Basicity of amines

Amines are weakly basic compounds. Alkyl amines are more basic than anunonia, and aryl amines are less basic than ammonia. 

Arrange the following compounds in the increasing order of boiling points  

Amines range from simple structures to very complex structures. Some simple amines and their values are given below. 

There are a wide variety of naturally occurring amines. Amines include caffeine, morphine, cocaine, quinine, and amphetamines, just to name a few. Amines are also biologically important. Some of the biologically important amines include thiamine, adrenaline, acetyl choline, and riboflavin. 

Gamma-aminobutyrate is an amine and a neurotransmitter. It has mainly an inhibitory function and is extensively found as a neurotransmitter in the Purkinje cells of the central nervous system. 

Among isomeric amines, primary amines have the highest boiling points, and tertiary amines the lowest. 

Primary and secondary amines can participate in intermolecular hydrogen bonding, but tertiary amines lack N—H bonds and so cannot. 

Amines that have fewer than six or seven carbon atoms are soluble in water. All amines, even tertiary amines, can act as proton acceptors in hydrogen bonding to water molecules. 

When considering the basicity of amines, bear in mind that  

The more basic the amine, the weaker its conjugate acid. 

The chemistry of amines is dominated by the lone pair of electrons on nitrogen, which makes amines both basic and nucleophilic. They react with acids to form acid-base salts, and they react with electrophiles in many of the polar reactions seen in past chapters. Note in the following electrostatic potential map t f trimethylamine how the negative (red) region corresponds to the lone-pair of electrons on nitrogen. 

In practice, values are not often used. Instead, the most convenient way to measure the basicit of an amine (RNH2) is to look at the acUIity of the corresponding ammonium ion (RNH +). 

I liese equations say that the of an amine multiplied by theiCg of The corresponding ammonium ion is equal to the ion-product constant for water (1.00 X 10 ). Thus, if we know for an ammoniiim ion, we also know for the corresponding amine base because The more acidic the ammo- 

In contrast with amines, amides RCONII2) are nonbasic. Amides don t undergo substantial protonation by aqueous acids, and they are poor nucleophiles. The main reason for this difference in basicity between amines and amides is that an amide is stabilized by delocalization of the nitrogen lone-pair electrons through orbital overlap with the carbonyl group. In resonance tenns, amides are more stable and less reactive than amines becau.se thev are hvbrids of two resonance forms. This amide resonance stabilization is lost when the nitrogen atom is protonated, so protonation is disfavored. Electrostatic potential maps show clearly the decreased electron density on the amide nitrogen. 

s often possible to take advantage of their basicity to purify amines. l or c.xample, if a mixture of a basic amine and a neutral compound such as a ketone or alcohol is dissolved in an organic solvent and aqueous acid is added, the basic amine dissolves in the water layer as its protonated salt, w hile the neutral compound remains in the organic solvent layer. Separation of the water layer and neutralization of the ammonium ion by addition of NaOll then provides the pure amine (1-igure 24.2). 

Methylamine Ethylamine Secondary alkylamine Diethylamine Pyrrolidine 

In addition to their behavior as bases, primary and secondary amines can also act as very weak acids because an N-H proton can be removed by a sufficiently 

One other characteristic of amines is their odor. Low-molecular-weight amines. such as trimethylamine have a distinctive fishlike aroma, while diamines such as 1,5-pentanediamine, commonly called cadaverine, have the appalling odors you might expect from their common names. 

In addition to their behavior as bases, primary and secondary amines can also act as very weak acids because an N-H proton can be removed by a sufficiently strong base. We ve seen, for example, how diisopropylamine (p/C., = 40) reacts with butyllithium to yield lithium diisopropylamide (LDA Section 22.5). Dialkylamine anions like LDA are extremely powerful bases that are often used 

An amine is a nucleophile (a Lewis base) because its lone pair of nonbonding electrons can form a bond with an electrophile. An amine can also act as a Br0nsted-Lowry base by accepting a proton from a proton acid. 

Because amines are fairly strong bases, their aqueous solutions are basic. An amine can abstract a proton from water, giving an ammonium ion and a hydroxide ion. The equilibrium constant for this reaction is called the base-dissociation constant for the amine, symbolized by K.  

Values of K for most amines are fairly small (about 10 or smaller), and the equilibrium for this dissociation lies toward the left. Nevertheless, aqueous. solutions of amines are distinctly basic, and they turn litmus paper blue. 

Because they vary by many orders of magnitude, base-dissociation constants are usually listed as their negative logarithms, or pX b values. For example, if a certain amine has ATb = 10 , then pX b - 3. Just as we used pXa values to indicate acid strengths (stronger acids have smaller pXa values), we use pXb values to compare the relative strengflis of amines as proton bases. 

The values of pXb for some representative amines are listed in Table 19-3. 

Aniline is a weaker base than aliphatic amines because the lone pair of electrons is conjugated with the Ji-system of the aromatic ring and structures such as 11-13 contribute to the actual structure of aniline. Thus, the lone pair of electrons on the nitrogen atom is less available for coordination to a proton. The effect is considerable and aniline has a pK of 

6 compared to methylamine s pKa of 10.6 it thus reduces the basicity a million-fold. 

As we discussed in Section 1.15, it is more useful to describe the basicity of amines in terms of the ipK s of their conjugate acids than as basicity constants K, Always bear in mind that  

Citing amine basicity according to the of the conjugate acid makes it possible to analyze acid-base reactions of amines according to the usual Br0nsted relationships. For example, we see that amines are converted to ammonium ions by acids even as weak as acetic acid  

Recall that acid-base reactions are favorable when the stronger acid is on H—OCCH3 /s = 10 + CH3NH3 + II OCCH  

Conversely, adding sodium hydroxide to an ammonium salt converts it to the free 

PROBLEM 22.6 Apply the Henderson-Hasselbalch equation (see Quantitative Relationships Involving Carboxylic Acids, the box accompanying Section 19.4) to [ calculate the CH3NH3 /CH3NH2 ratio in water buffered at pH 7. 

