Skip to main content
Open Access Publications from the University of California

NMR Studies of Proton Exchange in Amides


Acid-catalyzed proton exchange in a number of primary and secondary amides has been studied by Acid-catalyzed proton exchange in a number of primary and secondary amides has been studied by NMR methods. Exchange may conceivably occur by protonation on nitrogen, or by protona­ tion on oxygen followed by N-deprotonation to the imidic-acid tautomer. These mechanisms may be distinguished experimentally, since the former pathway requires that the rate of acid-catalyzed intramolecular exchange of the diastereotopic E and Z protons be comparable to the rates of solvent exchange, whereas the latter pathway requires that the rate of acid-catalyzed intramolecular exchange be zero.

To measure rate constants in these three-site proton ex­change reactions, we have extended the NMR saturation-transfer technique of Forsen and Hoffman. The method involves the measure­ ment of intensities and spin-lattice relaxation rates in Fourier trans­form NMR spectra under conditions of selective saturation. Satura­tion-transfer experiments have been supplemented with line-broad­ening and lineshape analysis measurements where necessary.

Uncatalyzed rotation about the C-N bond in a number of amides was initially studied with the saturation-transfer method. The rate of rotation is very small for formaide, N-methylformamide, N-t-butylformamide, ethyl oxamate, malonamide, and dichloro­ acetamide, and slightly larger for acetamide, cyanoacetamide, and chloroacetamide. The rate of rotation is considerably larger in acrylamide, methacrylamide, benzamide, and salicylamide. These variations in rotation rate are rationalized in terms of the effect of substituents on the transition-state for rotation.

To confirm the reliability of the three-site saturation-transfer method, we have examined the base-catalyzed exchange in a number of primary and secondary amides, where there is no mechanistic ambiguity. In all the amides examined, there is no base-catalyzed intramolecular exchange, as expected, and the E and Z protons ex­change at different rates. The latter observation is rationalized in terms of electronic effects in the resulting imidate anions. We have additionally studied solvent effects on exchange rates, and have elucidated the role of the o-hydroxy substituent of salicylamide in providing intramolecular catalysis of proton exchange in this compound.

Water-catalyzed proton exchange in two protonated imidic esters, ethyl acetimidate and 2-iminotetrahydrofuran, has been studied by saturation-transfer, since exchange in these compounds serves as a model for the imidic-acid route. We find that HZ exchanges faster than HE in ethyl acetimidate, and slower than HE in 2-iminotetrahydrofuran. These results are consistent with the expectations that the Eap and Zsp configurations, respectively, the more stable forms of the imidic esters.

Proton exchange in fuming sulfuric acid has been examined for acetamide, 3, 5-dinitrobenzamide, and trichloroacetamide. In this solvent, where the amides are quantitatively O-protonated, exchange proceeds by proton removal from oxygen, followed by reprotonation on nitrogen, as evidenced by the observation that HE and Hz exchange at equal rates with solvent and with each other.

With a combination of saturation-transfer and lineshape analysis methods, we have elucidated the mechanism of the dilute acid-catalyzed exchange in ten primary and two secondary amides. For acetamide, acrylamide, methacrylamide, benzamide, and formamide, where the rate of acid-catalyzed intramolecular exchange of the E and Z protons is comparable to the rates of solvent exchange, it is concluded that exchange proceeds predominantly by protonation on nitrogen. Nevertheless, HE exchanges faster, and this is interpreted in terms of competition between rapid deprotona­tion of RCONH+3 and rotation about its C-N single bond. In cyano­ acetamide, ethyl oxamate, chloroacetamide, malonamide, and dichloroacetamide, intramolecular exchanges is significantly slower than solvent exchange. This result is evidence for exchange proceed­ing primarily or exclusively via the imidic-acid pathway. For all these amides except the last one, HE exchanges faster than HZ, opposite to the behavior observed in the model compound ethyl acetimidate.

In N-methylformamide, exchange occurs largely via the imidic-acid pathway, whereas in N-t-butylformamide, exchange occurs through protonation on nitrogen. In both cases, HZ exchanges faster than HE. These conclusions are supported by the observation of general-acid catalysis in N-methylformamide, and the absence of such catalysis in N-t-butylformamide.

Several additional aspects of the exchange pathways have been investigated, including the effects of solvent polarity on the relative stabilities of the isomeric imidic acids and imidate anions, the inter­ action between the -NH+3 group and solvent, and the effect of substi­ tuents on the barrier to rotation in the N-conjugate acid. Finally, the variability of mechanism in dilute acid is rationalized in terms of a polar effect of substituents, and the dominance of the N-protonation pathway in strong acid is rationalized in terms of the acidity depend­ ence of the two pathways.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View