Amines Reactions

Chapter 23 

Amines II. Reactions

Reactions

• Like ammonia, the three classes of amines contain nitrogen that bears an unshared pair of electrons; as a result, amines closely resemble ammonia in chemical properties. The tendency of nitrogen to share this pair of electrons underlies the entire chemical behavior of amines: their basicity, their action as nucleophiles, and the unusually high reactivity of aromatic rings bearing amino or substituted amino groups.

Basicity of amines. Basicity constant

• Like ammonia, amines are converted into their salts by aqueous mineral acids and are liberated from their salts by aqueous hydroxides. Like ammonia, therefore, amines are more basic than water and less basic than hydroxide ion:

• We found it convenient to compare acidities of carboxylic acids by measuring the extent to which they give up hydrogen ion to water; the equilibrium constant for this reaction was called the acidity constant, Ka. In the same way, it is convenient to compare basicity's of amines by measuring the extent to which they accept hydrogen ion from water; the equilibrium constant for this reaction is called a basicity constant, KiB.

• (As in the analogous expression for an acidity constant, the concentration of the solvent, water, is omitted.) Each amine has its characteristic Keb, the larger the KiB, the stronger the base. We must not lose sight of the fact that the principal base in an aqueous solution of an amine (or of ammonia, for that matter) is the amine itself, not hydroxide ion. Measurement of [OH~] is simply a convenient way to compare basicity's. We see in Table 22.1 (p. 729) that aliphatic amines of all three classes have KiB's of about 10' 3 to 10~ 4 (0.001 to 0.0001); they are thus somewhat stronger bases than ammonia (KiB = 1.8 x 10 ~ 5). Aromatic amines, on the other hand, are considerably weaker bases than ammonia, having A^s of 10' 9 or less. Substituents on the ring have a marked effect on the basicity of aromatic amines, p-nitroaniline, for example, being only 1/4000 as basic as Anili.

Structure and basicity

• Let us see how basicity of amines is related to structure. We shall handle basicity just as we handled acidity: we shall compare the stabilities of amines with the stabilities of their ions; the more stable the ion relative to the amine from which it is formed, the more basic the amine. First of all, amines are more basic than alcohols, ethers, esters, etc., for the same reason that ammonia is more basic than water: nitrogen is less electronegative than oxygen and can better accommodate the positive charge of the ion. An aliphatic amine is more basic than ammonia because the electron-releasing alkyl groups tend to disperse the gusitivej^harj^ and therefore stabilize it in a way that is not possible for the unsubstituted antonym ion. Thus, an ammonium ion is stabilized by electron release in the same way as a carbonium ion. From another point of view, we can consider that an alkyl group pushes electrons toward nitrogen, and thus makes the fourth pair more available for sharing with an acid. (The differences in basicity among primary, secondary, and tertiary aliphatic amines are due to a combination of solvation band electronic factors.)

• How can we account for the fact that aromatic amines arc weaker bases than ammonia? Let us compare the structures of aniline and the anilinism ion with the structures of ammonia and the ammonium ion. We see that ammonia and the ammonium ion are each represented satisfactorily by a single structure:

• both amine and ion to the same extent. It lowers^ teenagerly content of each by the same number of kcal/moles, and hence deuton affect indifference in their energy contents, that is, does not affect A<7 of ionization. If there were no other factors involved, then, we might expect the basicity of aniline to be about the same as the basicity of ammonia.

• However, there are additional structures to be considered. To account for the powerful activating effect of the NH2 group on electrophilic aromatic substitution (Sec. 11.20), we considered that the intermediate carbonium ion is stabilized by structures in which there is a double bond between nitrogen and the ring; contribution from these structures is simply a way of indicating the tendency for nitrogen to share its fourth pair of electrons and to accept a positive charge. It is generally believed that the -NH 2 group tends to share electrons with the ring, not only in the carbonium ion, which is the intermediate in electrophilic aromatic substitution, but also in the aniline molecule itself.

