Amides protonation site

Consider a nucleus that can partition between two magnetically nonequivalent sites. Examples would be protons or carbon atoms involved in cis-trans isomerization, rotation about the carbon—nitrogen atom in amides, proton exchange between solute and solvent or between two conjugate acid-base pairs, or molecular complex formation. In the NMR context the nucleus is said to undergo chemical exchange between the sites. Chemical exchange is a relaxation mechanism, because it is a means by which the nucleus in one site (state) is enabled to leave that state. 

The amide and peptide linkages are much more difficult to hydrolyze than the ester grouping. Both free and metal bound groups hydrolyze with second-order rate constants approximately 10 -10 less than for the corresponding esters. There are two potential sites for coordination in the -CONHR residue, namely at the carbonyl O in 13 and at the amide N in 14 where ionization of the amide proton is induced (Sec. 6.4.3). Cu + promotes hydrolysis of glycinamide at low pH where it is present as 13. However it inhibits hydrolysis at high pH, where it is 14, to such a degree that hydrolysis cannot be observed. ... 

The ambiguity of infrared criteria for the identification of protonation sites in imidazoles and 2-pyrazolines has been discussed by Elguero et al. (1967a), who have also provided new information on the infrared spectra of the hydrochloride of 3,5,5-trimethyl-2-pyrazoline in chloroform solution. There is a shift of the stretching vibration of the C=N bond from 1624 cm in the base to 1649 cm" in the hydrochloride salt in chloroform, i.e., in the N-1 protonated cation. This is analogous to similar shifts of the carbonyl frequency in some amide salts (see page 338). 

Carboxylic acids, esters, and amides are shown in this table to be protonated on the carbonyl oxygen. There has been some controversy on this point, but the weight of evidence is in that direction. See, for example, Katritzky Jones Chem. Ind. (London) 1961, 722 Ottenheym van Raayen Smidt Groenewege Veerkamp Reel. Trav. Chim. Pays-Bas 1961, SO, 1211 Stewart Muenster Con. J. Chem. 1961,39, 401 Smith Yates Can. J. Chem. 1972, 50. 771 Benedetti Di Blasio Baine J. Chem. Soc. Perkin Trans. 2 1980, 500 Ref. 8 Homer Johnson, in Zabicky The Chemistry of Amides Wiley New York, 1970, pp. 188-197. It has been shown that some amides protonatc at nitrogen see Perrin Acc. Chem. Res. 1989, 22, 268-275. For a review of alternative proton sites, see Liler Adv. Phys. Org. Chem. 1975, II, 267-392. 

Twelve-residue peptides have been synthesized as structural analogues of the 63-74 fragment, which contains the Ca2+-specific binding site II. In one analogue, Phe-72 was replaced by tyrosine, and in the other Gly-66 was also substituted by serine. From the enhancement of Tb3+ emission, a 1 1 binding stoichiometry was confirmed, and association constants around 2x 10s dm3 mol-1 determined. NMR studies show that binding of La3+ induced considerable perturbation of the amide proton resonances of aspartate, tyrosine and glutamate residues.243... 

Receptor 93 incorporates a zinc porphyrin backbone with four ferrocene amides [65]. This shares the design of the cobaltocenium receptor 4, except that now a zinc atom occupies the centre of the porphyrin. The Lewis acid metal centre provides an additional binding site for anion recognition. In dichloro-methane solution no significant anion-induced shifts in the lH NMR signals of the amide protons were seen in the free-base precursor of 93, whereas the... 

Fig. 15. Schematic illustration of the design of SAR by NMR. The HSQC spectra yield a single peak for each backbone amide proton in the target protein. Ligands that bind to the protein perturb the chemical shifts of localized regions of the protein, thus identifying the binding site. When two proximate binding ligands are identified, they are chemically linked to produce a tight-binding lead molecule.

The structural characteristics of cyclen and cyclam and their carboxylic and amidic derivatives in variously protonated states as well as their metal complexes were excellently reviewed by Guilard and co-workers <1998CCR1313>. As those derivatives are frequently used in the complexation of transition metal or lanthanide ions, the space arrangement, exact protonation sites, and presence of intramolecular hydrogen bonds are of interest from the point of view of kinetics of complex formation/dissociation. Since the number of related structures is very high, but no new remarkable information appeared since Guilard s review, derivatives of these macrocycles are not discussed in detail. 

For H+ addition, the amide group is a very weak base, and there once was considerable debate over whether the amide oxygen or the amide nitrogen was the most favorable protonation site. However, NMR experiments have decisively established that the oxygen atom serves as the main protonation site over the entire range of acidic solutions. Several groups have estimated the ratio of the O- to N-protonated amide cations to be 10. ... 

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