Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2025 May 8.
Published in final edited form as: J Org Chem. 2025 Jan 2;90(2):939–948. doi: 10.1021/acs.joc.4c02726

Mechanisms of Activating Agents to Form Organozinc Reagents from Zinc Metal: Lessons for Reaction Design

Martin Stang a, Erin M Hanada a, Suzanne A Blum a
PMCID: PMC12061042  NIHMSID: NIHMS2078023  PMID: 39745146

Abstract

Activating agents enable the efficient preparation of organozinc complexes from zinc metal and organohalides, but their mechanisms had been obscured by the heterogenous nature of these systems. Fluorescence microscopy, with the sensitivity to detect surface reaction intermediates, reveals distinct activating mechanisms of widely used activation strategies: trimethylsilyl chloride, LiCl, and DMSO, and Rieke zinc powder. The resulting development of mechanistic models provides a better understanding of the oxidative-addition–solubilization sequence in organozinc reagent formation and contains lessons for methods development.

Graphical Abstract

graphic file with name nihms-2078023-f0001.jpg

I. Introduction

Organozinc reagents participate in a myriad of carbon–carbon bond-forming reactions, including Negishi cross-coupling,1–6 Reformatsky,7–9 and Barbier10 reactions. Generation of organozinc reagents via direct insertion of metallic zinc powder to organohalides is plausibly the most convenient and direct pathway for the synthesis of these reagents.11 Many reported modern synthetic methods activate the otherwise sluggish zinc metal powder by addition of a chemical “activating agent” or specific solvent that may serve as a pretreatment or be present throughout the reaction (Figure 1). Early reports in this area activated zinc metal by first soaking it in HCl, followed by rinsing to remove residual HCl.7 The surface of zinc was thought to be purified through rapid washing with HCl.12 Subsequent preactivation methods included chemical treatment with TMSCl,8,9,13 dibromoethane,14 and iodine11. Chemical activation during the reaction (rather than pretreatment), through addition of LiCl, as developed by Knochel,14 also sees wide use. Alternatively, activating agents can seemingly be avoided—or at least swapped for—polar aprotic cosolvents like dimethylacetamide and DMSO, which predated the LiCl protocol but which presented solvent removal and compatibility problems.11,15,16 Due to complexities characterizing mechanisms of these activating agents, reaction design and improvement for heterogenous metal powder reactions have been largely indirect, relying heavily on screening approaches—including for these zinc reactions.17,18 Subsequent similar advances have been made with additives to enable direct insertion of aluminum,19 manganese,20 indium,21–24 and bismuth25–27. As with zinc, the identification of additives and solvents has been largely screening-based. Further, the reasons for any variations between the different metals are not well understood. Thus, an individual-step-level understanding of the mechanistic roles of additives and solvents in promoting direct insertion with zinc may offer guidance for methods development with other metals as well.

Figure 1.

Figure 1.

Open in a new tab

Example chemical activation strategies for zinc metal in organic synthesis. a. HCl; b. TMSCl; c. I2; d. TMSCl, dibromoethane, and LiCl.

II. Reasons Why it Is Not Effective to Simply Study the Structures of the Solution Organozinc Products to Learn about Mechanisms of their Formation

Given the difficulty with studying the oxidative addition reaction at the zinc surface, one might wonder if, as an alternative, the composition of the resulting solution-phase organozinc complexes might hold clues to the mechanisms of their formation. Studies of the resulting complexes are more straight-forward, as the complexes are soluble and may buildup to quantities required for detection by NMR spectroscopy and mass spectrometry.28

These solution studies, however, are not without their own set of complementary complications. First, in practice many of these studies have the significant limitation of being indirect in that they do not characterize the organozinc species, but instead characterize the final derivatized products. The prevalence of derivatization methods is due to both the high sensitivity of most organozinc complexes to protonolysis by moisture in air, and to the desirability of their downstream products. For example, iodide titrations measure the quantity of the resulting organoiodide after zinc–iodide exchange.14,29,30 Alternatively, the organozinc species have been quenched either with water (leading to protodemetalation and characterization11,31,32) or with ethyl bromoacetate and formate (or orthoformate)8,9. Second, these indirect characterization methods lose information about the speciation of zinc (e.g., monoorganozinc, diorganozinc, or zincate).3,5,33,34 Organ has provided beautiful insight into the concentration- and salt-dependent speciation of organozinc complexes in solution, through careful measurement of the impact of this speciation on accelerating or decelerating participation in palladium-catalyzed (i.e., “Negishi”) cross-coupling reactions.5,6,35–37

Mass spectrometry (MS) has been used previously to study solution-phase organozinc-complex speciation without the need for derivatization.35 Koszinowski especially has provided several key reports.33,34 These reports detail formation of higher-order zincates in these mixtures detected with electrospray ionization (ESI) mass spectrometry, for example, [Zn(nBu)Cl2]− and [Zn2(nBu)Cl4]−.33 However, MS detects charged species, and may therefore disproportionally favor detection of complexes that are already charged in reaction mixtures, potentially skewing the measured ratio of complexes away from the true distribution of species in solution.

Case in point, our own research group originally published two suggested structures for organozinc complexes in solution, [RZnICl]− and [RZnI2]−, on the basis of high-resolution MS data,38 only to find later that these charged complexes are sufficiently minor so as to be unobservable by 1H NMR spectroscopy. Instead, the predominant solution species, and the only organozinc species in solution visible by 1H NMR spectroscopy, was the neutral R2Zn (containing no halide).36,37,39 The minor quantity of [RZnIX]− was established to be in rapid Schlenk equilibrium with R2Zn and was detected preferentially by MS.

Further, our recent mechanistic studies showed that the dominant organozinc species in solution at equilibrium are unlikely to be the species relevant to the kinetic processes of activation toward oxidative addition or solubilization. Thus, the premise of studying the product organozinc species to make determinations about the reaction path contains many confounding variables. In answer to the original question: solution studies are not enough.

