In this paper we describe H/D isotope effects on the chemical shifts of intermolecular hydrogen-bonded complexes exhibiting low barriers for proton transfer, as a function of the position of the hydrogen bond proton. For this purpose, low-temperature (100−150 K) 1H, 2H, and 15N NMR experiments were performed on solutions of various protonated and deuterated acids AL (L = H, D) and pyridine-15 N (B) dissolved in a 2:1 mixture of CDClF2/CDF3. In this temperature range, the regime of slow proton and hydrogen bond exchange is reached, leading to resolved NMR lines for each hydrogen-bonded species as well as for different isotopic modifications. The experiments reveal the formation of 1:1, 2:1, and 3:1 complexes between AH(D) and B. The heteronuclear scalar 1H−15N coupling constants between the hydrogen bond proton and the 15N nucleus of pyridine show that the proton is gradually shifted from the acid to pyridine-15 N when the proton-donating power of the acid is increased. H/D isotope effects on the chemical shifts of the hydrogen-bonded hydrons (proton and deuteron) as well as on the 15N nuclei involved in the hydrogen bonds were measured for 1:1 and 2:1 complexes. A qualitative explanation concerning the origin of these low-barrier hydrogen bond isotope effects is proposed, from which interesting information concerning the hydron and heavy atom locations in single and coupled low-barrier hydrogen bonds can be derived. Several implications concerning the role of low-barrier hydrogen bonds in enzyme reactions are discussed.

1H, (2)H, and (13)C NMR spectra of enriched CH(3)(13)COOH acid without and in the presence of tetra-n-butylammonium acetate have been measured around 110 K using a liquefied Freon mixture CDF(3)/CDF(2)Cl as a solvent, as a function of the deuterium fraction in the mobile proton sites. For comparison, spectra were also taken of the adduct CH(3)(13)COOH.SbCl(5) 1 and of CH(2)Cl(13)COOH under similar conditions, as well as of CH(3)(13)COOH and CH(3)(13)COO(-) dissolved in H(2)O and D(2)O at low and high pH at 298 K. The low temperatures employed allowed us to detect several well-known and novel hydrogen-bonded complexes in the slow hydrogen bond exchange regime and to determine chemical shifts and coupling constants as well as H/D isotope effects on chemical shifts from the fine structure of the corresponding signals. The measurements show that self-association of both carboxylic acids in Freon solution gives rise exclusively to the formation of cyclic dimers 2 and 3 exhibiting a rapid degenerate double proton transfer. For the first time, a two-bond coupling of the type (2)J(CH(3)COOH) between a hydrogen-bonded proton and the carboxylic carbon has been observed, which is slightly smaller than half of the value observed for 1. In addition, the (1)H and (2)H chemical shifts of the HH, HD, and the DD isotopologues of 2 and 3 have been determined as well as the corresponding HH/HD/DD isotope effects on the (13)C chemical shifts. Similar "primary", "vicinal", and "secondary" isotope effects were observed for the novel 2:1 complex "dihydrogen triacetate" 5 between acetic acid and acetate. Another novel species is the 3:1 complex "trihydrogen tetraacetate" 6, which was also characterized by a complex degenerate combined hydrogen bond- and proton-transfer process. For comparison, the results obtained previously for hydrogen diacetate 4 and hydrogen maleate 7 are discussed. Using an improved (1)H chemical shift-hydrogen bond geometry correlation, the chemical shift data are converted into hydrogen bond geometries. They indicate cooperative hydrogen bonds in the cyclic dimers; i.e., widening of a given hydrogen bond by H/D substitution also widens the other coupled hydrogen bond. By contrast, the hydrogen bonds in 5 are anticooperative. The measurements show that ionization shifts the (13)C signal of the carboxyl group to low field when the group is immersed in water, but to high field when it is embedded in a polar aprotic environment. This finding allows us to understand the unusual ionization shift of aspartate groups in the HIV-pepstatin complex observed by Smith, R.; Brereton, I. M.; Chai, R. Y.; Kent, S. B. H. Nature Struct. Biol. 1996, 3, 946. It is demonstrated that the Freon solvents used in this study are better environments for model studies of amino acid interactions than aqueous or protic environments. Finally, a novel correlation of the hydrogen bond geometries with the H/D isotope effects on the (13)C chemical shifts of carboxylic acid groups is proposed, which allows one to estimate the hydrogen bond geometri...

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