Effect of substituents on basicity of aromatic amines

• How is the basicity of an aromatic amine affected by substituents on the ring? In Table 23.1 (p. 749) we see that an electron-releasing substituent like CH3 increases the basicity of aniline, and an electron-withdrawing substituent like X Oven^ decreases the basicity. These effects are understandable. Electron release tends to disperse the positive charge of Bisamidinium ion, and thus stabilizes the ion relative to the amine. Electron withdrawal tends ostensory the positive charge of the, anilinism ion, and thus destabilizes the ion relative to the amine

• We notice that the base-strengthening substituents are the ones that activate an aromatic ring toward electrophilic substitution; the base-weakening substituents are the ones that deactivate an aromatic ring toward electrophilic substitution. Basicity depends upon position of equilibrium, and hence on relative stabilities of reactants and products. Reactivity in electrophilic aromatic substitution depends upon rate, and hence on relative stabilities of reactants and transition state. The effect of a particular substituent is the same in both cases, however, since the controlling factor is accommodation of a positive charge.

Quaternary ammonium salts. Exhaustive methylation. Hofmann elimination

• Like ammonia, an amine can react with an alkyl halide; the product is an amine of the next higher class. The alkyl halide undergoes nucleophilic substitution, with the basic amine serving as the nucleophilic reagent. We see that one

• the hydrogens attached to nitrogen has been replaced by an alkyl group; the reaction is therefore often referred to as alkylation of amines. The amine can be aliphatic or aromatic, primary, secondary, or tertiary; the halide is generally an alkyl halide. We have already encountered alkylation of amines as a side reaction in the preparation of primary amines by the ammonolysis of halides, and as a method of synthesis of secondary and tertiary amines. Let us look at one further aspect of this reaction, the formation of quaternary ammonium salts. Quaternary ammonium salts are the products of the final stage of alkylation of nitrogen. They have the formula R4 N+X~. Four organic groups are covalently bonded to nitrogen, and the positive charge of this ion is balanced by some negative ion. When the salt of a primary, secondary, or tertiary amine is treated with hydroxide ion, nitrogen gives up a hydrogen ion and the free amine is liberated. The quaternary ammonium ion, having no proton to give up, is not affected by hydroxide ion. 

Conversion of amines into substituted amides

• We have learned that ammonia reacts with acid chlorides of carboxylic acids to yield amides, compounds in which Cl has been replaced by

• In these reactions ammonia serves as a nucleophilic reagent, attacking the carbonyl carbon or sulfur and displacing chloride ion. In the process nitrogen loses a proton to a second molecule of ammonia or another base. In a similar way primary and secondary amines can react with acid chlorides to form substituted amides, compounds in which Ci has been replaced by the NHR or NR2 group

• There is, fortunately, a simple way out of these difficulties. We protect the amino group: we acetylate the amine, then carry out the substitution, and finally hydrolyze the amide to the desired substituted amine. For example:

Sulfonation of aromatic amines. Dipolar ions

• Aniline is usually sulfonated by "baking" the salt, anilinism hydrogen sulfate, at 180-200; the chief product is the /Mommer. In this case we cannot discuss orientation on our usual basis of which isomer is formed faster. Sulfonation is

• known to be reversible, and the p-isomer is known to be the most stable isomer; it may well be that the product obtained, the ^-isomer, is determined by the position of an equilibrium and not by relative rates of formation (see Sec. 8.22 and Sec. 12.11). It also seems likely that, in some cases at least, Sulfonation of amines proceeds by a mechanism that is entirely different from ordinary aromatic substitution. Whatever the mechanism by which it is formed, the chief product of this reaction is/?-aminobenzenesulfonic acid, known as sulfonic acid; it is an important and interesting compound.

• 'First of all, its properties are not those we would expect of a compound containing an amino group and a sulfonic acid group. Both aromatic amines and aromatic sulfonic acids have low melting points; benzenesulfonic acid, for example, melts at 66, and aniline at -6. Yet sultanic acid has such a high melting point that on being heated it decomposes (at 280-300) before its melting point can be reached. Sulfonic acids are generally very soluble in water; indeed, we have seen that the sulfonic acid group is often introduced into a molecule to make it water soluble. Yet sulfonic acid is not only insoluble in organic solvents, but also nearly insoluble in water. Amines dissolve in aqueous mineral acids because of their conversion into water-soluble salts. Sulfonic acid is soluble in aqueous bases but insoluble in aqueous acids. 