III. Fluorescence Microscopy as an Enabling Technology for Observing Surface Reaction Intermediates.

An analytical method capable of observing small quantities of organozinc surface intermediates and revealing their behaviors under reaction conditions therefore would be an enabling technology—providing motivation for its development by our laboratory.17 Indeed, the persistence of organozinc reaction intermediates on the surface of zinc metal during direct insertion was an unknown aspect of these reactions prior to their discovery through the use of highly sensitive fluorescence microscopy methods, as will now be summarized.38

IV. Types of Additives and Solvents: Mechanistic Lessons Learned

Lithium halide salts

Piquing our interest, Knochel had discovered that organozinc reagents could be synthesized in THF via direct insertion of zinc into unactivated aryl iodides using lithium chloride as an activating agent (Figure 2a).14 This discovery increased the accessibility of these reagents by decreasing the reaction temperatures required for their synthesis, removing the need for high-boiling polar aprotic cosolvents (e.g., DMSO, DMF),11 and/or avoiding the need to have electron-withdrawing ortho substituents on the aryl iodide,14,29 and rapidly became a widespread synthetic protocol.

Figure 2.

Figure 2.

Open in a new tab

a. Addition of LiCl increases reactivity of organohalides towards oxidative addition but the mechanism was previously unclear; b. In-house designed BODIPY imaging agents employed to identify oxidative addition and solubilization steps on the surface of zinc metal powder.

In 2016, our laboratory investigated the mechanistic role of LiCl in accelerating organozinc formation by fluorescence microscopy. The experiment involved designing alkyl and aryl iodide fluorescent boron dipyrromethene (BODIPY) probes 1 and 2 (Figure 2b), which were capable of oxidative addition through their carbon–iodide bonds with metallic zinc powder of the same mesh and supplier as reported by Knochel (Figure 3a).14

Figure 3.

Figure 3.

Open in a new tab

a. Initial observation of organozinc surface intermediates and characterization of a two-main-step direct insertion mechanism; b. Oxidative addition of alkyl iodide at 25 °C and subsequent solubilization with LiCl; c. Oxidative addition of aryl iodide at 60 °C and subsequent solubilization with LiCl; d. Reaction coordinate diagram depicting effect of LiCl. Adapted from ref. 38 Copyright 2017. American Chemical Society.

Samples with 1 and 2 showed intense green fluorescent “hot spots” of oxidative addition intermediate 3 on the otherwise dark zinc-particle surfaces (Figure 3b and 3c). Intensity served as an indicator of quantity of material, with more material appearing brighter. In contrast, a control sample with BODIPY 1-control, which lacked the reactive carbon–iodide bond remained dark (not shown). Together, these experiments indicated accumulation of oxidative addition intermediate on the surface of the zinc, making it the first time organozinc intermediates had been detected on the surface of zinc metal during an oxidative addition reaction.

Addition of LiCl in the same flask resulted in removal of the intermediates, as seen by (re)generation of dark zinc powder. This data revealed the role of LiCl to be solubilization of the organozinc intermediates from the surface of zinc.40

These data therefore revealed that the formation of solution organozinc species is a two-primary-step mechanism: first formation of surface organozinc intermediates by oxidative addition, and second solubilization of those intermediates (Figure 3a). Thus, any activating procedures may accelerate both steps or one step selectively.

These surface reaction intermediates were in such low concentrations that alterative analytical techniques were insufficiently sensitive for their detection. Further, common surface characterization techniques (e.g., XPS, SEM, and EDS) typically require high vacuum,41 and therefore even if they were to become sensitive enough in the future, are not able to detect these surface intermediates under the conditions of the synthetic organic/organometallic reaction with solvent, substrate, and other reagents present.

A temperature dependence of oxidative addition by aryl iodide (60 °C) vs. alkyl iodides (25 °C) established that LiCl causes a switch of the rate-determining step from otherwise slow solubilization, to the oxidative addition step, by accelerating solubilization (Figure 3d)).38

Salt investigation by microscopy showed that LiCl, LiBr and LiI promoted solubilization of organozinc from the zinc surface, whereas LiF, (nBu)4NCl, NaCl, and LiOTf did not. 1H NMR spectroscopic analysis of NMR-scale synthetic reactions showed a difference in 1H NMR spectroscopy yields depending on which set (effective or ineffective at solubilization enhancement) of the above salts was used, and further, that the two sets of salts formed two different solution species. This finding allowed formulation of a mechanistic model explaining the difference between the effective and ineffective salts (Figure 4). It is hypothesized that LiCl, LiBr and LiI work by coordinating to the zinc to form “ate” complexes with soluble cations. Thus, they promote formation of more soluble (THF)nLi[RZnX2] which then disproportionates into R2Zn and (THF)nLi[ZnX3], whereas the ineffective salts LiF and LiOTf do not form zincates and therefore require mechanical stirring or heat for solubilization.

Figure 4.

Figure 4.

Open in a new tab

Model depicting formation of different organozinc species under different conditions. Adapted from ref. 38. Copyright 2017 American Chemical Society.

The formation of two different organozinc species (monoorganozinc halide and diorganozinc) in solution depended upon addition of effective lithium salt in THF. Control over the organozinc species formed is valuable for understanding potential differences in downstream reactivity. The selective choice over the species of organozinc formed allows for better synthetic planning and may inform on the potential of Negishi coupling reactions.42

The key mechanistic lessons learned are that the direct insertion mechanism contains two primary steps: 1) oxidative addition to form surface organozinc intermediate 3, and 2) solubilization of 3 to form solution organozinc complex 4. Further, lithium chloride accelerates the rate of formation of solution organozinc reagents through accelerating the solubilization step.

Polar aprotic solvents

Prior to the discovery of LiCl as an activating agent, the reaction of organohalides with zinc required polar aprotic solvents like DMSO and DMF to efficiently synthesize organozinc reagents.11 With the understanding of two main reaction steps it became conceivable that the reported solvent effect could accelerate either step (Figure 5). Specifically, 1) Unlike LiCl, apolar protic solvents accelerate oxidative addition to form the surface organozinc intermediates, or 2) similar to LiCl, the solubilization after oxidative addition occurred could be accelerated. As the two steps are not mutually exclusive, acceleration of both steps could also occur. At the time of our studies, it was challenging to find a direct rate comparison in solvents under identical conditions in the literature. The reported qualitative acceleration of solution organozinc formation in DMSO compared to in THF was reproduced quantitatively in our hands (kinetic runs, Figure 5b).39 These kinetic data quantified the accelerative effect of DMSO on the reaction overall but did not pinpoint its effect to an individual mechanistic step.

Figure 5.

Figure 5.

