Amides, resonance

The RAHB effect may be illustrated by the ubiquitous C=0- -H—N hydrogen bond of protein chemistry. As shown in Section 5.2.2, the simplest non-RAHB prototype for such bonding, the formaldehyde-ammonia complex (5.31c), has only a feeble H-bond (1.41 kcalmol-1). However, when the carbonyl and amine moieties are combined in the resonating amide group of, e.g., formamide, with strong contributions of covalent (I) and ionic (II) resonance structures,... 

Amides The general formula of a primary amide is RCONH2. A primary amide has two H atoms bonded to N and results when the hydroxyl group of a carboxylic acid is replaced by —NH2. In secondary or tertiary amides, one or two H atoms in the —NH2 are replaced by alkyl or aryl groups. Because of resonance, amides are much weaker bases than are ammonia or amines. 

Chi Z H, Chen X G, Holtz J S W and Asher S A 1998 UV resonance Raman-selective amide vibrational enhancement quantitative methodology for determining protein secondary structure Biochemistry 27 2854-64... 

Gutowsky H S and Holm C H 1956 Rate processes and nuclear magnetic resonance spectra. II. Hindered internal rotation of amides J. Chem. Phys. 25 1228-34... 

Figure 2-51. a) The rotational barrier in amides can only be explained by VB representation using two resonance structures, b) RAMSES accounts for the (albeit partial) conjugation between the carbonyl double bond and the lone pair on the nitrogen atom. 

As an example, experimental kinetic data on the hydrolysis of amides under basic conditions as well as under acid catalysis were correlated with quantitative data on charge distribution and the resonance effect [13]. Thus, the values on the free energy of activation, AG , for the acid catalyzed hydrolysis of amides could be modeled quite well by Eq. (5)... 

The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group Resonance m carboxylate anions is more effective than resonance m carboxylic acids acyl chlorides anhydrides thioesters esters and amides... 

The amide is activated toward nucleophilic attack by protonation of its carbonyl oxygen The cation produced m this step is stabilized by resonance involving the nitro gen lone pair and is more stable than the intermediate m which the amide nitrogen is protonated... 

Most stable resonance forms of an O protonated amide... 

Amide resonance within the N acetyl group competes with delocalization of the nitro gen lone pair into the ring... 

By analogy to phenols we would expect the isomers with —OH groups on benzene like rings to be more stable This turns out not to be true because the keto forms are also aromatic owing to amide resonance... 

Polyamides. The next two compounds are the amide counterparts of the esters listed under item (4). Although the values of AH j are less for the amides than for the esters, the values of T j, are considerably higher. This is a consequence of the very much lower values of AS j for the amides. These, in turn, are attributed to the low entropies of the amide in the liquid state owing to the effects of hydrogen bonding and chain stiffness arising from the contribution of the resonance form... 

Instmmental methods of analysis provide information about the specific composition and purity of the amines. QuaUtative information about the identity of the product (functional groups present) and quantitative analysis (amount of various components such as nitrile, amide, acid, and deterruination of unsaturation) can be obtained by infrared analysis. Gas chromatography (gc), with a Hquid phase of either Apiezon grease or Carbowax, and high performance Hquid chromatography (hplc), using siHca columns and solvent systems such as isooctane, methyl tert-huty ether, tetrahydrofuran, and methanol, are used for quantitative analysis of fatty amine mixtures. Nuclear magnetic resonance spectroscopy (nmr), both proton ( H) and carbon-13 ( C), which can be used for quaHtative and quantitative analysis, is an important method used to analyze fatty amines (8,81). 

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (45 X = NH) the a carbon signal is shifted by about 20 p.p.m., to ca. S 47.7, while in A-methylpiperidine (45 X = Me) it appears at S 56.7. Quaternization at nitrogen produces further effects similar to replacement of NH by A-alkyl, but simple protonation has only a small effect. A-Acylpiperidines show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 p.p.m., and the mean shift is close to that of the unsubstituted amine (45 X=NH). The nitroso compound (45 X = N—NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 p.p.m.). The (3 and y carbon atoms of piperidines. A- acylpiperidines and piperidinium salts are all upfield of the cyclohexane resonance, by 0-7 p.p.m. 

Clearly, in the case of (66) two amide tautomers (72) and (73) are possible, but if both hydroxyl protons tautomerize to the nitrogen atoms one amide bond then becomes formally cross-conjugated and its normal resonance stabilization is not developed (c/. 74). Indeed, part of the driving force for the reactions may come from this feature, since once the cycloaddition (of 72 or 73) has occurred the double bond shift results in an intermediate imidic acid which should rapidly tautomerize. In addition, literature precedent suggests that betaines such as (74) may also be present and clearly this opens avenues for alternative mechanistic pathways. 

The N—CO distance of 1.38 A in (58) is rather greater than that of a normal amide (ca. 1.32 A) this has been attributed to ring strain and to inhibition of normal amide resonance by interaction with the N-aryl substituent. This inhibition of resonance is more pronounced in the N-tosyl-4-thioxoazetidin-2-one (59), which exhibits very short C=0 and C=S distances as well as the unusually long C—N bonds (80TL4247). NMR investigations... 

The higher frequencies of the /3-lactam carbonyl absorption in fused systems has been attributed to increased inhibition of amide resonance as the /3-lactam ring becomes less planar (b-72mI50900 p. 303). For the 3-cephems (61) there is also the possibility of enamine resonance which could further reduce the ability of the /3-lactam nitrogen to contribute to amide resonance. 

The role of IR spectroscopy in the early penicillin structure studies has been described (B-49MI51103) and the results of more recent work have been summarized (B-72MI51101). The most noteworthy aspect of a penicillin IR spectrum is the stretching frequency of the /3-lactam carbonyl, which comes at approximately 1780 cm" This is in contrast to a linear tertiary amide which absorbs at approximately 1650 cm and a /3-lactam which is not fused to another ring (e.g. benzyldethiopenicillin), which absorbs at approximately 1740 cm (the exact absorption frequency will, of course, depend upon the specific compound and technique of spectrum determination). The /3-lactam carbonyl absorptions of penicillin sulfoxides and sulfones occur at approximately 1805 and 1810 cm respectively. The high absorption frequency of the penicillin /3-lactam carbonyl is interpreted in terms of the increased double bond character of that bond as a consequence of decreased amide resonance, as discussed in the X-ray crystallographic section. Other aspects of the penicillin IR spectrum, e.g. the side chain amide absorptions at approximately 1680 and 1510 cm and the carboxylate absorption at approximately 1610 cm are as expected. 

The two methyl groups are not equivalent at 303 K (3 = 2.86 and 3.14), rotation about the CN bond is frozen, because this bond has partial tt character as a result of the mesomerlc (resonance) effects of the dimethylamino group (+Af) and of the aldehyde function (-M), so that there are cis and trans methyl groups. Hence one can regard 3-(A(A -dlmethylamlno)acrolein as a vinylogue of dlmethylformamide and formulate a vlnylogous amide resonance. 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

Amides are weak bases with pA values in the range of 0 to —2. When amide resonance is prevented, as in l-azabicyclo[2.2.2]octanone, N-protonation is preferred. ... 

Acylimidazoles and related amides in which the nitrogen atom is part of an aromatic ring hydrolyze much more rapidly than other amides. A major factor is the decreased resonance stabilization of the carbonyl group, which is opposed by the delocalization of the nitrogen lone pair as part of the aromatic sextet. 

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