Nitrogen lone pair, basicity

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

In contrast with amines, amides (RCONH ) 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 terms, amides are more stable and less reactive than amines because they are hybrids 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. 

As noted previously, arylamines are generally less basic than alkylamines. Anilinium ion has pKa = 4.63, for instance, whereas methylammonium ion has pfCa = 10.64. Arylamines are less basic than alkylamines because the nitrogen lone-pair electrons are delocalized by interaction with the aromatic ring tt electron system and are less available for bonding to H+. In resonance terms, aryl-amines are stabilized relative to alkylamines because of their five resonance forms. 

The relatively high aromaticity of the parent 1,2,5-thiadiazole renders it good thermal stability (stable up to 220 °C) despite this, 3,4-diphenyl-l,2,5-thiadiazole 8 suffers slow photochemical degradation to give benzonitrile and sulfur. The low basicity of 1,2,5-thiadiazole indicates a relatively high electron density in the Jt-orbital and corresponding low electron density of the nitrogen lone pairs. Addition reactions such as Walkylation do not occur readily. A-Oxidation is... 

However, in more complicated amines, this straight correlation is violated. The bicyclic tertiary amine l-azabicyclo[4.4.4]tetradecane (22) and the acyclic tertiary amine n-Bu3N have nearly the same first IP (7.84 and 7.90 eV, respectively), but the proton affinity of the bicyclic amine is 20 kcal mol 1 lower than that of the acyclic52. On the other hand, for other bridge-head tertiary amines like l-azabicyclo[2.2.2]octane (quinuclidine, 20) and l-azabicyclo[3.3.3]undecane (manxine, 21) the expected relation between proton affinities and IP values is observed. The extraordinary properties of l-azabicyclo[4.4.4]tetradecane (22) are caused by its unusual conformation the nitrogen lone-pair is directed inward into the bicycle where protonation is not possible. In the protonated form, the strained out-conformation is adopted. This makes it the least basic known tertiary amine with purely saturated alkyl substituents. Its pKa, measured in ethanol/water, is only +0.693. Strain effects on amine basicities have been reviewed by Alder88. 

In the two systems so far discussed it is impossible to obtain a quantitative idea of the relative importance of the inductive and resonance effects because it is impossible to achieve the operation of one of the effects without the other. When nitrogen is the basic centre, this becomes possible by steric fixation of the nitrogen lone pair orbital in the plane of the benzene ring, which virtually eliminates its overlap with the 7r-electron orbital of the ring carbon and hence also the mesomerism. So the enhanced acidity of the anilinium ion (pAT = 4-62) as compared with methylammonium (pAfg = 10-67) has been shown (Wepster, 1952) to be half inductive and half mesomeric in origin by a consideration of the following systems ([10]-[12]) ... 

Accordingly, we find that a nitrile nitrogen (lone pair in an sp orbital) is not at all basic (pATa about — 10), though ethylamine (lone pair in an sp orbital)... 

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. 

Note that the side-chains of glutamine and asparagine are not basic these side-chains contain amide functions, which do not have basic properties (see Section 4.5.4). The heterocyclic ring in tryptophan can also be considered as non-basic, since the nitrogen lone pair electrons form part of the aromatic jt electrons and are unavailable for bonding to a proton (see Section 11.8.2). 

Nicotine has two nitrogen atoms, one as a cyclic tertiary amine and one in a pyridine ring. The basicities are easily distinguished, in that a pyridine system is much less basic than a simple amine. This is essentially a hybridization effect, the nitrogen lone pair in pyridine being held in an sp orbital. This means the lone pair electrons are held closer to the nitrogen, and are consequently less available for protonation than in an sp -hybridized aliphatic amine. Hence, as mentioned above, pyridine has p Ta approximately 5. It follows that pA"a 8.1 is more appropriate for the pyrrolidine nitrogen. 

Monomeric structures are also observed in sterically crowded borylamides such as [(Et2O)2LLN(R)BMes2] (R = Ph " or Mes b or [(tmeda)LiN(Bu )BBu 2 where B-N n bonding may lower the basicity of the nitrogen lone pair and disfavour aggregation. 

Hydrogen bond basicity is of much relevance to the problem of drug design. Hydrogen bond basicity was shown to correlate with the location of the electrostatic potential local minimum along the axis of the nitrogen lone pair in a series of heterocycles (94JCS(P2)199). The experimental and calculated basicities for oxazole, 2,4,5-trimethyloxazole, and pyridine are shown in Table 2. 

In Mechanisms 1 and 2 the reactions are considered to proceed via an equilibrium concentration of the free base. Mechanism 3, Scheme (4), which was first proposed by Wenkert and Liu [10], starts with protonation at Nb, the most basic site and so the most likely to be protonated first. After protonation, the C-3 - Nb bond is cleaved due to participation of the indole nitrogen lone pair, giving a carbocation intermediate. Ring reclosure is assisted by the Nb lone pair to effect the inversion at C-3. 

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