Protons on Nitrogen

The common 14N nucleus has a spin number I of 1 and, in accordance with the formula 21 + 1, should cause a proton attached to it and a proton on an adjacent carbon atom to show three equally intense peaks. There are two factors, however, that complicate the picture the rate of exchange of the proton on the nitrogen atom and the electrical quadrupole moment of the 14N nucleus (see Section 3.2.1). 

Protons on nitrogen may undergo rapid, intermediate, or slow exchange. If the exchange is rapid, the 

NH proton(s) is decoupled from the nitrogen atom and from protons on adjacent carbon atoms. The NH proton peak is therefore a sharp singlet, and the adjacent CH protons are not split by NH. Such is the case for most aliphatic amines.  

At an intermediate rate of exchange, the NH proton is partially decoupled, and a broad NH peak results. The adjacent CH protons are not split by the NH proton. Such is the case for /V-mcthyl-p-nitroaniline. 

Aliphatic and cyclic amine NH protons absorb from S 3.0 to 0.5 aromatic amines absorb from S 5.0 to 3.0 in CDC13 (see Appendix E) because amines are subject to hydrogen bonding, the shift depends on concentration, solvent, and temperature. Amide, pyrrole, and indole NH groups absorb from 8 8.5 to 5.0 the effect on the absorption position of concentration, solvent, and temperature is generally smaller than in the case of amines. The nonequivalence of the protons on the nitrogen atom of a primary amide and of the methyl groups of N, /V-dimethylamides is caused by 

If the NH exchange rate is low, the NH peak is still broad because the electrical quadrupole moment of the nitrogen nucleus induces a moderately efficient spin relaxation and, thus, an intermediate lifetime for the spin states of the nitrogen nucleus. The proton thus sees three spin states of the nitrogen nucleus (spin number = 1), which are changing at a moderate rate, and the proton responds by giving a broad peak. In this case, coupling of the NH proton to the adjacent protons is observed. Such is the case for pyrroles, indoles, secondary and primary amides, and carbamates (Fig. 4.34). 

In the spectrum of ethyl A-methylcarbamate (Fig. 4.34), CH,NHCOCH2CH , the NH proton shows a 

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The amine must be primary (RNH2) or secondary (R2NH) Tertiary amines (R3N) can not form amides because they have no proton on nitrogen that can be replaced by an acyl group... 

Replacement of the proton on nitrogen in succinimide by bromine gives N bromo succinimide a reagent used for allylic and benzylic brominations (Sections 10 4 and 1112)... 

In acid the nitnle is protonated on nitrogen Nucleophilic addition of water yields an imino acid... 

Although it has not been possible to study the protonation of isoindole itself, it is clear that isoindoles are more basic than indoles or pyrroles. For example, 2,5-dimethyl-1,3-diphenylisoindole (40) has a p/sTa of 4-2.05 protonation of isoindoles occurs at positions 1 or 3. The pK for protonation of indolizine (10) at position 3 is 4-3.94 and that for carbazole (41) for protonation on nitrogen is estimated at -6.0. 

The reaction of 2-phenyl-l-azirine (201) with benzoic acid gaveN-benzoylphenacylamine (204) (67BCJ2938). The overall mechanism of the reaction involves initial protonation on nitrogen followed by addition of the nucleophile to the azirinium ion and finally ring opening. 

In the case of enamines protonation on nitrogen or carbon is possible and gives the conjugate acids 4 and 5, respectively. Whereas the final isolated product has the iminium salt structure (5), recent work 10-12) has shown... 

Reaction of an aldehyde or ketone with a secondary amine, R2NH, rather than a primary amine yields an enamine. The process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the a carbon), yielding an enamine (Figure 19.10). 

Molecular orbital based molecular mechanical (MOMM) calculations have been carried out on 3H-2-benzazepinyl phosphonates.43 Similar calculations on 5//-dibenz[Z>,/]azepine lead to the prediction that there are two stable boat conformations for the seven-membered ring both of which are more stable than the planar form by 22.6 and 10.9 kJ moP, respectively the more stable conformer being the one in which the proton on nitrogen is exo lo the azepine... 

