Small heavy-atom and secondary hydrogen kinetic isotope effects (KIEs) can provide detailed information about the mechanism of an exceptional range of chemical reactions.1•2 However, there are significant general limitations in methods for the determination of these KIEs. Because absolute rate measurements are rarely sufficiently precise, small KIEs are usually determined in competition reactions of isotopically labeled and unlabeled materials. This is possible only in systems carefully chosen to allow the precise measurement of isotopomer ratios with appropriate analytical techniques, such as scintillation counting for 3H and l4C KIEs. The synthesis of isotopically labeled materials can be arduous, often prohibitively so, and a new synthesis, competition reaction, and analysis are required for each KIE of interest. A broadly useful alternative, particularly for l3C KIEs, is to employ the high precision of isotope ratio mass spectrometry to study KIEs in materials labeled only at natural abundance.3 A major restriction is that each site of interest must be selectively degradable without isotopic fractionation into an analyzable small molecule, most often CO2.The isotope-and position-specific information inherent in NMR techniques seems ideally suited to measuring KIEs at natural abundance. The utility of 2H NMR for determining large 2H KIEs at natural abundance has been established,4 and in theory, all of the individual KIEs in reactions of complex natural abundance materials can be determined simultaneously!5 In practice, however, NMR quantitation has not been sufficiently precise to be useful with small KIEs, the uncertainty in the few cases tried generally rivaling or exceeding the size of the isotope effects.4•5 We report here a simple general method for attaining chemically significant precision while simultaneously measuring all of the KIEs for reactions at natural abundance.As any reaction proceeds, the starting materials are fractionatively enriched in isotopically slower-reacting components. The

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