Their basicity provides a means by which amines may be separated from neutral organic compounds. A mixture containing an amine is dissolved in diethyl ether and shaken with dilute hydrochloric acid to convert the amine to an ammonium salt. The ammonium salt, being ionic, dissolves in the aqueous phase, which is separated from the ether layer. Adding sodium hydroxide to the aqueous layer converts the ammonium salt back to the free amine, which is then removed from tlie aqueous phase by extraction with a fresh portion of ether. 

Amines are weak bases, but as a class, amines are the strongest bases of all neutral molecules. Table 22.1 lists basicity data for a number of amines. The most important relationships to be drawn from the data are 

Alkylamines are slightly stronger bases than ammonia. 

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Basicity of Amines As Measured by the of Their Conjugate Acids ... 

The noteworthy properties of amines are their basicity and their nucleophilicity The basicity of amines has been discussed m Section 22 4 Several reactions m which amines act as nucleophiles have already been encountered m earlier chapters These are sum marized m Table 22 4... 

The basicity of amines is conveniently expressed m terms of the of their conjugate acids... 

The unshared pair of electrons on the nitrogen atom provides the basic character to the fatty amines. Basicity of amines has been deterrnined as... 

The basicities of amines, ethers, and carbonyl compounds are invariably decreased by fluonnation. 2,2,2-Tnfluoroethylamine (p f = 3.3 [61]) and C 5NH2 = -0.36 [62]) are about 10 times less basic than CH3CH2NH2 and CgH5NH2, respectively, and (CF3)2CHNH2 (p j, = 1 22 [71]) is over 10 times less basic than 1-C3H2NH2. The relative gas-phase acidities in Table 15 illustrate the large effect of fluonnation. Perfluoro-rerf-amines (R )3N and ethers R Rf have no basic character m solution [, 74], and CF3COCF3 is not protonated by superacids [72]. 

The strong electronegativity of the fluorinated substituents is reflected in the effect that this group has upon the acidity of alcohols and carboxylic acids, as well as the effect it has on the basicity of amines (Tables 1.3-1.5). 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

As seen in Table V, there is a clear dependence of the equilibrium position on the basicity of amines, excluding triethylamine. However, it is necessary to take into account not only the proton affinity of the amine, but also the ability of the amine to form a dative bond with a boron atom. The equilibrium position also depends on the structure of the phosphorus-... 

It is well known that alkyl substitution changes the basicity of amines. However, solvation effects lead to an anomalous order of basicities in solution (NH3 tertiary amine < primary amine < secondary amine). From gas-phase proton affinity data the intrinsic effects of alkyl substituents can be evaluated and a quite regular order (NH3 < primary amine < secondary amine < tertiary amine) is obtained91. 

Basicity of amines is related to their structure. Basic character of an amine depends upon the ease of formation of the cation by accepting a proton from the acid. The more stable the cation Is relative to the amine, more basic is the amine. 

Pre-eminent amongst examples is the case of amides, which do not show the typical basicity of amines. Acetamide, for example, has pATa — 1.4, compared with a 10.7 in the case of ethylamine. This reluctance to protonate on nitrogen is caused by delocalization in the neutral amide, in which the nitrogen lone pair is able to overlap into the n system. This type of resonance stabilization would not be possible with nitrogen protonated, since the lone pair is already involved in the protonation process. Indeed, if amides do act as bases, then protonation occurs on oxygen, not on nitrogen. Resonance stabilization is still possible in the D-protonated amide, whereas it is not possible in the A-protonated amide. Note that resonance stabilization makes the D-protonated amide somewhat less acidic than the hydronium ion (pATa — 1.7) the amide oxygen is more basic than water. 

More generally, as seen in Figure 6-16, there is no correlation between calculated (Hartree-Fock 6-3IG ) and experimental aqueous-phase basicities of amines. (As shown earlier in this chapter, Hartree-Fock and other simple calculation models are quite successful in reproducing relative gas-phase basicities in amines. Therefore, a plot of measured gas-phase basicities vs. measured aqueous-phase basicities would be expected to show poor correlation.) On the other hand, calculated (6-3IG ) relative basicities of amines corrected for the effects of aqueous solvation using the Cramer/Truhlar SMS.4 model shows reasonable correlation with the experimental (aqueous-phase) data (Figure 6-17). This further confirms that the simple solvation model is at least qualitatively correct. 

Figure 6-16 6-31G vs. Experimental Aqueous-Phase Relative Basicities of Amines... 

Reaction with ammonia and primary and secondary amines can also give two types of products, 0-hydroxyamides or amino acids (equation 49). The amide is obtained from the reaction of 0-propiolactone with ammonia in water, while the amino acid is obtained from the reaction in acetonitrile, both in good yield. 0-Lactones react very generally with both aliphatic and aromatic amines, but the type of product does not correlate with polarity of solvent or basicity of amine. Fortunately, conditions can usually be found for the formation of the desired product. 

The basicity of amines is a function of the hybridization of the nitrogen atom.59 The more electronegative the nitrogen atom, the less readily it will share its kme pair electrons and act as a base. The series of nitrogen bases, aliphatic attunes, pyridine, and nitriles, exhibits this property ... 

Tanaka and Mika 42) suggest that the higher basicity of amine relative to epoxide makes the formation of an amine-proton donor adduct more likely, and they proposed the following equations as an alternative to Eqs. (3-12) and (3-13). 

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