Open in a new tab

a. Potential effects of DMSO on the two elemental steps during organozinc formation on either (or both) of two primary steps; b. Bench-scale 1H NMR kinetics of organozinc formation in DMSO-d6 and THF-d8 quantify the accelerative effect of DMSO on the overall synthetic reaction. Adapted with permission from ref 39. Copyright 2020 Wiley-VCH GmbH.

Next, fluorescence microscopy methods were harnessed to pinpoint the effect of this acceleration to (an) individual step(s). Fluorescence microscopy functioned as a “snapshot” of the status by taking a quantifiable (by intensity) picture of the surface bound oxidative-addition intermediate at each stage. Thus, comparison of images with time and under different conditions identified at which point the reactivity in each solvent diverged.

Substantially more accumulation of oxidative-addition intermediate 6 on the surface of the zinc particles after 30 min occurred in DMSO (very bright) compared to THF (relatively dark), identifying the mechanistic influence of DMSO on lowering the barrier to Step 1 (Figure 6a). On the other hand, producing 6 first, followed by treatment with THF or DMSO, showed similar sustained persistence against solubilization in both solvents as indicated by continued intense fluorescence (Figure 6b). These experimental findings pinpoint the acceleration by DMSO (and by association possibly DMF) to the oxidative addition step but not the solubilization step. The granular mechanism of this acceleration, however, remains unknown.39

Figure 6.

Figure 6.

Open in a new tab

a. Fluorescence microscopy images comparing the effect of DMSO and THF on the rate of buildup of intermediate 6 during oxidative addition (Step 1); b. Images comparing the effect of DMSO and THF on the rate of solubilization (Step 2). Adapted with permission from ref 39. Copyright 2020 Wiley-VCH GmbH.

DMSO and organozinc halide form RZnI(DMSO) complex 8 observable by 1H NMR spectroscopy. This complex (8) is equilibrating in solution with organozinc iodide 7, as showcased by the addition of more DMSO which caused concurrent chemical shift change (Figure 7). These solution observations highlight that the structure of the ultimate organozinc reagent is solvent dependent.

Figure 7.

Figure 7.

Open in a new tab

Solvent dependence on structure of solution organozinc product. Adapted with permission from ref 39. Copyright 2020 Wiley-VCH GmbH.

The key mechanistic lessons learned from these experiments are that DMSO (and possibly other polar protic solvents) accelerate formation of organozinc solution species by (selectively) accelerating the oxidative addition step.

Salt byproducts in Rieke zinc

One notable method to activate zinc metal is to form “Rieke zinc.”18 (In addition to Rieke zinc, many other “Rieke metals” have been reported.18,43–50) Rieke zinc is generated through the (often in situ) reduction of zinc(II) salts, typically halides, by lithium naphthalenide or sodium metal.18,43,51,52 This reaction produces zinc that is highly reactive toward oxidative addition of organoiodides, organobromides31,53–55 and, in at least one example, organochlorides56. In contrast, commercial zinc powder exhibits lower reactivity, and is not reactive toward organochlorides, with the exception of a few activated substrates demonstrated by Knochel in 199032 and 1992,15 including benzyl chloride.

The higher reactivity of Rieke zinc had previously been attributed to three factors: its smaller particle size, its lack of oxide coating, and the foreign material embedded in its solids.50 Consistent with the latter, data from bulk analysis at the time showed that the metal powders generated from the Rieke’s preparations were complex mixtures containing C, H, O, halogens, and alkali metal.43 As will now be detailed, data from our laboratory decades later showed36 that this earlier conclusion missed a key activation mechanism. Thus, this case serves as a prime example of how information can be misinterpreted or lost without the ability to study small quantities of surface reaction intermediates.

Rieke zinc produced by lithium reduction of ZnCl2 produces LiCl salt byproduct. Rieke zinc synthesized this way and treated with imaging agent 2 appeared dark by fluorescence microscopy, i.e., the zinc surface did not show buildup of arylzinc reaction intermediate 9 on its surface.36 In contrast, sodium-reduced ZnCl2 (NaCl byproduct) did show buildup on intermediates (bright green “hot spots,” Figure 8a). Thus, the lithium-reduced Rieke zinc behaved similarly to commercial zinc to which solution-phase LiCl was added (see prior section of Synopsis). The conclusion from these data is that soluble LiCl byproduct in the supernatant was the mechanistic cause of the activation, through solubilization enhancement, a mechanism not suggested in the published studies by Rieke. Consistent with this conclusion, addition of exogeneous LiCl to alkylzinc intermediate 6 on the surface of sodium-reduced Rieke zinc led to its rapid solubilization to form 10 (Figure 8b).

Figure 8.

Figure 8.

Open in a new tab

a. Comparison of sodium- and lithium-reduced Rieke zinc observed by fluorescence microscopy; b. Sodium-reduced Rieke zinc, oxidative addition product solubilizes upon treatment with LiCl. Adapted from ref. 36. Copyright 2022 American Chemical Society.

These microscale observations correlated with macroscale rate enhancements. 1H NMR spectroscopy kinetics measurements of bench-scale direct insertion reactions with alkyl bromide 11 to form 12 or 13 identified LiCl as a viable activator of Rieke zinc, whether it was present “naturally” as a byproduct from reduction or added separately. Specifically, the supernatant from the generation of Rieke zinc through reduction only accelerated the rate of downstream organozinc formation in the case that it contained LiCl and not if it contained NaCl (compare orange and gray traces with blue trace, Figure 9 left; or gray trace with orange and blue traces, Figure 9 right).

Figure 9.

Figure 9.

Open in a new tab

Bulk scale reaction with sodium- and lithium-reduced Rieke zinc and the corresponding 1H NMR spectroscopy derived kinetics traces. Adapted from ref. 36. Copyright 2022 American Chemical Society.

