Alkyne copper-free, mechanism

Bohm, V. P. W., Herrmann, W. A. Coordination chemistry and mechanisms of metal-catalyzed C-C coupling reactions, 13 a copper-free procedure for the palladium-catalyzed Sonogashira reaction of aryl bromides with terminal alkynes at room temperature. Eur. J. Org. Chem. 2000,3679-3681. 

POC-click is formed by thermo-cross-linking the mixture of pre-POC-N (azide-containing POC prepolymer) and pre-POC-Al (alkyne-containing POC prepolymer) the process applies synchronous binary cross-link mechanism, esterification, and thermal click reaction, and the residual azide groups on the surface of POC-click film or scaffold paved the way of surface bioconjugation through strain-promoted alkyne-azide cycloaddition (SPAAC), another copper-free click reaction. 

Two alternative mechanisms are proposed for the copper-free Sonogashira reactions, performed from Phi and HO—CH GHj—C=CH (Scheme 19.34) path A when the alkyne is a better ligand than the amine for the Pd center in PhPdlL [43a, c] or path B when the amine is a better ligand than the alkyne [43a]. This explains why the catalytic reactions are very sensitive to the base (path B more efficient than path A) [43a]. Consequently, the amine does not react as a simple base in copper-free Sonogashira reactions but may also be involved as ligand for aryl-Pd complexes [43a, b]. 

Over the last years, two reaction mechanisms proposed for the copper-free Sonogashira reaction have been somewhat discussed in the literature. Recently, the experimental group of Martensson demonstrated that one of them can be discarded, and further proposed two alternatives for the other mechanism on the basis of the electronic nature of the alkyne s substituents. Hence, in order to shed light on the reaction mechanism for this process, we decided to carry out a theoretical study in close contact with the experimental group of Prof. Carmen Nijera with the following main objectives ... 

As above stated, the reaction steps in the anionic mechanism take place in reverse order than in the cationic mechanism (Fig. 5.8). Thus, in the anionic mechanism the deprotonation of the alkyne by the external base in complex 2 occurs first, followed by the iodide-for-phosphine substitution. The Gibbs energy profile obtained for the copper-free Sonogashira reaction with phenylacetylene (R = H) through the anionic mechanism is shown in Fig. 5.10. 

For the copper-free Sonogashira reaction, the mechanistic study reported in this thesis revealed that, just like in other cross-coupling reactions (i.e. Stille, Negishi), there are several competing reaction pathways and a change on the reaction conditions (e.g. solvent, ligands, substrates, base) might favor one over the other ones. Moreover, a new mechanism in which the acetylide (formed by deprotonation of the alkyne) directly reacts with the catalyst was also proposed. 

This side-reaction is most serious in the case of acetylenes RC=CH with a relatively low acidity aliphatic 1-alkynes, e.g. 1-octyne, and acetylenic alcohols HCaC(CH2)nOH with n > 2, give reduced yields (40-50%) in the coupling reaction. In many other reactions, yields are high. Since the bromoalkyne usually has the highest "added value", economical considerations prescribe the use of an excess of the free acetylene, especially when it is inexpensive, e.g. propargyl alcohol. The mechanism of the Cadiot-Chodkiewicz reaction has not been studied in detail, but is seems likely that a copper acetylide ROCCu is formed first it often appears as a yellowish suspension. 

Intramolecular addition of 0-H and N-H bonds across C=C bonds in (197) and (198) to form five- or six-membered rings (199) and (200) can be catalysed by the MeCu-NHC complex (201) (Ar = 2,6-diisopropylphenyl). The reaction of 4-pentyn-l-ol has been found to be first order in the copper catalyst and zero order in the substrate, with Alfi = 18.7(4) kcalmol" and AS = -26(1) eu. Experimental andDFT studies are consistent with a mechanism that involves alkyne insertion into a Cu-O bond, followed by protonolysis upon reaction with free alkynyl alcohol. ... 

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