Amide ions

Water can also be a Brpnsted acid donating a proton to a base Sodium amide (NaNH2) for example is a source of the strongly basic amide ion which reacts with water to give ammonia... 

Example A common misconception is that the conjugate base of a weak acid is strong This is sometimes but not always true It is true for example for ammo nia which is a very weak acid (pK 36) Its conjugate base amide ion (H2N ) is a much stronger base than HO It is not true however for acetic acid both acetic acid and its conjugate base acetate ion are weak The conjugate base of a weak acid will be strong only when the acid is a weaker acid than water... 

Amide ion is a much stronger base than acetylide ion and converts acetylene to its conjugate base quantitatively... 

Nucleophilic aromatic substitution can also occur by an elimination-addition mechanism This pathway is followed when the nucleophile is an exceptionally strong base such as amide ion m the form of sodium amide (NaNH2) or potassium amide (KNH2) Benzyne and related arynes are intermediates m nucleophilic aromatic substitutions that pro ceed by the elimination-addition mechanism... 

The NMR spectra of both the parent [2,3-f ] and [3,4-f ] pyridopyrazine systems have been analyzed (66JCS(C)999). Shift values are given in Table 3. These studies were extended to the phenomenon of covalent hydration in both systems (66JCS(C)999,79JHC301) (see Section 2.15.13.2), as well as the addition of other nucleophiles such as amide ion (79JHC301, 79JHC305). 

No systematic study of the mass spectra of pyridopyrazines has been noted, but those of 2,3-dialkyl and 2,3-diaryl derivatives have been recorded 750MS97), and mass spectrometry has been used in the elucidation of problems in the reactions of pyrido[2,3-f ]pyrazines with amide ion (including use of and derivatives) (79JHC305), and of pyrido[2,3-f ]pyrazinium salts with indoles (78ZOR431). The mass spectra of some 1-deazaflavins have been recorded (74JCS(P1)1965). 

Amines are insufficiently nucleophilic to react with most azoles which do not contain a ring oxygen, and the stronger nucleophile NH2 is required. When treated with amide ions, thiazoles can be aminated in the 2-position by NaNHa at 150 °C. Only TV-substituted condensed imidazoles such as 1-alkylbenzimidazole react in such Chichibabin reactions. Imidazoles are aminated by alkaline NH2OH. 

The commonest of these for oxirane opening are amines and azide ion [amide ions promote isomerization to allylic alcohols (Section 5.05.3.2.2)]. Reaction with azide can be used in a sequence for converting oxiranes into aziridines (Scheme 49) and this has been employed in the synthesis of the heteroannulenes (57) and (58) (80CB3127, 79AG(E)962). 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

In the absence of the carbonyl or similar stabilizing group, the onium salts are much less acidic. The pATp so of methyltriphenylphosphonium ion is estimated to be 22. Strong bases such as amide ion or the anion of DMSO are required to deprotonate alkylphos-phbnium salts ... 

The principal difference hes in the poorer ability of amide ions to act as leaving groups, compared to alkoxides. As a result, protonation at nitrogen is required for breakdown of the tetrahedral intermediate. Also, exchange between the carbonyl oxygen and water is extensive because reversal of the tetrahedral intermediate to reactants is faster than its decomposition to products. 

This variation from the ester hydrolysis mechanism also reflects the poorer leaving ability of amide ions as compared to alkoxide ions. The evidence for the involvement of the dianion comes from kinetic studies and from solvent isotope effects, which suggest that a rate-limiting proton transfer is involved. The reaction is also higher than first-order in hydroxide ion under these circumstances, which is consistent with the dianion mechanism. 

A partial explanation of the above findings must lie in the known ease of addition of nucleophilic reagents to the conjugated double bond of pregn-16-en-20-ones. The amide ion that is a by-product of the reduction probably adds to a portion of the unreduced pregn-16-en-20-one giving the lithium enolate of amino ketone (74). This enolate may well be relatively stable at — 33° and would be protonated to the free 16-amino-20-one during work-up... 

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