The key mechanistic lessons learned from these experiments are that organozinc formation from Rieke zinc is accelerated in presence of LiCl through enhanced solubilization of the surface organozinc intermediates; This LiCl can be present either by 1) employing lithium for the reduction of ZnCl2 and then keeping the supernatant (where the LiCl resides) or 2) using alternative reductants but by then adding exogenous soluble LiCl. Option 1 is particularly noteworthy, as a subset of prior published procedures report a solvent exchange after reduction that removes the supernatant with its dissolved LiCl; these practitioners were presumably unaware of the impact of removal of the supernatant on suppressing the reactivity of the generated Rieke zinc toward oxidative addition.57–59 Further, exogenous addition of LiCl to enhance reactivity provides a substantially easier manipulation than the previously targeted alternative of morphology control of the solid Rieke zinc.17,52

Trimethylsilyl chloride (TMSCl)

The generally proposed mechanism of action of trimethylsilyl chloride (TMSCl) is removal of the oxide layers on zinc to reveal more metal(0) for oxidative addition. Studies by Utimoto were consistent with this proposal and also found an additional effect of TMSCl to overcome a suppressive effect of lead impurities.13 Later, scientists at Merck found that TMSCl counteracts metal agglomeration specifically when lead impurities are present.60

Most synthetic procedures do not remove the residual TMSCl, meaning that TMSCl is generally present in the subsequent organozinc-forming reaction mixture. Thus, we became interested in whether TMSCl may play a complementary role in accelerating steps after oxidative addition.

Fluorescence lifetime imaging microscopy (FLIM) allowed investigation into this question, by providing the ability to observe the effect of TMSCl on subsequent steps after the zinc preactivation step (Figure 10).61 Generally, fluorescence lifetime measurements enable imaging of environmental changes.62

Figure 10.

Figure 10.

Open in a new tab

a. Experimental schematic; b. False color FLIM images showing lifetime changes over time; c. Physisorption control experiment; d. Control without TMSCl. Adapted with permission from ref 61. Copyright 2023 Wiley-VCH GmbH.

In these experiments, the fluorescent intermediates (9) derived from aryl iodide imaging agent 2 and zinc treated with TMSCl13,60,63 showed a steady increase in fluorescence lifetime (from blue-to-red), consistent with less quenching as the organozinc complexes solubilized and moved further away from the bulk zinc surface (also seen in brightening of the solution background fluorescence, Figure 10b; images false-colored corresponding to fluorescence lifetime).

A control experiment with imaging agent 2-control, otherwise similar but without a C–I bond, excluded the possibility of physisorption causing the surface fluorescence (Figure 10c). A comparison without TMSCl revealed persistent intermediate 9 on the zinc surface, which remained constant in both intensity and lifetime (Figure 10d). These experiments combined allowed the conclusion that the microenvironment of the organozinc intermediate initially attached to the zinc surface slowly changed, which was consistent with its slow solubilization assisted by TMSCl.

While the exact mechanism of this TMSCl-promoted solubilization is not known, it was proposed that TMSCl could react with zinc in a redox process, as had been reported for the more reactive TMSI in the presence of tetramethylethylenediamine (Figure 11a).64 The result may be etching the surface (possibly reversibly) that may compromise the integrity of the zinc and lead to enhanced solubilization.

Figure 11.

Figure 11.

Open in a new tab

a. Proposed mechanism of the effect of TMSCl. b. 1H NMR spectroscopy kinetics characterize overall reaction rate acceleration. Adapted with permission from ref 61. Copyright 2023 Wiley-VCH GmbH.

Utimoto’s earlier kinetics studies established that TMSCl accelerated the overall reaction, specifically by reducing the induction period of organozinc formation, when used in combination with HCl.13 What was missing, however, was the effect of TMSCl alone (no HCl) on the rate of reaction. To distinguish the bulk scale effect of TMSCl on the organozinc formation alone, 1H NMR spectroscopic kinetic studies were conducted (Figure 11b). The results show an accelerated formation of solution state organozinc species when TMSCl is present and an induction period in absence of TMSCl.

The key mechanistic lessons learned from these experiments are introduction of an additional, previously unknown effect of TMSCl on zinc–organohalide reactions: acceleration of the solubilization of organozinc surface intermediates. Contrary to other actions of TMSCl that occur before oxidative addition, this solubilization effect occurs after oxidative addition.

V. Conclusions and Future Directions

The mechanistic understanding of solvents and additives on individual steps during organozinc formation provides an advance towards reaction prediction, stepping beyond the empirical screening approach. The primary guiding mechanistic lessons are that organozinc formation is a two-step process, which consists of initial formation of surface organozinc intermediates followed by their solubilization. The varying effects of different additives on the barriers of each step are summarized in Table 1.

Table 1.

Summary of the effects of additives, reductants and solvents on the organozinc formation.

Preparation Accelerates surface oxidative addition step? Accelerates solubilization of surface organozinc intermediate step?
LiCl in THF No Yes37,38,36
Polar aprotic solvent (DMSO) Yes39 No
TMSCl Probably, through removal of ZnO and reduction in agglomeration, but not studied as individual step13,60 Yes61
Rieke zinc Probably, through smaller particle size and no ZnO layer, but not studied as individual step18 Yes, when LiCl byproduct is present36
Open in a new tab

The formation of surface intermediates by oxidative addition is accelerated by polar aprotic solvent. The solubilization of these intermediates is accelerated by lithium salts with coordinating anions in THF through formation of soluble “ate” complexes (effective for both commercial powders and Rieke zinc), or by TMSCl, which appears to act through a distinct etching mechanism.

Future directions and outstanding questions include the granular mechanisms for TMSCl acceleration of solubilization and DMSO acceleration of oxidative addition, and determination of the extent to which mechanistic lessons learned may be extendable to promoting direct insertion reactions of other metals beyond zinc. For example, starting with LiCl for early indium direct insertion procedures (undoubtedly guided by the empirical findings for zinc),21,22 subsequent methods for direct insertion by aluminum, manganese, indium, and bismuth, identified lead salts,20,65 copper salts,23,66,67 cobalt salts,68 cesium carbonate,69 InCl3,19,20,65,70 and iodine71 as promotors—in some cases even multiple of these promotors in the same reaction. Development of these other-metal methods is also progressing without a granular, step-specific mechanistic understanding of the effects of additives. The frequent appearance of lithium halides as beneficial additives for direct insertion reactions19,20,24,25,72,73 further points to the potential of the mechanistic modes of action identified for zinc to be transferrable to other metals.

The fluorescence microscopy methods collected in this Synopsis present a valuable addition to acquire, up until now, hidden mechanistic details for heterogenous systems like this. Such mechanistic information enables preparative chemists and methods developers to make informed decisions in regard to additive, supernatant, and/or solvent choice toward more efficient reactions, thereby allowing for better control of reaction outcomes.