Sulfanilamide. The sulfa drugs

• The amide of sulfamic acid (sulfanilamide) and certain related substituted amides are of considerable medical importance as the sulfa drugs. Although they have been supplanted to a wide extent by the antibiotics (such as penicillin, duramycin, chloromycetin, and aureomycin), the sulfa drugs still have their medical uses, and make up a considerable portion of the output of the pharmaceutical industry. Sulfonamides are prepared by the reaction of a sulfonyl chloride with ammonia or an amine. The presence in a sulfonic acid molecule of an amino group, however, poses a special problem: if sulfonic acid were converted to the acid chloride, the sulfonyl group of one molecule could attack the amino group of another to form an amide linkage. This problem is solved by protecting the amino group through acetylation prior to the preparation of the sulfonyl chloride. Sulfanilamide and related compounds are generally prepared in the following way: 

• Just how good a drug the sulfanilamide is depends upon the nature of the group R attached to amido nitrogen. This group must confer just the right degree of acidity to the amido hydrogen, but acidity is clearly only one of the factors involved. Of the hundreds of such compounds that have been synthesized, only a half dozen or so have had the proper combination of high antibacterial activity and low toxicity to human beings that is necessary for an effective drug; in nearly all these effective compounds the group R contains a heterocyclic ran.

Reactions of amines with nitrous acid

• Each class of amine yields a different kind of product in its reaction with nitrous acid, HONO. This unstable reagent is generated in the presence of the amine by the action of mineral acid on sodium nitrite. Primary aromatic amines react with nitrous acid to yield diazonium salts; this is one of the most important reactions in organic chemistry. Following sections are devoted to the preparation and properties of aromatic diazonium salts. 

•      Primary aliphatic amines also react with nitrous acid to yield diazonium salts; but since aliphatic diazonium salts are quite unstable and break down to yield a complicated mixture of organic products (see Problem 23. 1 1, below), this reaction is of little synthetic value. The fact that nitrogen is evolved quantitatively is of some RNH2 + NaNO2 + HX > [RN2 +X-J S5> N2 + mixture of alcohols and ArNH2 + NaNO2 + 2HX -^-> ArN2 + X- + NaX + 2H2

• Secondary amines, both aliphatic and aromatic, react with nitrous acid to yield N-nitroso amines.

• Tertiary aromatic amines undergo ring substitution, to yield compounds in which a nitroso group, ~N O, is joined to carbon; thus N, N-dimethylaniline yields chiefly ;>-metros-N, N-dimethylaniline. 

• Ring intrastation is an electrophilic aromatic substitution reaction, in which the attacking reagent is either the nitrocefin ion, +NO, or some species (like + H2O NO or NOC1) that can easily transfer +NO to the ring. The nitro onium ion is very weakly electrophilic compared with the reagents involved in nitration, sulfonation, halogenation, and the Friedel-Crafts reaction; nitridation ordinarily occurs only in rings bearing the powerfully activating dialkylamino (NR2) or hydroxy (OH) group.

Diazonium salts. Preparation and reactions

• When a primary aromatic amine, dissolved or suspended in cold aqueous mineral acid, is treated with sodium nitrite, there is formed a diazonium salt.

• Since diazonium salts slowly decompose even at ice-bath temperatures, the solution is used immediately after preparation. The large number of reactions undergone by diazonium salts may be divided into two classes: replacement, in which nitrogen is lost as N2, and some other atom or group becomes attached to the ring in its place; and coupling, in which the nitrogen is retained in the product.

• In addition to the atoms and groups just listed, there are dozens of other groups that can be attached to an aromatic ring by replacement of the diazonium nitrogen, as, for example, -AR, -NO2, OR -SH, -SR, NCS, -NCO, -PO3 H2, AsO3 H2, SbO3H2; the best way to introduce most of these groups is via diazotization. The coupling of diazonium salts with aromatic phenols and amines yields azo compounds, which are of tremendous importance to the dye industry.

