to diminish acidity (because the hydronium ion is on the right hand side of the equation), while stabilization of the product side tends to increase acidity.
q Aniline is rather strongly stabilized by resonance, whereas the anilinium ion is not. The resonance structures for aniline are shown below, where it is shown that the ring becomes electron rich, with partial negative charge (carbanion character) at the ortho and para positions, while the nitrogen tends to become electron deficient (partial positive charge).
q This resonance or delocalization stabilization is possible because the unshared pair of electrons on nitrogen are in conjugation with (able to directly overlap with) the 2p AO on the directly attached ring carbon. These electrons are then delocalized around the ring on to the positions indicated. See the indicated overlap in the orbital picture shown below:
q This conjugation is only possible 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 is resonance stabilized in the case of aniline, but of course not in the case of methylamine, which does not have a p type orbital available to overlap with. This makes aniline much more stable thermodynamically than methylamine or any alkylamine, and thus much less readily protonated (weaker base).
q Finally, the anilinium ion (the conjugate acid of aniline) lacks this conjugated system, because the nitrogen atom is positively charged (highly electron deficient) and thus it cannot contribute any electrons to the ring. Of course it could not accept electrons from the ring because it doesn’t have any vacant orbitals to use for such acceptance (this would violate the octet rule). Note that the resonance structure on the right, below, is not a valid resonance structure.
PYRIDINE. Pyridine is an aromatic amine, but in a very different sense from aniline. Pyridine is essentially benzene with one of the CH groups of benzene replace by a N atom.
q Note below that the unshared electron pair in pyridine is in the trigonal plane, perpendicular to the pi system consisting of overlapping pz AO’s, so the unshared pair is not a part of the aromatic system, but is independent of it.
q Pyridine, like aniline, is much less basic 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 aliphatic amines, which is in an sp3 AO. Therefore, pyridine is less easily protonated than typical aliphatic amines such as piperidine. The pKa of pyridine is 5.25.
q Interestingly, the pyridinium ion (the conjugate acid) remains aromatic, because when the unshared pair bond to a proton, the C-H bond is in the trigonal plane, and doesn’t remove any electrons from the pi electron system, which remains a 6 pi electron system, like benzene.
Reactions of Amines.
q First, we note that the amide ion (NH2--) is even more strongly basic than a hydroxide 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 simplest case, this would be ammonia (NH3), which is not too strong a base (albeit more basic than water or a halide ion).
q In acidic solution, we would not have a very good base to abstract the beta proton, we would have to settle for water as the base. The question is, is ammonia a good enough leaving group to effectively leave when the weak base water is the best base available. It is not! The difference between the eliminations of alcohols and amines in acidic solution is the poorer leaving group ability of ammonia than that of water (remember, ammonia is a stronger base; therefore a poorer leaving group.)
q What is the solution to this apparent dilemma? Essentially, convert the ammonium ion function to a functional group which will allow the use of a strong base, like hydroxide anion. Since the amide ion is such a terrible leaving group, it would still have to be converted to the ammonium form, so that the leaving group could be a neutral amine. This can only be done if all of the acidic protons of the ammonium ion are removed and replace by alkyl groups, specifically methyl groups.
q Since amines are pretty decent nucleophiles, as well as bases, they can react with alkyl halides in an SN2 displacement, as shown below.
q The primary amine is first converted to a secondary amine function, the secondary amine to a tertiary amine, and finally this reacts with a third molecule of methyl iodide to give the quaternary ammonium salt. At this point, there are no more acidic protons, so base can be employed in an E2 reaction.
q This is usually done by first reacting the quaternary ammonium iodide, which is initially formed to a quaternary ammonium hydroxide, by treatment with silver oxide (giving insoluble silver iodide). At this point we have a good base and a reasonable leaving group. Heating this ionic compound up to arount eighty degrees usually succeeds in effecting elimination of trimethylamine.
Transition State for the Hoffmann Elimination Reaction.
q Like all E2 reactions, this reaction is concerted.
q We would like, then, to develop a transition state model for the reaction, so we can rationalize and/or make predictions of such things as selectivity (especially regioselectivity).
q We do this in the usual way, using canonical structures for the reactant and the product, but also for a non-reactant and non-product-like structure (an “X” structure).