ACKNOWLEDGMENT

We thank the National Institutes of Health (R01GM131147) and the University of California, Irvine, for funding.

Biographies

graphic file with name nihms-2078023-b0002.gif

Martin Stang joined Prof. Suzanne A. Blum’s laboratory at the University of California, Irvine, for graduate studies, to develop electrophilic cyclizations with a focus on isolating reaction intermediates and the mechanistic understanding thus gained. He has a strong interest in NMR spectroscopy.

graphic file with name nihms-2078023-b0003.gif

Dr. Erin Hanada’s research interests focus on the mechanistic understanding and development of metal-mediated and metal-catalyzed reactions in organic synthesis. During graduate studies in Prof. Suzanne A. Blum’s laboratory at the University of California, Irvine, she developed fluorescence microscopy methods to investigate the mechanistic behaviors of organozinc intermediates.

graphic file with name nihms-2078023-b0004.gif

Prof. Suzanne A. Blum received a Ph.D as an NSF Graduate Fellow at UC-Berkeley under the guidance of Prof. Robert G. Bergman. She completed an NIH Postdoctoral Fellowship with Prof. Christopher T. Walsh at Harvard Medical School. Her research at UC-Irvine focuses on the mechanistic study of chemical reactions in organic synthesis and catalysis, where she and her laboratory design and develop sensitive fluorescence microscopy tools to image reaction intermediates and processes.

Footnotes

The authors declare no competing financial interest.

