Why LiCl accelerates the formation of organozinc reagents
In order to investigate the mechanism of a chemical reaction, people have developed more and more testing methods for analysis and verification. With the increasing number and complexity of reaction types, the existing analytical methods are sometimes unable to meet the demand for mechanism studies. For example, Prof. Paul Knochel of the University of Munich, Germany, made an important contribution to the study of organometallic reagents (e.g., Grignard reagents and organozinc reagents.) In 2006, he discovered that LiCl could accelerate the insertion of metal Zn into halogenated hydrocarbons to form organozinc reagents, whereas before only Grignard reagents could be prepared by direct insertion of metal monomers into the halogenated hydrocarbons. This discovery subsequently led to the efficient synthesis of a series of other organometallic reagents, such as organoindium, organomanganese, and organoaluminum reagents.
However, the role of LiCl in accelerating the formation of organozinc reagents and the changes in the structure of organozinc reagents is not well understood. Previous studies have speculated that LiCl may have the following effects: (1) LiCl can promote the dissolution of the formed organozinc reagent, effectively exposing the zinc metal surface to continue to participate in the reaction; (2) LiCl can promote the electron transfer process by electrophilic activation of halogenated aromatic hydrocarbons through complexation with their aromatic rings; (3) LiCl solution has a high ionic strength, which promotes the separation of charges and accelerates the insertion of the metal. However, these hypotheses have not been confirmed by corresponding experiments.
Recently, Prof. Suzanne A. Blum of the University of California, Irvine, combined single-metal particle fluorescence microscopy with NMR 1H spectroscopy to explain this problem. Single-metal particle fluorescence microscopy is sensitive up to the single-molecule level and provides important information about the formation of intermediates in the radical reaction, overcoming the previous limitations of other analytical tools that have been insufficiently sensitive in monitoring the reaction. Nuclear magnetic resonance spectroscopy analysis, on the other hand, provides information on the total reaction rate and product structure. The combination of the two yields information on the effect of different lithium salts on each of the radical steps in the synthesis of organometallic reagents as well as the structure of the organozinc reagent in solution, thus laying an important foundation for the further expansion of similar salt-promoted effects as well as other types of organometallic reagents. The work has been published in J. Am. Chem. Soc.
▲Single-metal particle fluorescence microscopy coupled with nuclear magnetic resonance 1H spectroscopy
The authors firstly designed single-particle fluorescence microscopy characterization experiments using iodobutane (1), which modifies the fluorescent probe structure, as the oxidative addition developer. The fluorescent luminescent structure is boron fluoride complexed dipyrrole methacrylate (BODIPY), which can be used to label and track the reaction site of iodobutane inserted into Zn monomers to form the surface intermediate of oxidative addition (2).1 When it is not involved in the reaction it diffuses rapidly in the solution state, and therefore no fluorescent imaging can be observed, whereas when it is used for the oxidative addition of Zn to form 2 on a metal surface the fluorescent luminescent moiety stays in the absence of mechanical disturbance. When the oxidative addition of Zn to the metal surface forms 2, the fluorescent light-emitting group remains static without mechanical perturbation, and a bright green “hot spot” appears on the surface of the non-light-emitting Zn particles.
Flowchart of the method of fluorescence microscopy analysis of monometallic particles
In the absence of any lithium salt, the bright green 2 was stable, but after adding LiCl, it rapidly dissolved and the fluorescence disappeared. The authors also examined the effect of other lithium halides (LiX, X = F, Br, I) salts and LiOTf on 2 and found that LiBr and LiI could be used equally well as additives to facilitate the synthesis of organozinc reagents. They also stirred and heated the system without the addition of any lithium salt, respectively, and the experimental results showed that the former led to a partial dissolution of 2, while the latter led to a substantial dissolution of 2, but at a significantly slower rate than in the presence of LiX (X = Cl, Br, I). This important information cannot be obtained by traditional detection means, thus demonstrating the great advantage of fluorescence microscopy in terms of sensitivity and spatial localization.
▲Fluorescence microscopy analysis of the changes in the reaction system after the addition of different lithium salts.
▲Fluorescence microscopy analysis of the effect of different operations on the reaction system without adding lithium salt.
In order to verify whether the results observed by fluorescence microscopy can effectively predict which salt can promote the synthesis of organozinc reagents, the authors further designed NMR 1H spectroscopy experiments to investigate the reaction of (2-iodoethyl)benzene (4) as a template substrate for its conversion to the corresponding organozinc reagent (5). They found that the conversion was low in the absence of lithium salts as well as in the addition of LiX (X = F, OTf) (denoted as group 1), whereas the reaction occurred at almost quantitative conversions with the addition of LiX (X = Cl, Br, I) (denoted as group 2). From this, it can be inferred that group 2 lithium salts are soluble
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