A more recent example is the twisted amide (2) devised by Kirby, which despite the lack of electron-withdrawing groups (other than nitrogen) is completely hydrated upon protonation on nitrogen here the amide is unable to delocalize the nitrogen electrons onto the carbonyl, which means there is none of the usual amide stabilization. 

The diamines and their mono- and di-protonated ions can exist in various conformations, in which the nitrogen lone pairs and the protons on nitrogen are directed in (i or i+) or directed out (o or o+) from the molecular cavity. Diprotonated l,10-diazabicyclo[8.8.8]hexacosane, for example, may exist in either of the three forms in equation (79). When the out-out isomer of l,10-diazabicyclo[8.8.8]hexacosane bis hydrochloride (o+ o+) is dissolved in aqueous acidic solution, isomerisation to the in-in isomer (i+ i+) occurs so... 

Table 1 provides examples of amino enediynes which become much more reactive toward the Bergman cyclization upon protonation on nitrogen because the presence of a positively charged ammonium moiety alleviates the re-re repulsion of the in-plane re-orbitals. 

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. 

Amides may be hydrolysed to carboxylic acids by either acids or bases, though hydrolysis is considerably slower than with esters. Although amines are bases and become protonated on nitrogen via the lone pair electrons, we know that amides are not basic (see Section 4.5.4). This is because the lone pair on the nitrogen in amides is able to overlap into the carbonyl... 

C-2 or C-A will be unfavourable, in that one of the resonance forms features an unstable electron-deficient nitrogen cation. Attack at C-3 is the more likely, simply based on an inspection of resonance structures for the addition cation. However, electrophilic attack still tends to be unfavourable, because many electrophilic reagents, e.g. HNO3-H2SO4, are strongly acidic, and the first effect is protonation on nitrogen. Attack of E+ on to a positively... 

The abbreviation of a parent species shows the number of ionizable protons on nitrogen. On protonation or deprotonation the same abbreviation with increase or decrease in number of protons is given (Figure 3). 

Some generalizations have been made about the effect of various substituents on the absorption maxima and molar absorptivities (165). As expected, the absorption band around 280 nm is displaced to lower wavelengths when two methoxyls are replaced by a methylenedioxy group. The UV spectra of pavines are slightly affected by protonation on nitrogen (755). Similarly, quaternary species furnish UV spectra which closely resemble those of their tertiary counterparts (153). In some pavine bases such as norargemonine (13), the expected bathochromic shift on addition of alkali has not been observed (702). 

Moving one of the carbonyl groups away from the amide function of course markedly reduces the acidity of the proton on nitrogen. It is interesting that... 

Base-catalysed hydrolysis. The hydroxide ion attacks the nitrile carhon, followed hy protonation on the unstable nitrogen anion to generate an imidic acid. The imidic acid tautomerizes to the more stable amide via deprotonation on oxygen and protonation on nitrogen. The base-catalysed amide is converted to carboxylic acid in several steps as discussed earlier for the hydrolysis of amides. 

It is well documented that the isoimide is the kinetically favoured product and that isomerization yields the thermodynamically stable imide when sodium acetate is used as the catalyst. High catalyst concentrations provide maleimides with low isoimide impurity. The mechanism by which the chemical imidization is thought to occur is shown in Fig. 3. The first step in the dehydration reaction may be formation of the acetic acid-maleamic acid mixed anhydride. This species could lose acetic acid in one of the two ways. Path A involves participation by the neighboring amide carbonyl oxygen to eject acetate ion with simultaneous or subsequent loss of proton on nitrogen to form the isoimide. Path B involves loss of acetate ion assisted by the attack of nitrogen with simultaneous or subsequent loss of the proton on nitrogen to form the imide. If the cyclodehydration is run in acetic anhydride in the absence of the base catalyst, isoimide is the main reaction product. 

Exercise 24-6 Explain how the temperature variation of the proton nmr spectrum of A/,A/-dimethylmethanamide in strongly acidic solution might be used to decide whether amides accept a proton on nitrogen or oxygen. Review Section 24-1D. 

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