Data Availability Statement

The data underlying this study are available in the published article

REFERENCES

  • (1).Haas D; Hammann JM; Greiner R; Knochel P Recent Developments in Negishi Cross-Coupling Reactions. ACS Catal. 2016, 6 (3), 1540–1552. 10.1021/acscatal.5b02718. [DOI] [Google Scholar]
  • (2).Han C; Buchwald SL Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and Chlorides. J. Am. Chem. Soc 2009, 131 (22), 7532–7533. 10.1021/ja902046m. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (3).Casares JA; Espinet P; Fuentes B; Salas G Insights into the Mechanism of the Negishi Reaction: ZnRX versus ZnR2 Reagents. J. Am. Chem. Soc 2007, 129 (12), 3508–3509. 10.1021/ja070235b. [DOI] [PubMed] [Google Scholar]
  • (4).Joshi-Pangu A; Ganesh M; Biscoe MR Nickel-Catalyzed Negishi Cross-Coupling Reactions of Secondary Alkylzinc Halides and Aryl Iodides. Org. Lett 2011, 13 (5), 1218–1221. 10.1021/ol200098d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (5).Eckert P; Sharif S; Organ MG Salt to Taste: The Critical Roles Played by Inorganic Salts in Organozinc Formation and in the Negishi Reaction. Angew. Chemie Int. Ed 2021, 60 (22), 12224–12241. 10.1002/anie.202010917. [DOI] [PubMed] [Google Scholar]
  • (6).Achonduh GT; Hadei N; Valente C; Avola S; O’Brien CJ; Organ MG On the Role of Additives in Alkyl–Alkyl Negishi Cross-Couplings. Chem. Commun 2010, 46 (23), 4109–4111. 10.1039/C002759F. [DOI] [PubMed] [Google Scholar]
  • (7).Newman MS; Evans FJJ The Reformatsky Reaction: Effect of Alkyl Group in Alkyl α-Bromopropionates. J. Am. Chem. Soc 1955, 77 (4), 946–947. 10.1021/ja01609a043. [DOI] [Google Scholar]
  • (8).Gawroński JK Tandem Reformatsky Reactions of 2-Bromopropionates in the Presence of Chlorotrimethylsilane. Tetrahedron Lett. 1984, 25 (24), 2605–2608. 10.1016/S0040-4039(01)81242-9. [DOI] [Google Scholar]
  • (9).Picotin G; Miginiac P Activation of Zinc by Trimethylchlorosilane. An Improved Procedure for the Preparation of .Beta.-Hydroxy Esters from Ethyl Bromoacetate and Aldehydes or Ketones (Reformatsky Reaction). J. Org. Chem 1987, 52 (21), 4796–4798. 10.1021/jo00230a029. [DOI] [Google Scholar]
  • (10).Cahiez G; Chavant P-Y Organomanganese (II) Reagents XX: Manganese Mediated Barbier and Reformatsky like Reactions an Efficient Route to Homoallylic Alcohols and β-Acetoxyesters. Tetrahedron Lett. 1989, 30 (52), 7373–7376. 10.1016/S0040-4039(00)70700-3. [DOI] [Google Scholar]
  • (11).Huo S Highly Efficient, General Procedure for the Preparation of Alkylzinc Reagents from Unactivated Alkyl Bromides and Chlorides. Org. Lett 2003, 5 (4), 423–425. 10.1021/ol0272693. [DOI] [PubMed] [Google Scholar]
  • (12).Rathke MW The Reformatsky Reaction. In Organic Reactions; John Wiley & Sons, Inc., 2011; pp 423–460. 10.1002/0471264180.or022.04. [DOI] [Google Scholar]
  • (13).Takai K; Kakiuchi T; Utimoto K A Dramatic Effect of a Catalytic Amount of Lead on the Simmons-Smith Reaction and Formation of Alkylzinc Compounds from Iodoalkanes. Reactivity of Zinc Metal: Activation and Deactivation. J. Org. Chem 1994, 59 (10), 2671–2673. 10.1021/jo00089a003. [DOI] [Google Scholar]
  • (14).Krasovskiy A; Malakhov V; Gavryushin A; Knochel P Efficient Synthesis of Functionalized Organozinc Compounds by the Direct Insertion of Zinc into Organic Iodides and Bromides. Angew. Chemie Int. Ed 2006, 45 (36), 6040–6044. 10.1002/anie.200601450. [DOI] [PubMed] [Google Scholar]
  • (15).Jubert C; Knochel P Preparation of New Classes of Aliphatic, Allylic, and Benzylic Zinc and Copper Reagents by the Insertion of Zinc Dust into Organic Halides, Phosphates, and Sulfonates. J. Org. Chem 1992, 57 (20), 5425–5431. 10.1021/jo00046a026. [DOI] [Google Scholar]
  • (16).Duddu R; Eckhardt M; Furlong M; Knoess HP; Berger S; Knochel P Preparation and Reactivity of Chiral β-Amido-Alkylzinc Iodides and Related Configurationally Stable Zinc Organometallics. Tetrahedron 1994, 50 (8), 2415–2432. 10.1016/S0040-4020(01)86959-3. [DOI] [Google Scholar]
  • (17).Fürstner A Chemistry of and with Highly Reactive Metals. Angew. Chemie Int. Ed. English 1993, 32 (2), 164–189. 10.1002/anie.199301641. [DOI] [Google Scholar]
  • (18).Rieke RD Preparation of Highly Reactive Metal Powders and Their Use in Organic and Organometallic Synthesis. Acc. Chem. Res 1977, 10 (8), 301–306. 10.1021/ar50116a005. [DOI] [Google Scholar]
  • (19).Blümke T; Chen Y-H; Peng Z; Knochel P Preparation of Functionalized Organoaluminiums by Direct Insertion of Aluminium to Unsaturated Halides. Nat. Chem 2010, 2 (4), 313–318. 10.1038/nchem.590. [DOI] [PubMed] [Google Scholar]
  • (20).Peng Z; Knochel P Preparation of Functionalized Organomanganese(II) Reagents by Direct Insertion of Manganese to Aromatic and Benzylic Halides. Org. Lett 2011, 13 (12), 3198–3201. 10.1021/ol201109g. [DOI] [PubMed] [Google Scholar]
  • (21).Chen Y-H; Knochel P Preparation of Aryl and Heteroaryl Indium(III) Reagents by the Direct Insertion of Indium in the Presence of LiCl. Angew. Chemie Int. Ed 2008, 47 (40), 7648–7651. 10.1002/anie.200802292. [DOI] [PubMed] [Google Scholar]
  • (22).Papoian V; Minehan T Palladium-Catalyzed Reactions of Arylindium Reagents Prepared Directly from Aryl Iodides and Indium Metal. J. Org. Chem 2008, 73 (18), 7376–7379. 10.1021/jo801074g. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (23).Kim S; Kim C-E; Seo B; Lee PH In Situ Generation of Phosphoryl Alkylindiums and Their Synthetic Application to Arylalkyl Phosphonates via Palladium-Catalyzed Cross-Coupling Reactions. Org. Lett 2014, 16 (21), 5552–5555. 10.1021/ol502540z. [DOI] [PubMed] [Google Scholar]
  • (24).Shen Z-L; Wang S-Y; Chok Y-K; Xu Y-H; Loh T-P Organoindium Reagents: The Preparation and Application in Organic Synthesis. Chem. Rev 2013, 113 (1), 271–401. 10.1021/cr300051y. [DOI] [PubMed] [Google Scholar]
  • (25).Liu X-Y; Cheng B-Q; Guo Y-C; Chu X-Q; Li Y-X; Loh T-P; Shen Z-L Bismuth-Mediated Diastereoselective Allylation Reaction of Carbonyl Compounds with Cyclic Allylic Halides or Cinnamyl Halide. Adv. Synth. Catal 2019, 361 (3), 542–549. 10.1002/adsc.201801297. [DOI] [Google Scholar]