Diazonium salts. Replacement by halogen* Sandmeyer reaction

• Replacement of the diazonium group by Cl or Br is carried out by mixing the solution of freshly prepared diazonium salt with cuprous chloride or cuprous bromide. At room temperature, or occasionally at elevated temperatures, nitrogen is steadily evolved, and after several hours the aryl chloride or aryl bromide can be isolated from the reaction mixture. This procedure, using cuprous halides, is generally referred to as the Sandmeyer.

• ArN2 +X~ ^U Arax + N

• Sometimes the synthesis is carried out by a modification known as the Gattermann reaction, in which copper powder and hydrogen halide are used in place of the cuprous halide. Replacement of the diazonium group by I does not require the use of a cuprous halide or copper; the diazonium salt and potassium iodide are simply mixed together and allowed to react. ArN2 + X- + I- > Arl + N2 + X~

• Replacement of the diazonium group by F is carried out in a somewhat different way. Addition of fluoborite acid, HBF4 , to the solution of diazonium salt causes the precipitation of the diazonium fluoborite, ArN2 +BF4 ~, which can be collected on a filter, washed, and dried. The diazonium fluoborites are unusual among diazonium salts in being fairly stable compounds. On being heated, the dry diazonium fluoborite decomposes to yield the aryl fluoride, boron trifluoride, ArN2 + X~ HBF 4> ArN2 +BF4 ***' > Aarf + BF3 + 

Diazonium salts. Replacement by CN. Synthesis of carboxylic acids

• Replacement of the diazonium group by CN is carried out by allowing the diazonium salt to react with cuprous cyanide. To prevent loss of cyanide as HCN, the diazonium solution is neutralized with sodium carbonate before being mixed with the cuprous cyanide.

• Hydrolysis of nitriles yields carboxylic acids. The synthesis of nitrites from diazonium salts thus provides us with an excellent route from nitro compounds to carboxylic acids. For example:

• This way of making aromatic carboxylic acids is more generally useful than either carbonation of a Grignard reagent or oxidation of side chains. We have just seen that pure bromo compounds, which are needed to prepare the Grignard reagent, are themselves most often prepared via diazonium salts; furthermore, there are many groups that interfere with the preparation and use of the Grignard reagent. The nitro group can generally be introduced into a molecule more readily than an alkyl side chain; furthermore, conversion of a side chain into a carboxyl group cannot be carried out on molecules that contain other groups sensitive to oxidation.

Diazonium salts. Replacement by OH. Synthesis of phenols

• Diazonium salts react with water to yield phenols. This reaction takes place ArN2 +X- + H2 > Aroha + N2 + H

• slowly in the ice-cold solutions of diazonium salts and is the reason diazonium salts are used immediately upon preparation; at elevated temperatures it can be made the chief reaction of diazonium salts. As we shall see, phenols can couple who diazonium salts to form azo compounds (Sec. 23.17); the more acidic the solution, however, the more slowly this coupling occurs. To minimize coupling during the synthesis of a phenol, therefore coupling, that is, between phenol that has been formed and diazonium ion that has not yet reacted the diazoimine solution is added slowly to a large volume of boiling dilute sulfuric acid. This is the best general way to make the important class of compounds, the phenols.

Diazonium salts Replacement by- H

• Replacement of the diazonium group by H can be brought about by a number of reducing agents; perhaps the most useful of these is hypo phosphorus Stilbite diazonium salt is simply allowed to stand in the presence of the hypo phosphorous acid; nitrogen k lost, and hypo phosphorous acid is oxidized to phosphorous acid: 

• ArN2 +X- + H3PO2 + H2O > Arh + N2 + H3PO3 + HX

• An especially elegant way of carrying out this replacement is to use hypophosphorous acid as the diazotizing acid. The amine is dissolved in hypophosphorous acid, and sodium nitrite is added; the diazonium salt is reduced as fast as it is formed. This reaction of diazonium salts provides a method of removing an NH2 or NO2 group from an aromatic ring. This process can be extremely useful in synthesis, as is shown in some of the examples in the following section.

