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Related to this, transition metal\u2010catalyzed hydrogen isotope exchange (HIE) has become a prominent technique for the rapid and selective late\u2010stage installation of a deuterium or tritium label. Despite having a generally wide applicability, the current state\u2010of\u2010the\u2010art in this specific field is limited when particularly co\u2010ordinating motifs are present within a given molecule to be labelled. For example, the exceptional binding strength and sterically unencumbered nature of the nitrile functionality leads to inhibition of catalyst turnover, and has hindered the development of efficient methods for the HIE of nitrile\u2010containing molecules. Herein, <jats:italic>in silico<\/jats:italic> solvent binding energy parameter approaches have been disclosed which have facilitated the discovery of uniquely tolerant neutral iridium catalyst species that demonstrate a significantly lower binding strength with nitrile functionality. In turn, we describe the first effective nitrile\u2010tolerant HIE methodology enabled <jats:italic>via ortho<\/jats:italic>\u2010directed C(<jats:italic>sp<\/jats:italic><jats:sup>2<\/jats:sup>)\u2212H activation using air\u2010 and moisture\u2010stable iridium pre\u2010catalysts of the type Ir(COD)(NHC)Cl under an atmosphere of deuterium gas. This methodology proceeds under mild and practically accessible reaction conditions with a range of directing groups, including heterocycles, ketones, and amines, with this class of catalyst also shown to be applicable towards bioactive molecules, resulting in products with high levels of isotopic labelling.<\/jats:p>","DOI":"10.1002\/chem.202500449","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T09:03:50Z","timestamp":1739783030000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Nitrile\u2010tolerant Iridium\u2010catalysed Hydrogen Isotope Exchange"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4542-4401","authenticated-orcid":false,"given":"Nathan M. 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