Amides, tertiary quaternary

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

In general, the Michael addition of a-substituted amide dienolates to a,/j-unsaturated esters is a method with great future potential for the diastereoselective construction of adjacent tertiary and quaternary stereogenic centers80. 

Amines are ammonia derivatives in which one or more hydrogen atoms have been replaced by an organic radical. Amines are sometimes called nitrogen bases. Basic chemistries include fatty amines (as primary, secondary, tertiary, and polyamines), amine salts, quaternary ammonium compounds, amine oxides, and amides. 

Benzylic quaternary ammonium salts, when treated with alkali metal amides, undergo a rearrangement called the Sommelet-Hauser rearrangementSince the product is a benzylic tertiary amine, it can be further alkylated and the product again subjected to the rearrangement. This process can be continued around the ring until an ortho position is blocked. ... 

Other nitrogen compounds, among them hydroxylamine, hydrazines, and amides (15-9), also add to alkenes. Even with amines, basic catalysts are sometimes used, so that RNH or R2N is the actual nucleophile. Tertiary amines (except those that are too bulky) add to Michael-type substrates in a reaction that is catalyzed by acids like HCl or HNO3 to give the corresponding quaternary ammonium salts. " ... 

To synthesize new surfactants, having incorporated both structural elements, the known siloxanyl modified halogenated esters and ethers of dicyclopentadiene [5] were treated with different amines according to the reaction scheme. Triethylamine yielded quaternary ammonium salts directly. Alternatively, after reaction with diethylamine or morpholine, the isolated siloxanyl-modified tertiary amines were also converted to quaternary species. To obtain anionic surfactants, the halogenated precursors were initially reacted with n-propylamine. In subsequent reaction steps the secondary amines formed were converted with maleic anhydride into amides, and the remaining acid functions neutralized. Course and rate of each single reaction strongly depended on the structure of the initial ester or ether compound and the amine applied. The basicity of the latter played a less important role [6]. 

Amines with three different substituents are potentially chiral because of the pseudotetrahedral arrangement of the three groups and the lone-pair electrons. Under normal conditions, however, these enantiomers are not separable because of the rapid inversion at the nitrogen center. As soon as the lone-pair electrons are fixed by the formation of quaternary ammonium salts, tertiary amide N-oxide, or any other fixed bonding, the inversion is prohibited, and consequently the enantiomers of chiral nitrogen compounds can be separated. 

The reluctance of tertiary amides to undergo hydrolysis, especially those produced in the Birch reduction-alkylation with a quaternary center next to the carbonyl group, has inspired the development of a variety of intramolecular transacylation reactions as illustrated by the cleavage of the SEM ether in 16... 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

Biochemical recalcitrance of biomolecules is related to their molecular weight and complexity, as well as, to the presence of ether-bridges, quaternary and tertiary C-atoms, amide groups, phenyl- and heterocyclic N-groups, long-chain hydrocarbons and polymerized aromatic groups (Haider and Martin, 1981 von Liitzow et al.,... 

The intramolecular Heck reaction is a powerful method for the synthesis of constrained tertiary and quaternary carbon centers and has been applied as a key step in the synthesis of a number of pyridine alkaloids. Mann et al. have accessed the bicyclononane core structure of huperzine A 150 in moderate yield by intramolecular Heck reaction of bromopyridine 151 (Equation 117). Another notable application of this methodology is the intramolecular a-arylation of the amide enolate generated from 152 to give the carbon skeleton of cytosine <20040BC1825> (Equation 118). 

The primary (1), secondary (2 ), tertiary (3) and quaternary (4) nomenclature is used in a number of situations to define a carbon centre, or to define functional groups like alcohols, halides, amines and amides. Identifying functional groups in this way can be important because the properties and reactivities of these groups vary depending on whether they are primary, secondary, tertiary or quaternary. 

Fig. Primary, secondary, tertiary, and quaternary carbon centres. Amines and Amides...

Amines and amides are classified as primary, secondary, tertiary, or quaternary depending on the number of bonds from nitrogen to carbon(Following fig.). Note that a quaternary amine is positively charged and is therefore known as a quaternary ammonium ion. It is not possible to get a quaternary amide. 

The elements of protein structure are divided into four classes primary, secondary, tertiary, and quaternary. Primary structure refers to the linear sequence of amino acids linked by amide bonds along protein chains. These polymer chains vary in length from a few amino acid residues (oligopeptides) to molecules containing 2000 or more amino acids. Most proteins are from 100 to 500 amino acid residues in length. One or more of each of 20 natural amino acids may be present in each protein molecule. In some cases the amino acids undergo posttranslational chemical modification, which introduces still more variety into protein structure. 

For alkyl amines, a direct correlation between the steric bulk at the a-carbon and the yield of the reaction was found amines attached to a secondary carbon gave higher yields than amines connected to a tertiary carbon, while amines connected to a quaternary carbon led only to the formation of an amide-carboxylic acid intermediate, rather than the corresponding imide. In the case of amino acids whose ot-carbons are tertiary, a lower temperature was surprisingly required for high NMI selectivity in the first step (40 °C instead of 75 °C). This was explained by the presence of the COOR group, which assists in the collapse of the tetrahedral intermediate precursor to the imide formation. The amino acid derived NMIs were obtained as a mixture of open and closed forms due to the addition of triethylamine in the reaction. At high temperatures this promotes the formation of... 

Alkylation of phenols, alcohols, amides, and acids. N-Alkylation of indoles and pyrroles by means of solid KOH in DMSO was reported a few years ago. Actually this method is applicable to a number of substrates. The substrate and alkyl halide are added to powdered KOH and stirred in DMSO, usually at 20°. Methyl-ation of phenols, alcohols, and amides occurs in high yield in about 5-30 minutes. Esterification of acids is slower. Dehydrohalogenation is a competing or predominating reaction when secondary or tertiary halides are used. Another limitation is that amino groups are converted into quaternary salts under these conditions. The general method can be used for permethylation of peptides. 

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