Syntheses using diazonium salts

• Let us look at a few examples of how diazonium salts can be used in organic synthesis. To begin with, we might consider some rather simple compounds, the three isomeric bromadiolone's. The best synthesis of each employ's diazotization, but not for the same purpose in the three cases. The o- and /j-bromadiolone's are prepared from the corresponding o- and/Nitrotoluenes:

• The advantage of these many-step syntheses over direct bromination is, as we have seen, that a pure product is obtained. Separation of the o- and />-bromadiolones obtained by direct bromination is not feasible. Synthesis of m-Bromo toluene is a more complicated matter. The problem here is one of preparing a compound in which two 0r/fa>, /Usra-directing groups are situated meta to each other. Bromination of toluene or methylation of bromobenzene would not yield the correct isomer. m-Bromo toluene is obtained by the following sequence of reactions.

Coupling of diazonium salts. Synthesis of azo compounds

• Under the proper conditions, diazonium salts react with certain aromatic compounds to yield products of the general formula Aarn Narr', called azo compounds. In this reaction, known as coupling, the nitrogen of the diazonium group is retained in the product, in contrast to the replacement reactions we have studied up to this point, in which nitrogen is lost. ArN2 + + Arrah Are N=N AR' + 

• The aromatic ring (Arh) undergoing attack by the diazonium ion must, in general, contain a powerfully electron-releasing group, generally OH, NR2, NHR, or NH2. Substitution usually occurs para to the activating group. Typically, coupling with phenols is carried out in mildly alkaline solution, and with amines in mildly acidic solution. Activation by electron-releasing groups, as well as the evidence of kinetics studies, indicates that coupling is electrophilic aromatic substitution in which the diazonium ion is the attacking reagent: 

• It is significant that the aromatic compounds which undergo coupling are also the ones which undergo intrastation. Like the nitro onium ion, + NO, the diazonium ion, ArN2 *, is evidently very weakly electrophilic, and is capable of attacking only very reactive rings.

• Analysis of amines. 

Analysis of amines. Heinsberg test

• Amines are characterized chiefly through their compound that dissolves in cold dilute hydrochloric acid or a water-soluble compound whose aqueous solution turns litmus blue must almost certainly be an amine. Elemental analysis shows the presence of nitrogen. Whether an amine is primary, secondary, or tertiary is best shown by the Heinsberg test. 

• The amine is shaken with benzene sulfonyl chloride in the presence of aqueous potassium hydroxide. Primary and secondary amines form substituted sulfonamides; tertiary amines do not //the test is carried out properly. The monosubstituted sulfonamide from a primary amine has an acidic hydrogen attached to nitrogen. Reaction with potassium hydroxide converts this amide into a soluble salt which, if the amine contained fewer than eight carbons, is at least partly soluble. Acidification of this solution regenerates the insoluble amide. 

• The disubstituted sulfonamide from a secondary amine has no acidic hydrogen and remains insoluble in the alkaline reaction mixture. What do we observe when we treat an amine with benzenesulfonic chloride and excess potassium hydroxide? A primary amine yields a clear solution, from which, upon acidification, an insoluble material separate. A secondary amine yields an insoluble compound, which is unaffected by acid. A tertiary amine yields an insoluble compound (the unreacted amine itself) which dissolves upon acidification of the mixture.

Analysis of substituted amides

• A substituted amide of a carboxylic acid is characterized by the presence of nitrogen, insolubility in dilute acid and dilute base, and hydrolysis to a carboxylic acid and an amine. It is generally identified through identification of its hydrolysis products.

Spectroscopic analysis of amines and substituted amides

• Infrared. The number and positions of absorption bands depend on the class to which the amine belongs.

•  An amide, substituted or unsubstituted, shows the C band in the 1640- 1690 cm" 1 region. In addition, if it contains a free NH group, it will show N H stretching at 3050-3550 cm' 1 , and NH bending at 1600-1640 cm' 1 or 1530-1570 mi (RCONHR').