Structure–Reactivity Studies, Characterization, and Transformation of Intermediates by Lithium Chloride in the Direct Insertion of Alkyl and Aryl Iodides to Metallic Zinc Powder

Abstract

Employment of fluorophore-tagged alkyl and aryl iodides permitted detection of persistent surface intermediates during their direct insertion to commercially available zinc powder. The sensitivity of this subensemble microscopy technique enabled structure–reactivity studies in the formation of intermediates that are present in quantities sufficiently low as to have been undetected previously by traditional ensemble analytical techniques. These surface intermediates were transformed by lithium chloride, leading to the assignment of the mechanistic role of lithium chloride as changing the rate-determining step in the reaction by lowering the barrier for solubilization of these otherwise persistent surface organometallic intermediates. The temperature dependence/qualitative barrier of the direct insertion step was determined independently from the solubilization step and from the barrier for the overall reaction. Detection of these zinc surface intermediates at the single-molecule level, i.e., of individual surface organometallic species, has been achieved for the first time. Energy dispersive X-ray spectroscopy (EDS) measurements of the elemental composition of the surface of the zinc powder determined that lithium chloride does not clean the surface of the oxides; instead, pretreatment of the surface with TMSCl effects partial removal of surface oxides after the 2 h pretreatment time previously reported in the empirically optimized synthetic procedure. Current limitations of this microscopy approach are also determined and discussed with respect to the addition of solid reagents during in operando imaging. Characterization of the resulting soluble fluorophore-tagged organozinc/LiCl complex by 1H NMR spectroscopy, mass spectrometry, and fluorescence spectroscopy provided insight into its solution dynamics and chemical exchange processes.

Mechanism of an Elusive Solvent Effect in Organozinc Reagent Synthesis

“…Those prior studies demonstratedamechanismo fr eactiona cceleration of the salt additive, LiCl, in THF as solubilization of intermediates from the surface of zinc after oxidative addition. [16][17][18] It remained unanswered,then,i ft he two known synthetic routes to organozinc reagents from zinc metal (e.g.,L iCl in THF,o rp olar aprotic solvent) functionb yt he same mechanism (i.e.,i ncreases olubility of the surface organozinc intermediate, Hypothesis2, Scheme 1b), or if the two routes functionb yd ifferent mechanisms( e.g.,L iCl in THF accelerates solubilization of intermedi-ates, but polar aprotic solvents accelerate oxidative addition, Hypothesis 1). Previouse xperimental data, obtainedt hrough indirect stereochemical and radical-clocke xperiments,s trongly suggest that oxidative addition of alkyl iodides to zinc proceeds through single-electron transfer pathways.…”

“…To simplify this direct comparison, we opted to avoid ap retreatments tep with TMSCl or iodine, [7] whichp artially removes the inactive surface layer but whichg enerates additional variabilityd uring handling. [16][17][18] 1 HNMR spectroscopy kinetics were measured in triplicate in each solvent relative to an internal standard (Scheme 2b).…”

“…1) Formation of 2,i dentifiable by the substantialu pfield shift of its a-zinc methylene protons, was significantly faster in [ With ar obust understandingo ft he solvente ffect on the reaction overall,w en ext investigatedt he impact of solvento n the build-up andp ersistence of organozinc surfacei ntermediates by single-particle fluorescencem icroscopy.T hese experiments harnessed organohalide reagents with sensitivea nd chemoselective spectralh andles to observe organozinc surface intermediates by fluorescencem icroscopyt hat were not observable by NMR spectroscopy.A na lkyl iodide tagged with a green spectatorb orond ipyrromethene (BODIPY) fluorophore, 3 (2 mm), reacted with zinc metal to form observable surface oxidative addition intermediate 4 (Scheme2c). [16][17][18] Intermediate 4 was characterized as brightg reen "hot spots" on the sur- face of otherwise dark zinc particles. In THF,t hese intermediates are persistent, [16][17][18] unless the sample is treated with lithium salts, heating, or strong stirring.…”

“…[16][17][18] Intermediate 4 was characterized as brightg reen "hot spots" on the sur- face of otherwise dark zinc particles. In THF,t hese intermediates are persistent, [16][17][18] unless the sample is treated with lithium salts, heating, or strong stirring. [18] The brightness on ap article in these fluorescencem icroscopy images is am easureo f the quantity of 4.T hus, through this imaging technique, the impact solvents have on the build-up and persistence of intermediate 4 could now be characterizedb yd irect observation of changes in quantity of 4.…”

Structure–Reactivity Studies of Intermediates for Mechanistic Information by Subensemble Fluorescence Microscopy

“…Case Study 2 examines molecular structure-reactivity relationships in the propensity of substrates to form intermediates in the synthesis of soluble organozinc reagents, and of those intermediates to subsequently react. 2,3 Traditional ensemble studies are hobbled by providing overall reaction rate information in such systems where intermediates do not build up to the quantities needed for detection (Figure 2, right). Thus, the effect of changing structure on the reactivity of a specific intermediate cannot be determined directly by traditional approaches.…”