  • (26).Liu X-Y; Cheng B-Q; Guo Y-C; Chu X-Q; Rao W; Loh T-P; Shen Z-L Iron-Mediated Highly Diastereoselective Allylation of Carbonyl Compounds with Cyclic Allylic Halides. Org. Chem. Front 2019, 6 (10), 1581–1586. 10.1039/C9QO00210C. [DOI] [PubMed] [Google Scholar]
  • (27).Wu Z; Feng X-X; Wang Q-D; Liu X-Y; Rao W; Yang J-M; Shen Z-L An Efficient Bi/NH4I-Mediated Addition Reaction for the Highly Diastereoselective Synthesis of Homoallylic Alcohols in Aqueous Media. Chinese Chem. Lett 2020, 31 (2), 391–395. 10.1016/j.cclet.2019.07.030. [DOI] [Google Scholar]
  • (28).Hevia E; Mulvey RE Split Personality of Lithium Chloride: Recent Salt Effects in Organometallic Recipes. Angew. Chemie Int. Ed 2011, 50 (29), 6448–6450. 10.1002/anie.201102054. [DOI] [PubMed] [Google Scholar]
  • (29).Ikegami R; Koresawa A; Shibata T; Takagi K Functionalized Arylzinc Compounds in Ethereal Solvent: Direct Synthesis from Aryl Iodides and Zinc Powder and Application to Pd-Catalyzed Reaction with Allylic Halides. J. Org. Chem 2003, 68 (6), 2195–2199. 10.1021/jo026746s. [DOI] [PubMed] [Google Scholar]
  • (30).Metzger A; Schade MA; Knochel P LiCl-Mediated Preparation of Highly Functionalized Benzylic Zinc Chlorides. Org. Lett 2008, 10 (6), 1107–1110. 10.1021/ol7030697. [DOI] [PubMed] [Google Scholar]
  • (31).Guijarro A; Rosenberg DM; Rieke RD The Reaction of Active Zinc with Organic Bromides. J. Am. Chem. Soc 1999, 121 (17), 4155–4167. 10.1021/ja9844478. [DOI] [Google Scholar]
  • (32).Berk SC; Yeh MCP; Jeong N; Knochel P Preparation and Reactions of Functionalized Benzylic Organometallics of Zinc and Copper. Organometallics 1990, 9 (12), 3053–3064. 10.1021/om00162a016. [DOI] [Google Scholar]
  • (33).Koszinowski K; Böhrer P Formation of Organozincate Anions in LiCl-Mediated Zinc Insertion Reactions. Organometallics 2009, 28 (3), 771–779. 10.1021/om800947t. [DOI] [Google Scholar]
  • (34).Fleckenstein JE; Koszinowski K Lithium Organozincate Complexes LiRZnX2: Common Species in Organozinc Chemistry. Organometallics 2011, 30 (18), 5018–5026. 10.1021/om200637s. [DOI] [Google Scholar]
  • (35).Hunter HN; Hadei N; Blagojevic V; Patschinski P; Achonduh GT; Avola S; Bohme DK; Organ MG Identification of a Higher-Order Organozincate Intermediate Involved in Negishi Cross-Coupling Reactions by Mass Spectrometry and NMR Spectroscopy. Chem. – A Eur. J 2011, 17 (28), 7845–7851. 10.1002/chem.201101029. [DOI] [PubMed] [Google Scholar]
  • (36).Hanada EM; Tagawa TKS; Kawada M; Blum SA Reactivity Differences of Rieke Zinc Arise Primarily from Salts in the Supernatant, Not in the Solids. J. Am. Chem. Soc 2022, 144 (27), 12081–12091. 10.1021/jacs.2c02471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (37).Jess K; Kitagawa K; Tagawa TKS; Blum SA Microscopy Reveals: Impact of Lithium Salts on Elementary Steps Predicts Organozinc Reagent Synthesis and Structure. J. Am. Chem. Soc 2019, 141 (25), 9879–9884. 10.1021/jacs.9b02639. [DOI] [PubMed] [Google Scholar]
  • (38).Feng C; Easter QT; Blum SA Structure–Reactivity Studies, Characterization, and Transformation of Intermediates by Lithium Chloride in the Direct Insertion of Alkyl and Aryl Iodides to Metallic Zinc Powder. Organometallics 2017, 36 (13), 2389–2396. 10.1021/acs.organomet.6b00910. [DOI] [Google Scholar]
  • (39).Hanada EM; Jess K; Blum SA Mechanism of an Elusive Solvent Effect in Organozinc Reagent Synthesis. Chem. – A Eur. J 2020, 26 (66), 15094–15098. 10.1002/chem.202002214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (40).Feng C; Cunningham DW; Easter QT; Blum SA Role of LiCl in Generating Soluble Organozinc Reagents. J. Am. Chem. Soc 2016, 138 (35), 11156–11159. 10.1021/jacs.6b08465. [DOI] [PubMed] [Google Scholar]
  • (41).Copéret C; Chabanas M; Petroff Saint-Arroman R; Basset J-M Homogeneous and Heterogeneous Catalysis: Bridging the Gap through Surface Organometallic Chemistry. Angew. Chemie Int. Ed 2003, 42 (2), 156–181. 10.1002/anie.200390072. [DOI] [PubMed] [Google Scholar]
  • (42).Rio J; Perrin L; Payard P-A Structure–Reactivity Relationship of Organozinc and Organozincate Reagents: Key Elements towards Molecular Understanding. European J. Org. Chem 2022, 2022 (44), e202200906. 10.1002/ejoc.202200906. [DOI] [Google Scholar]
  • (43).Rieke RD Preparation of Organometallic Compounds from Highly Reactive Metal Powders. Science 1989, 246 (4935), 1260–1264. 10.1126/science.246.4935.1260. [DOI] [PubMed] [Google Scholar]
  • (44).Ebert G; Rieke RD Direct Formation of Organocopper Compounds by Oxidative Addition of Zerovalent Copper to Organic Halides. J. Org. Chem 1984, 49 (26), 5280–5282. 10.1021/jo00200a064. [DOI] [Google Scholar]
  • (45).Rieke RD; Kavaliunas AV Preparation of Highly Reactive Metal Powders. Preparation and Reactions of Highly Reactive Palladium and Platinum Metal Slurries. J. Org. Chem 1979, 44 (17), 3069–3072. 10.1021/jo01331a022. [DOI] [Google Scholar]
  • (46).Kavaliunas AV; Taylor A; Rieke RD Preparation of Highly Reactive Metal Powders. Preparation, Characterization, and Chemistry of Iron, Cobalt, Nickel, Palladium, and Platinum Microparticles. Organometallics 1983, 2 (3), 377–383. 10.1021/om00075a004. [DOI] [Google Scholar]
  • (47).Rieke RD; Li PT-J; Burns TP; Uhm ST Preparation of Highly Reactive Metal Powders. New Procedure for the Preparation of Highly Reactive Zinc and Magnesium Metal Powders. J. Org. Chem 1981, 46 (21), 4323–4324. 10.1021/jo00334a056. [DOI] [Google Scholar]
  • (48).Rieke RD; Wolf WJ; Kujundzic N; Kavaliunas AV Highly Reactive Transition Metal Powders. Oxidative Insertion of Nickel, Palladium, and Platinum Metal Powders into Aryl-Halide Bonds. J. Am. Chem. Soc 1977, 99 (12), 4159–4160. 10.1021/ja00454a046. [DOI] [Google Scholar]
  • (49).Rieke RD; Rhyne LD Preparation of Highly Reactive Metal Powders. Activated Copper and Uranium. The Ullmann Coupling and Preparation of Organometallic Species. J. Org. Chem 1979, 44 (19), 3445–3446. 10.1021/jo01333a050. [DOI] [Google Scholar]
