Reactions of Amides

All soaps are salts of fatty acids. The main difference between soaps Is the addition of other Ingredients that do not alter their cleaning properties dyes for color, scents for a pleasing odor, and oils for lubrication. Soaps that float are aerated so that they are less dense than water. 

Soaps—Salts of long-chain fatty acids 

Soaps are typically made from lard (from hogs), tallow (from cattle or sheep), coconut oil, or palm oil. All soaps work in the same way, but have somewhat different properties depending on the lipid source. The length of the carbon chain in the fatty acids and the number of degrees of unsaturation affect the properties of the soap to some extent. 

Problem 22.27 What Is the composition of the soap prepared by hydrolysis of this triacylglycerol  

Because amides have the poorest leaving group of all the carboxylic acid derivatives, they are the least reactive. Under strenuous reaction conditions, amides are hydrolyzed in acid or base to form carboxylic acids or carboxylate anions. 

In acid, the amine by-product is protonated as an ammonium ion, whereas in base, a neutral amine is formed. 

The relative lack of reactivity of the amide bond is notable in proteins, which are polymers of amino acids connected by amide linkages (Section 22.6B). Proteins are stable in aqueous solution in the absence of acid or base, so they can perform their various functions in the aqueous cellular environment without breaking down. The hydrolysis of the amide bonds in proteins requires a variety of specific enzymes. 

The mechanism of amide hydrolysis in acid is exactly the same as the mechanism of ester hydrolysis in acid (Section 22.11 A) except that the leaving group is different. 

The mechanism of amide hydrolysis in base has the usual two steps of the general mechanism for nucleophilic acyl substitution—addition of the nucleophUe followed by loss of a leaving group— plus an additional proton transfer. The initially formed carboxylic acid reacts further under basic conditions to form the resonance-stabilized carboxylate anion, and this drives the reaction to completion. Mechanism 22.10 is written for a 1° amide. 

Carbamoylpyrazines with various dehydrating agents afford cyanopyrazines. Ellingson et al. (1175) first dehydrated 2-amino-3-carbamoylpyrazine with phosphorus pentoxide in refluxing pyridine to 2-amino-3-cyanopyrazine this 

Esters also have a substantial chemistry involving the related enolate anions. We will develop this subject in detail in Chapter 19. 

PROBLEM 18.14 Suggest one reason why DIBAL-H might be slower than L1A1H4 to react with the aldehyde of Rgure 18.38. 

Even though amides are the least reactive of the acyl compounds, they can nevertheless be hydrolyzed in either acid or base. The mechanisms of these reactions are directly related to those of acid- or base-induced ester hydrolysis. In base, the carbonyl carbon of an amide is attacked to give tetrahedral intermediate A (Fig. 18.39). 

FIGURE 18.39 The base-induced hydrolysis of amides gives carboxylate anions. Acidification of the carboxylate at the end of the reaction would give the carboxylic acid. 

PROBLEM 18.15 In strong base, the hydrolysis of an amide is second order in hydroxide. In other words, two molecules of HO are required to hydrolyze one amide molecule. Write a modified mechanism to account for the need for two molecules of hydroxide. 

Propose a mechanism for the following reaction. (Hint Number the carbons to help you see where they end up in the product.) 

Amides are very unreactive compounds, which is comforting, since the proteins that impart strength to biological structures and catalyze the reactions that take place in cells are composed of amino acids linked together by amide bonds (Section 22.0). Amides do not react with halide ions, alcohols, or water because, in each case, the incoming nucleophile is a weaker base than the leaving group of the amide (Table 16.1). 

We will see, however, that amides do react with water and alcohols under acidic conditions (Section 16.16). 

The filled nonbonding orbital containing nitrogen s lone pair overlaps the empty 77 antibonding orbital of the carbonyl carbon. This stabilizes the lone pair and raises the energy of the tt orbital of the carbonyl carbon, 

Acylation inactivates the enzyme, and actively growing bacteria die because they are unable to synthesize functional cell walls. PenidUin has no effect on mammalian cells because they are not enclosed by cell walls. PeniciUins are stored at cold tempa-atures to minimize hydrolysis of the /3-lactam. 

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A/-Vinylamides and /V-vinylimides can be prepared by reaction of amides and imides with acetjiene (3), by dehydration of hydroxyethyl derivatives (4), by pyrolysis of ethyUdenebisamides (5), or by vinyl exchange (6), among other methods the monomers are stable when properly stored. 

The reactions of amides fall into hydrolysis, dehydration and degradation (to amines) acid hydrazides and acid azides undergo additional reactions. 

When the enamine is in conjugation with a carbonyl function, as in a-aminomethylene aldehydes (528,529), ketones (530), or esters (531), a Michael addition is found in vinylogous analogy to the reactions of amides. An application to syntheses in the vitamin A series employed a vinyl lithium compound (532). 

Substitution on the phenethyl side chain of the substrate is usually well tolerated. For example, reaction of carbamate 44 with POCI3 afforded a 75% yield of the corresponding lactam 45. However, in some instances substituents on the chain lead to low yields, such as in the reaction of amide 46, which provided only a 29% yield of the desired product 47 (albeit with 9 1 diastereoselectivity). ... 

