Accurately quantifying the strength, distance, and angular dependence of noncovalent interactions is central to understanding numerous aspects of biology and medicine, as well as supramolecular and synthetic chemistry.[1] However, specific weak interactions are often difficult to quantify. Known approaches [1,2] include computational modeling, informatics, and a variety of experimental techniques. Of the latter, most notable are systems in which internal motions are restricted to two conformations, interchangeable through bond rotation. [2] For example, the "molecular torsion balance", developed by Wilcox et al., has successfully quantified a range of weak interactions by determining the equilibrium population of these two conformers.[ 2b-d,g,h] Here, we demonstrate how molecular motion in the form of pyramidal inversion in aziridines may be used for detecting and assessing the strength of an individual H-bond.The key concepts behind the use of aziridine scaffolds for measuring noncovalent interactions are summarized in Scheme 1. Suppose aziridine 1 benefits from a favorable noncovalent interaction between substituents X and Y in the ground state (GS); the rate of N inversion will decrease relative to aziridine 3 lacking this interaction (provided X···Y dissociation is required for N inversion). The difference in Gibbs free energy barrier between cases 1 and 3 (DDG°) should provide a direct measure of the X···Y interaction strength in 1, once secondary interactions (see below) are accounted for. Alternatively, suppose X and Y interact only in the transition state (TS). The inversion barrier for 2 will then be lowered by TS stabilization and hence the rate of N inversion will increase relative to 3. Again, DDG°will correlate with the X···Y interaction strength. Geometric constraints placed on X and Y by linkers attaching them to the aziridine scaffold in any specific system will dictate whether X and Y can interact effectively in either the GS or TS and hence modulate the rate of N inversion.Aziridine based scaffolds confer a number of attributes making them well-suited for this application. These include: 1) favorable synthetic accessibility with respect to other systems; [2c,d] 2) inversion rates that can be accurately quantified by dynamic NMR spectroscopy; [3] 3) spatial control of ring substituents in predictable, well-defined orientations; 4) the relatively weak basicity of the aziridine nitrogen atom (less likely to compete with X···Y interactions); and 5) system sizes that are amenable to ab initio calculations.To explore the potential of this new approach, a simple and well known intramolecular interaction was sought in the first instance, with a single H-bond between an orthosubstituted pyridine and a secondary amide fitting these criteria.[4] Compound 4 was accordingly synthesized, along with control compounds 5-8 (Scheme 2).H-bonding in 4, 5, and 8 was probed by 1 H NMR spectroscopy (298 K, ca. 10 mm). Interestingly, only small downfield shifts for the amide NH signals of 4 in [D 2 ]tetrachloroethane...