  • (50).Rieke RD Chemical Synthesis Using Highly Reactive Metals; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2017. 10.1002/9781118929124. [DOI] [Google Scholar]
  • (51).Rieke RD; Uhm SJ; Hudnall PM Activated Metals. Preparation of Highly Reactive Zinc. J. Chem. Soc. Chem. Commun 1973, No. 8, 269b–270. 10.1039/C3973000269B. [DOI] [Google Scholar]
  • (52).Kudret S; Haen JD; Lutsen L; Vanderzande D; Maes W An Efficient and Reliable Procedure for the Preparation of Highly Reactive Rieke Zinc. Adv. Synth. Catal 2013, 355 (2–3), 569–575. 10.1002/adsc.201201077. [DOI] [Google Scholar]
  • (53).Rieke RD; Hanson MV; Brown JD; Niu QJ Direct Formation of Secondary and Tertiary Alkylzinc Bromides and Subsequent Cu(I)-Mediated Couplings. J. Org. Chem 1996, 61 (8), 2726–2730. 10.1021/jo952104b. [DOI] [PubMed] [Google Scholar]
  • (54).Hanson MV; Brown JD; Rieke RD; Niu QJ Direct Formation of Secondary and Tertiary Alkylzinc Bromides. Tetrahedron Lett. 1994, 35 (39), 7205–7208. 10.1016/0040-4039(94)85361-4. [DOI] [PubMed] [Google Scholar]
  • (55).Guijarro A; Rieke RD Structure–Reactivity Relationship in the Reaction of Highly Reactive Zinc with Alkyl Bromides. Angew. Chemie Int. Ed 1998, 37 (12), 1679–1681. . [DOI] [PubMed] [Google Scholar]
  • (56).Hanson M; Rieke RD Direct Formation of Alkylzevc Chlorides Using a New Active Zinc. Synth. Commun 1995, 25 (1), 101–104. 10.1080/00397919508010794. [DOI] [Google Scholar]
  • (57).Anderl F; Größl S; Wirtz C; Fürstner A Total Synthesis of Belizentrin Methyl Ester: Report on a Likely Conquest. Angew. Chem. Int. Ed. Engl 2018, 57 (33), 10712–10717. 10.1002/anie.201805125. [DOI] [PubMed] [Google Scholar]
  • (58).Tissot M; Body N; Petit S; Claessens J; Genicot C; Pasau P Synthesis of Electron-Deficient Heteroaromatic 1,3-Substituted Cyclobutyls via Zinc Insertion/Negishi Coupling Sequence under Batch and Automated Flow Conditions. Org. Lett 2018, 20 (24), 8022–8025. 10.1021/acs.orglett.8b03588. [DOI] [PubMed] [Google Scholar]
  • (59).Kealey S; Passchier J; Huiban M Negishi Coupling Reactions as a Valuable Tool for [11C]Methyl-Arene Formation; First Proof of Principle. Chem. Commun 2013, 49 (96), 11326–11328. 10.1039/C3CC47203E. [DOI] [PubMed] [Google Scholar]
  • (60).Yin J; Maguire CK; Yasuda N; Brunskill APJ; Klapars A Impact of Lead Impurities in Zinc Dust on the Selective Reduction of a Dibromoimidazole Derivative. Org. Process Res. Dev 2017, 21 (1), 94–97. 10.1021/acs.oprd.6b00370. [DOI] [Google Scholar]
  • (61).Hanada EM; McShea PJ; Blum SA Trimethylsilyl Chloride Aids in Solubilization of Oxidative Addition Intermediates from Zinc Metal. Angew. Chemie Int. Ed 2023, 62 (43), e202307787. 10.1002/anie.202307787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (62).López PA; Blum SA Fluorescence Lifetime Imaging Microscopy (FLIM) as a Tool to Understand Chemical Reactions and Catalysis. ACS Catal. 2024, 14 (22), 17132–17147. 10.1021/acscatal.4c05450. [DOI] [Google Scholar]
  • (63).Hanada EM; Lou H; McShea PJ; Blum SA Metal Activation Produces Different Reaction Environments for Intermediates during Oxidative Addition. Chem. – A Eur. J 2024, 30 (14), e202304105. 10.1002/chem.202304105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (64).Chandrasekaran R; Pulikkottil FT; Elama KS; Rasappan R Direct Synthesis and Applications of Solid Silylzinc Reagents. Chem. Sci 2021, 12 (47), 15719–15726. 10.1039/D1SC06038D. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (65).Chen B-Z; Wang C-X; Jing Z-H; Chu X-Q; Loh T-P; Shen Z-L Metallic Salt-Catalyzed Direct Indium Insertion into Alkyl Iodides and Their Applications in Cross-Coupling Reactions. Org. Chem. Front 2019, 6 (3), 313–318. 10.1039/C8QO01244J. [DOI] [PubMed] [Google Scholar]
  • (66).Shen Z-L; Goh KKK; Yang Y-S; Lai Y-C; Wong CHA; Cheong H-L; Loh T-P Direct Synthesis of Water-Tolerant Alkyl Indium Reagents and Their Application in Palladium-Catalyzed Couplings with Aryl Halides. Angew. Chemie Int. Ed 2011, 50 (2), 511–514. 10.1002/anie.201005798. [DOI] [PubMed] [Google Scholar]
  • (67).Shen Z-L; Goh KKK; Wong CHA; Yang Y-S; Lai Y-C; Cheong H-L; Loh T-P Direct Synthesis of Ester-Containing Indium Homoenolate and Its Application in Palladium-Catalyzed Cross-Coupling with Aryl Halide. Chem. Commun 2011, 47 (16), 4778–4780. 10.1039/C0CC05597B. [DOI] [PubMed] [Google Scholar]
  • (68).Wang P; Song X-D; Chen B-Z; Rao W; Shen Z-L Cobalt(II)-Catalyzed Preparation of Alkylindium Reagents and Applications in Cross-Coupling with Aryl Halides. Catal. Commun 2019, 132, 105824. 10.1016/j.catcom.2019.105824. [DOI] [Google Scholar]
  • (69).Feng X-X; Wu Z; Wang Q-D; Chen B-Z; Rao W; Yang J-M; Shen Z-L Cesium Carbonate-Catalyzed Indium Insertion into Alkyl Iodides and Their Synthetic Utilities in Cross-Coupling Reactions. Appl. Organomet. Chem 2019, 33 (9), e5110. 10.1002/aoc.5110. [DOI] [Google Scholar]
  • (70).Shen Z-L; Goh KKK; Cheong H-L; Wong CHA; Lai Y-C; Yang Y-S; Loh T-P Synthesis of Water-Tolerant Indium Homoenolate in Aqueous Media and Its Application in the Synthesis of 1,4-Dicarbonyl Compounds via Palladium-Catalyzed Coupling with Acid Chloride. J. Am. Chem. Soc 2010, 132 (45), 15852–15855. 10.1021/ja106925f. [DOI] [PubMed] [Google Scholar]
  • (71).Zhi M-L; Chen B-Z; Deng W; Chu X-Q; Loh T-P; Shen Z-L Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct Indium Insertion and Their Applications in Cross-Coupling Reactions. J. Org. Chem 2019, 84 (5), 3017–3023. 10.1021/acs.joc.9b00204. [DOI] [PubMed] [Google Scholar]
  • (72).Zhao K; Shen L; Shen Z-L; Loh T-P Transition Metal-Catalyzed Cross-Coupling Reactions Using Organoindium Reagents. Chem. Soc. Rev 2017, 46 (3), 586–602. 10.1039/C6CS00465B. [DOI] [PubMed] [Google Scholar]
  • (73).Araki S; Ito H; Butsugan Y Indium in Organic Synthesis: Indium-Mediated Allylation of Carbonyl Compounds. J. Org. Chem 1988, 53 (8), 1831–1833. 10.1021/jo00243a052. [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data underlying this study are available in the published article

RESOURCES