Amide , amines from basicity

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

A highly stereoselective synthesis of the (3-substituted P-amino sulfone 271 involves the addition of a sulfonyl anion, derived from A-PMB sultam 268 upon treatment with NaHMDS, to chiral A-sulfinyl imine (5)-269 <06OL789>. Removal of the A-sulfinyl followed by basic workup affords amine 271. The stereochemical outcome of the adduct 270 was established via proton NMR analysis of the Mosher s amide derived from 271. 

Whereas the pATa for the a-protons of aldehydes and ketones is in the region 17-19, for esters such as ethyl acetate it is about 25. This difference must relate to the presence of the second oxygen in the ester, since resonance stabilization in the enolate anion should be the same. To explain this difference, overlap of the non-carbonyl oxygen lone pair is invoked. Because this introduces charge separation, it is a form of resonance stabilization that can occur only in the neutral ester, not in the enolate anion. It thus stabilizes the neutral ester, reduces carbonyl character, and there is less tendency to lose a proton from the a-carbon to produce the enolate. Note that this is not a new concept we used the same reasoning to explain why amides were not basic like amines (see Section 4.5.4). 

The basic components in the structure of local anesthetics are the lipophilic aromatic portion (a benzene ring), an intermediate chain, and the hydrophilic amine portion (Fig. 27.1). The intermediate chain has either an ester linkage from the combination of an aromatic acid and an amino alcohol or an amide linkage from the combination of an aromatic amine and an amino acid. The commonly used local anesthetics can be classified as esters or amides based on the structure of this intermediate chain. 

The exo position of the chloropyridine is essential for the antinociceptive potency of epibatidine - its racemic endo diastereoisomer is inactive. Also inactive are amides derived from epibatidine through acylation of the secondary amine function (R = C(O)R ). On the other hand the potency of 7-methylepibatidine (R = Me) is comparable to epibatidine itself, so a basic nitrogen but not necessarily a secondary amine is needed for activity (Li et al., 1993). 

Protophillic H-bond donor solvents solvents such as amides, amines or and other compounds with at least one N—II bond, which may be shared or donated. These solvents also have a highly basic character in the Bronsted sense i.e., they have a likelihood of accepting a free proton or a proton from a proton donor molecule (protophillic). These solvents also show high electron donor and acceptor properties (basic and acidic in the Lewis sense). 

The rates of nucleophilic addition to carbonyl groups that you met in Chapter 6 depend on the basicity of nucleophiles. As nitrogen bases are much stronger than oxygen bases (or, if you prefer, ammonium ions are much weaker acids than H3O ), amines are also much better nucleophiles than water or alcohols. This is dramatically illustrated in an amide synthesis from aniline and acetic anhydride in aqueous solution. 

Because basicity is the most important property of amines, it is only natural to wonder if amides are also basic. The answer is no. Although they are formed from carboxylic acids and basic amines, amides are neither basic nor acidic they are neutral. The carbonyl group bonded to the nitrogen has destroyed the basicity of the original amine, and the nitrogen of the amine has replaced the acidic —OH of the carboxylic acid. 

Sodium tetrahydridoborate Preferential reduction Amines from carboxylic acid amides Piperazines from plperazinones Effect of basic solvents on reductions... 

The hydroamination of dienes with basic primary and secondary amines can be achieved with a variety of catalysts including aUcah metals and their readily available derivatives. Reactions of acyclic 1,3-dienes catalyzed by alkah metals [159, 160, 171], metal hydrides [172], and metal amides (generated from metal alkyls) [163, 173, 174] result in regioselective formation of the stericaUy less hindered 1,4-addition product in most cases (23) [174]. Primary aliphatic amines are capable of performing double hydroamination in these conditions, typically leading to complex mixtures of mono- and bis-aUyl amines, whereas reactions with secondary amines are more practical [160]. 

Pentafluoroaniline. Pentafluoroaniline [771 -60-8] i2is been prepared from amination of hexafluoroben2ene with sodium amide inbquid ammonia or with ammonium hydroxide in ethanol (or water) at 167—180°C for 12—18 h. It is weakly basic (p = 0.28) and dissolves only in concentrated acids. Liquid crystals have been prepared from Schiff bases derived from pentafluoroaniline (230). 

Caibamates ate formed from an amine with a wide variety of reagents, of which the chloroformate is the most common amides are formed from the acid chloride. -Alkyl caibamates are cleaved by acid-catalyzed hydrolysis A/-alkylamides are cleaved by acidic or basic hydrolysis at teflux. conditions that cleave peptide bonds. 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

When the -OH of a carboxylic acid is replaced by an -NH2, the compound produced is an amide. Amides are neutral to mildly basic compounds. They can be made from acids, acid chlorides, acid anhydrides, and esters by reaction with ammonia or primary and secondary amines. The amide linkage is found in polyamide resins such as nylon. 

Addihon of primary and secondary amines to 1,3-butadiene and isoprene at 0 to 180°C over solid bases such as MgO, CaO, SrO, LajOj, Th02, and ZrOj has also been studied. CaO exhibits the highest achvity, while ZrOj is inachve. MejNH is the most reactive amine, giving primarily the 1,4-addihon product which undergoes iso-merizahon to the enamine N,N-dimethyl-l-butenylamine. It has been proposed that addihon of amines to 1,3-dienes on basic catalysts proceeds via aminoallyl carban-ion intermediates which result from addihon of amide ions to the dienes [169, 170]. 

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