Cross coupling
Under cross-coupling is understood coupling reactions between two different molecules wherein organometallic catalyzed carbon -carbon bonds are formed.
meaning
Cross-coupling is an important tool in preparative organic chemistry and is of particular importance in the synthesis of drug libraries in order to investigate structure-activity relationships (SAR).
The organometallic compounds and complexes used here can be produced relatively easily via metalation , transmetalation or halogen-metal exchange or insertion into a halogen - carbon bond. Most cross-coupling reactions are transition metal catalyzed reactions. The platinum elements such as palladium and platinum are particularly important here. But comparatively inexpensive metals such as iron are also used here.
history
Until the 1960s, only coupling reactions of the Wurtz-Fittig type were known. In this process, an organometallic compound is reacted with a halide to form the coupling product and the cleavage of the corresponding metal halide. Here, organic lithium and magnesium compounds are of particular importance. The reactions are usually not catalyzed but are stoichiometric reactions. However, these old uncatalyzed couplings are limited to a few substrates such as alkyl , allyl , and benzyl halides. The implementation with z. B. vinyl or phenyl halides is not possible in this way, and the yields of this type of coupling are often quite modest. As a result, this type of cross-coupling has hardly achieved any importance.
It was only with the Stephens-Castro coupling in 1963 that the prototype of the modern cross-coupling was discovered. In this uncatalyzed coupling, a copper acetylide is converted into an aryl-acetylene coupling.
In 1972, the coupling reaction named after him was discovered by Kumada . In this reaction, catalyzed by nickel phosphine or palladium phosphine complexes, Grignard compounds are coupled with alkenyl or aryl halides in the sense of a Wurtz-Fittig coupling. In today's sense, however, it is not a question of cross-coupling, since the targeted coupling of two different reactants was still difficult to control.
Later, in 1977, Ei-ichi Negishi published the first true cross-coupling with the reaction named after him . In this coupling between an aryl halide and a zinc organyl, unsymmetrical biaryl compounds are produced under nickel or palladium catalysis. This laid the foundation for today's cross couplings. Other types of cross-coupling then followed, all of which are still important today and have made the classic coupling reactions practically meaningless.
Negishi, Richard Fred Heck, and Akira Suzuki were awarded the Nobel Prize in Chemistry in 2010 for their work on cross-coupling .
Palladium-, platinum-, and nickel-catalyzed cross-couplings
Most of the cross-couplings that are still important today are catalyzed by palladium, platinum or nickel - where palladium is again the most important. In industrial processes, however, one is tempted to switch to cheaper metals as a catalyst.
Reaction mechanism
Today's conception of the mechanism of the cross-coupling reaction is the same for all reaction types. During the catalytic cycle, the metal atom changes its oxidation state twice. In order for an asymmetric coupling to be possible, both reactants must be activated differently. Normally one of the reactants is provided with a leaving group , in whose bond with the carbon atom the metal atom of the catalyst can insert via an oxidative addition . In the next step, the organometallic compound is transmetallated with the catalyst-substrate complex. By means of reductive elimination , the catalyst is released in the original oxidation state and the coupling product is formed in the process.
Examples
- Kumada clutch
- The strong basicity of the reagent can be problematic when using the Kumada coupling. Therefore base-sensitive substrates can usually not be used, many functional groups are not tolerated, e.g. B. ketones and aldehydes that enter into addition reactions with the reagent (see also: Grignard reaction ).
- Negishi clutch
- The Negishi coupling tolerates many functional groups on the substrate. It is a very mild method and is therefore widely used. (Possible disadvantage: it must be possible to produce the reagent from the respective iodinated species. This is a technically complex method because it requires a lot of energy.)
- Silence coupling
- The Stille coupling also tolerates many functional groups on the substrate; it is the mildest of the methods presented. The reagent is neutral towards Brønsted acids and bases. However, the toxicity of the reagent is problematic, as is the case with most organotin compounds (see tributyltin hydride ).
- Suzuki clutch
- The Suzuki coupling is the most advanced method of cross-coupling. Even if the (mostly non-toxic) reagent is slightly basic, most of the functional groups are tolerated. The great advantage of this method is that residues R and R 'can also be linked via sp³-hybridized carbons.
Exceptions
Cacchi and Sonogashira (Hagihara) cross couplings
The principle of Cacchi and Sonogashira (Hagihara) cross-couplings is related to the cross-couplings already mentioned, so olefinic or aromatic substrates are also linked to one another on a palladium complex. However, they proceed via a completely different mechanism, which is described in the article of the same name.
Heck reaction
The Heck reaction is an important organic chemical name reaction for the palladium- catalyzed production of aryl olefins . Due to its special mechanism, it is not a classic cross-coupling and is therefore not dealt with individually here, but is listed here due to its ability to link two different substrates through C — C bond formation.
Cu-catalyzed cross-coupling
The following are to be mentioned as copper-catalyzed cross-couplings:
- Stephens-Castro coupling : preparation of arylalkynes from aryl iodides and terminal alkynes
- Cadiot-Chodkiewicz coupling : preparation of conjugated diynes from a terminal alkyne and a bromoalkyne
See also
Individual evidence
- ↑ Kohei Tamao, Koji Sumitani, Makoto Kumada: Selective carbon-carbon bond formation by cross-coupling of Grignard reagents with organic halides. Catalysis by nickel-phosphine complexes . In: Journal of the American Chemical Society . tape 94 , no. June 12 , 1972, p. 4374-4376 , doi : 10.1021 / ja00767a075 .
- ↑ RJP Corriu, JP Masse: Activation of Grignard reagents by transition-metal complexes. A new and simple synthesis of trans-stilbenes and polyphenyls . In: Journal of the Chemical Society, Chemical Communications . No. 3 , January 1, 1972, p. 144a , doi : 10.1039 / C3972000144A .
- ↑ Kohei Tamao et al: Nickel-phosphine complex-catalyzed Grignard coupling. I. Cross-coupling of alkyl, aryl, and alkenyl Grignard reagents with aryl and alkenyl halides: General scope and limitations. In: Bulletin of the Chemical Society of Japan . tape 49 , no. 7 , 1976, p. 1958–1969 , doi : 10.1246 / bcsj.49.1958 .
- ↑ Dennis G. Morrell, Jay K. Kochi: Mechanistic studies of nickel catalysis in the cross coupling of aryl halides with alkylmetals. Role of arylalkylnickel (II) species as intermediates . In: Journal of the American Chemical Society . tape 97 , no. December 25 , 1975, p. 7262-7270 , doi : 10.1021 / ja00858a011 .
- ↑ E. Negishi, T. Takahashi, S. Baba, DE Van Horn, N. Okukado: Palladium- or Nickel-Catalyzed Reactions of Alkenylmetals with Unsaturated Organic Halides as a Selective Route to Arylated Alkenes and Conjugated Dienes: Scope, Limitations, and Mechanism . In: Journal of the American Chemical Society . tape 109 , no. 8 , April 15, 1987, pp. 2393 .
Web links
In the portal for organic chemistry :
Pd-, Pt-, Ni-catalyzed cross-couplings
Cu-catalyzed cross-coupling