Why LiCl accelerates the formation of organozinc reagents
In order to investigate the mechanism of action of a chemical reaction, more and more assays have been developed 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 mechanistic 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, organozinc reagents) when he discovered in 2006 that LiCl could accelerate the insertion of halogenated hydrocarbons into metal Zn to form organozinc reagents, whereas until then only Grignard reagents could be prepared by direct insertion of halogenated hydrocarbons into metal monomers. This discovery subsequently led to the efficient synthesis of a series of other organometallic reagents, such as organoindium, organomanganese, and organoaluminum reagents.
However, there is no clear understanding of the role of LiCl in accelerating the formation of organozinc reagents and the changes in the structure of organozinc reagents. Previous studies speculated that the possible effects of LiCl are as follows: (1) LiCl can promote the dissolution of the formed organozinc reagents and effectively expose the zinc metal surface to continue to participate in the reaction; (2) LiCl can promote the electron transfer process by complexing with the aromatic rings of halogenated aromatic hydrocarbons for their electrophilic activation; (3) LiCl solutions have high ionic strength, which can promote charge separation and accelerate metal insertion. However, these hypotheses have not been confirmed by corresponding experiments.
Recently, Professor Suzanne A. Blum of the University of California, Irvine, combined single-metal particle fluorescence microscopy with nuclear magnetic resonance 1H spectroscopy to explain this problem. The sensitivity of single-metal particle fluorescence microscopy up to the single-molecule level provides important information on the formation of intermediates in the matrix reaction, overcoming the previous limitations of the lack of sensitivity when monitoring the reaction by other analytical means. Nuclear magnetic resonance spectroscopy, on the other hand, provides information on the total reaction rate and product structure. The combination of the two allows for the derivation of the effects of different lithium salts on each radical step in the synthesis of organometallic reagents and the structure of organozinc reagents in solution, thus providing an important basis for further expansion of similar salt-promoting effects as well as other types of organometallic reagents. The related work was published in the well-known chemistry journal J. Am. Chem. Soc.
▲ Single-metal particle fluorescence microscopy coupled with nuclear magnetic resonance 1H spectroscopy (Image credit: Ref. [1])
The authors first designed single-particle fluorescence microscopy characterization experiments using iodobutane (1) with a modified fluorescent probe structure as an oxidative addition developer. The fluorescent luminescent structure is boron fluoride complexed dipyrrole methacuan (BODIPY), which can be used to label and track the reaction site of iodobutane inserted into Zn monomers to form an oxidative addition surface intermediate (2).1 When not involved in the reaction, it diffuses rapidly in the solution state, so no fluorescence imaging is observed, while when its oxidative addition to Zn forms 2 on the metal surface, the fluorescent luminescent group without mechanical perturbation remains The surface of the non-luminous Zn particles will appear as a bright green “hot spot” at this time.
▲ Flow chart of the method of fluorescence microscopy analysis of single metal particles (image source: Ref. [1])
In the absence of any lithium salt addition, the bright green 2 is stable, but the fluorescence disappears when LiCl is added and dissolves rapidly. The authors also examined the effect of other lithium halide (LiX, X = F, Br, I) salts and LiOTf on 2 and found that LiBr and LiI can be used as additives to facilitate the synthesis of organozinc reagents as well. They also stirred and heated the system without adding any lithium salt, respectively, and the experimental results showed that the former led to partial dissolution of 2, while the latter led to 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 conventional detection means, thus demonstrating the great advantage of fluorescence microscopy in terms of sensitivity and spatial localization.
Image ▲ Fluorescence microscopy analysis of the changes of the reaction system after adding different lithium salts (Image source: Ref. [1])
▲Fluorescence microscopy analysis of the effect of different operations on the reaction system without the addition of lithium salt (Image source: Ref. [1])
In order to verify whether the results observed by fluorescence microscopy can effectively predict which salt can facilitate the synthesis of organozinc reagents, the authors further designed NMR1H 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 without the addition of lithium salt as well as with the addition of LiX (X = F, OTf) (noted as group 1), while the reaction occurred at almost quantitative conversion with the addition of LiX (X = Cl, Br, I) (noted as group 2). It can be inferred that group 2 lithium salts can dissolve the oxidative addition surface intermediates formed on the surface of zinc metal (2), which is an important reason for the accelerated formation of organozinc reagents.
At the same time, they also found that the chemical shifts and peak shapes of the α-position methylene 1H characteristic peaks of the organozinc reagents obtained from the two groups of experiments were obviously different by NMR 1H spectroscopy and had different structures in solution. Based on these experimental results, the authors propose a theoretical and predictive model for the formation of organozinc reagents promoted by lithium salts.
Thus, Professor Suzanne A. Blum has experimentally confirmed the reason why LiCl accelerates the formation of organozinc reagents and demonstrated the important role of combining different analytical tools in investigating the reaction mechanism. Fluorescence microscopy has shown irreplaceable advantages in terms of detection sensitivity compared to conventional analytical tools. Reviewing the outstanding questions in previous mechanistic studies, one may consider to design reasonable reaction models for further exploration with the help of this method.
