Direct Observation and Analysis of the Halo-Amino-Nitro Alkane Functional Group

Conventional amide synthesis is a mainstay in discipline-spanning applications, and it is a reaction type that historically developed as a singular paradigm when considering the carbon-nitrogen bond-forming step. Umpolung amide synthesis (UmAS) exploits the unique properties of an α-halo nitroalkane in its reaction with an amine to produce an amide. The “umpolung” moniker reflects its paradigm-breaking C–N bond formation on the basis of evidence that the nucleophilic nitronate carbon and electrophilic nitrogen engage to form a tetrahedral intermediate (TI) that is an unprecedented functional group, a 1,1,1-halo-amino-nitro alkane (HANA). Studies probing HANA transience have failed to capture this (presumably) highly reactive intermediate. We report here the direct observation of a HANA, its conversion thermally to an amide functionality, and quantitative analysis of this process using computational techniques. These findings validate the HANA as a functional group common to UmAS and diverted UmAS, opening the door to its targeted use and creative manipulation. [Display omitted] •The HANA functional group has been proposed previously as a fleeting intermediate•A stable form of the HANA has been prepared and crystallographically characterized•Experiments establish its competency as an intermediate to amides and oxadiazoles•Computational analysis of these conversions provides additional mechanistic insight Functional groups are the “cities” on a map of mechanistic pathways (the “roads”), and chemists use functional groups as pivot points to valuable chemical intermediates. Functional groups are defined by a collection of atoms, and variations on these atoms can define a group’s behavior, especially its stability and reaction trajectory. Once recognized as a distinct arrangement of atoms connected by a discrete pathway to a specific product, new opportunities are presented to manipulate its conversion to new outcomes. Herein, we prepare and characterize an intermediate containing halogen (F), amine (N), and nitro (NO2) at an alkane (C-sp3) carbon and establish it as a precursor to both amide and oxadiazole products, thereby codifying two key mechanistic pathways united by the HANA functional group. A computationally driven study of the pathway connecting these species identifies additional diversion points, and the HANA itself might be targeted with novel entry points. Preparation and characterization of a new functional group, HANA, is described. A study of i