Alteration of the relative reactivity of the ring-positions of quinoline is expected and observed when cyclic transition states can intervene. Quinoline plus phenylmagnesium bromide (Et20,150°, 3 hr) produces the 2-phenyl derivative (66% yield) phenyllithium gives predominantly the same product along with a little of the 4-phenylation product. Reaction of butyllithium (Et 0, —35°, 15 min) forms 2-butylquinoline directly in 94% yield. 2-Aryl- or 6-methoxy-quinolines give addition at the 2-position with aryllithium re-agents, and reaction there is so favored that appreciable substitution (35%) takes place at the 2-position even in the 4-chloroquinoline 414. Hydride reduction at the 2-position of quinoline predominates. Reaction of amide ion at the 2-position via a cyclic... 

There was some dispute over the product resulting from the benzoylation reaction of amide 266, which, according to the original investigators, has the furazan stmcture 267 (Scheme 172) (29LA54). 

Yet another compound that exhibits antidepressant properties, that does not fit the classical mold, is a rather simple substituted ami dine. Reaction of amide with triethyloxoniurn fluoroborate (Meerwein reagent) affords the corresponding imino ether Exposure of this inter-... 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Reactions of amides (Section 21.7) (a) Hydrolysis to yield acids... 

The N-bromination of amides with bromine and alkali has been extensively researched as the first step of the Hofmann degradation. However, it is difficult to isolate the N-bromoamides because of their subsequent reaction to produce amines, which proceeds very readily under excessive alkaline conditions. Now, the reaction of amides with a stoichiometric amount of BTMA Br3 and sodium hydroxide in ice-water gave N-bromoamides in fairly good yields. Our method can be applied to various types of aliphatic, aromatic, and heterocyclic amides (Fig. 31) (ref. 39). 

The reaction of amides with half equiv. of BTMA Bf3 and one equiv. of DBU in dichloromethane-methanol at room temperature gave N-substituted acylureas in fairly good yields (Fig. 34). Furthermore, in the presence of a large excess of methanol, the reaction of amides with one equiv. of BTMA Bt3 and two equiv. of DBU in dichloromethane gave methyl carbamates as main products (Fig. 35). In these reactions, we assumed that in the presence of DBU, intermediary isocyanates react with excess of amides to afford acylureas, and react with excess of methanol to afford methyl carbamates (ref. 42). 

Reaction of amides such as 1546 with PPh3/CCl4 and NaN3, or with PPh3/azo-ester then addition of Me3SiN3 17, affords, via 1547 and 1548, 1,2,3,4-tetrazoles... 

The Peterson reactions of amides of bis(trimethylsilyl)methylamines such as 1620 with TBAF in THE afford HMDSO 7 and the 1,2-dihydroisoquinolines 1621... 

It has been suggested that the preferential formation of ( )-alkene on Wittig reaction of amide-substituted phenyl 3-pyridyl ketones with non-stabilized phosphorus ylides which contain a carboxyl terminus is a consequence of either hydrogen bonding or salt... 

A nitrogen isotope effect (1 006,1 010, and 1 006 at pH 6 73, 8 0, and 9 43) has been observed in the chymotrypsin-catalysed hydrolysis of NTacetyl-L-tryptophanamide which requires the C—N bond of the amide to be broken in the rate-determining step (O Leary and Kluetz, 1972). The isotope effect is similar to that observed for the reaction of amides with hydroxide ion which is known to proceed through a tetrahedral intermediate. 

Saito, S. Kobayashi, S. Highly Anti-selective Catalytic Aldol Reactions of Amides with Aldehydes, f Am. Chem. Soc. 2006, 128, 8704-8705. 

The reactions of amides have similarities to those of esters. Specifically, the reactions covered in this section involve the loss or gain of water (dehydration or hydrolysis). 

A variety of protonic and Lewis acids initiate the cationic polymerization of lactams [Bertalan et al., 1988a,b Kubisa, 1996 Kubisa and Penczek, 1999 Puffr and Sebenda, 1986 Sebenda, 1988]. The reaction follows the mechanism of acid-catalyzed nucleophilic substitution reactions of amides. More specibcally, polymerization follows an activated monomer mechanism. Initiation occurs by nucleophilic attack of monomer on protonated (activated) monomer (XXIV) to form an ammonium salt (XXV) that subsequently undergoes proton exchange with monomer to yield XXVI and protonated monomer. The conversion of XXIV to XXV involves several steps—attachment of nitrogen to C+, proton transfer from... 

Pyrimido[l,3]oxazines are reactive toward amines anhydride 121 undergoes ring opening and decarboxylation on treatment with ethanolamine to give the amide 122 <1996MI459>. The reactions of amide 123 <2002MI10> with amines to form pyrimido[5,4- pyrimidines have already been mentioned, while the equivalent process with pyr-imido[5,4- ]oxazinium salt 124 is discussed in CHEC-II(1996) <1996CHEC-II(7)737>. 

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