CARBANION AND ALKENE CHARACTER IN THE TS’S FOR ELIMINATION REACTIONS.
q Note that when we derived the TS model for the elimination of HX from an organic halide by a base such as hydroxide ion, for simplicity we used only the reactant and product-like structures, so we only were able to see the alkene character of the TS. Fortunately, it is the alkene character which is dominant in the eliminations of alkyl halides.
q However, some carbanion character is also present in that type of elimination, and in all such eliminations. The importance of including the more complete treatment which reveals the carbanion character in the present instance (eliminations where the leaving group is an amine) is that it is now the carbanion character which is dominant over alkene character, resulting in a sharp change in the regiochemical selectivity.
q Recall that the elimination of alkyl halides tended to favor the more highly substituted alkene which is the more stable alkene. We called that Saytzeff regiochemistry.
q In the Hoffman elimination reactions of alkylammonium hydroxides, the less stable alkene is favored, fundamentally as a result of more favorable carbanion character. This kind of regiochemistry is called Hoffmann regiochemistry.
q For example, in the elimination of the quaternary ammonium salt shown below, 1-butene is very strongly favored over the 2-butenes, even though the alkene character in the TS would tend to favor the latter.
q The TS models for the two competing TS’s are shown below:
q The TS leading to 1-butene is favored, because it has primary Cb carbanion character, while that leading to 2-butene has secondary carbanion character.
q Carbanions are destabilized by alkyl groups (remember that alkyl groups are electron donating groups; they stabilize positive charge, but destabilize negative charge. The order of carbanion stability is: methyl more stable than primary than secondary than tertiary.
q Note that the TS leading to 1-butene has primary carbanion character, while that leading to either of the 2-butenes has secondary carbanion character.
q The ratio of 1- to 2-butenes is approximately 90:10.
q Finally, we raise the question of why the drastic change in the relative amounts of carbanion and alkene character in the two types of elimination (alkyl halides and alkylammonium 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 drawing above). The structure will be of lower energy and contribute more when the leaving group is of lower energy (in this structure the leaving group has left.). That is, the better the leaving group the more alkene character there is in the TS. Since chloride (or bromide or iodide) ions are better leaving groups than trimethylamine, the alkyl halide eliminations have much more alkene character than do the alkylammonium ion eliminations.
q Interesting that fluoride ion, the worst of the halogen leaving groups, tends to give regiochemical preferences which are more like those of the alkylammonium ions, i.e., favoring the less substituted, less stable, alkene.
DIAZONIUM IONS AND THEIR REACTIONS.
All primary amines are readily converted by nitrous acid to diazonium salts. In the case of aliphatic R groups, the diazonium ions are extremely unstable, rapidly decomposing to give carbocations which undergo reaction with whatever nucleophiles may be present (such as water). The reason this especially high level of reactivity is that dinitrogen, being thermodynamically highly stable, is an outstanding leaving group. [Recall, again, good leaving groups are weak bases, and nitrogen is a really poor base]
q Note that the positive charge in the diazonium ion is delocalized, i.e., it is shared by both nitrogens. Positive charge on nitrogen is inherently not very favorable (electronegative atom), but resonance stabilization makes this ion stable enough to form.
q However, when the R group is alkyl, these diazonium ions readily decompose via an SN1 mechanism, with dinitrogen as the leaving group.
q Note that because nitrogen is such a thermodynamically stable molecule, it is perhaps the very best leaving group of all. Even when these diazonium ions are formed at ice bath temperatures, they lose nitrogen extremely quickly, forming a carbocation, which then reacts with available nucleophiles (e.g., solvent or chloride ion).
q However, when R is an aryl group, such as phenyl, the diazonium ion is moderately stable at about zero degrees centigrade, but when warmed up to room temperature it rapidly decomposes en route to room temperature. This permits the use of the aryldiazonium ions in reactions with substances supplied after the diazonium ion is generated.
q Aryldiazonium ions are more stable than alkyldiazonium ions because the Ar-N bond is partially double, as shown in the resonance structure below, which is an additional small contributor over the main two resonance structures written previously. In other words, the pi system of the N-N pi bond overlaps with the pi system of the benzene ring, providing delocalization of the positive charge onto the ortho and para positions of the benzene ring.
q Aryldiazonium ions are electron deficient and therefore are electrophilic. However, they are relatively mild (not highly reactive, but very selective) electrophiles, because of their resonance stabilization.
q One of their main uses in in electrophilic aromatic substitution reactions. As very mild and selective electrophiles, they do not react with benzene or toluene or even anisole (methoxybenzene—normally considered a highly reactive aromatic). They do, however, reactive with aromatics which have the powerfully electron donating amine function. In particular, N,N-dimethylaniline reacts readily with aryl diazonium ions as shown below:
q The final product of this reaction is generically called an azo comound.
q Azo compounds are highly colored compounds and are frequently used as dyes for textiles.
Another common use for aryldiazonium ions is in the transformation of the amino group of aniline or a derivative of aniline to other functionality such as a halide or a nitrile function. This involves the addition of an appropriate salt containing the desired nucleophile to the cold, aqueous solution containing the diazonium ion and the allowing the temperature to ascend to room temperature. In this way, the diazonium ion decomposes to the aryl carbocation, which then reacts with the appropriate nucleophile.
q In this way, the amino group can be converted to a chloro, bromo, iodo, or nitrile function (or even reduced to hydrogen by using an appropriate reducing agent).
q You may recall that aryl halides do not under either SN1 or SN2 substitution because the aryl halogen bond has double bond character and is too strong to easily break. However, when the potent leaving group is dinitrogen, even aryl systems can undergo an SN1 substitution reaction.