Glaser-Hay coupling reaction

As described in Section III.A.2, Sanders and McCallien assembled four Zn(II) dioxoporphyrins bearing acetylenic groups on the tetrakis(4-pyridyl) porphyrin template 61. They subsequently submitted the complex to the Glaser-Hay coupling reaction which produced the cyclic tetramer in 70% yield. Without a template, the same reaction was not so selective it afforded the tetramer and trimer species in 40%... 

Table 1. Oligomerization and polymerization of compound 1 by Glaser-Hay coupling. Catalyst formation CuCI, TMEDA, and 02 in 1,2-dichlorobenzene [5, 12]. The reaction was performed in the presence of molecular sieves (4 A). If PhC=CH was available immediately at beginning ofthe coupling process (procedure C) an equal amount was added again 1 h before the end of the reaction. (tr is the total reaction time and tadd is the time until addition of the end-capping reagent.)...

Metal coordination also enables organic ligands to be used as templates. Sanders and co-workers have synthesized cyclic porphyrin oligomers using Glaser-Hay coupling [16,40]. This reaction oxidatively combines two terminal acetylenes to give a 1,3-buta-diyne link. The syntheses of cyclic porphyrin dimer 38 and trimer 39 were effectively templated by 4,4 -bipyridine 37 and tripyridyltriazine 22, respectively (Scheme 1-10). 

The Glaser Coupling (or Hay Coupling) is a synthesis of symmetric or cyclic bisacetylenes via a coupling reaction of terminal alkynes. Mechanistically, the reaction is similar to the Eglinton Reaction the difference being the use of catalytic copper(I), which is reoxidized in the catalytic cycle by oxygen in the reaction medium. 

The related Hay Coupling has several advantages as compared with the Glaser Coupling. The copper-TMEDA complex used is soluble in a wider range of solvents, so that the reaction is more versatile. 

In the polycoupling reactions, the formation of the diyne units proceeded via a Glaser-Hay oxidative coupling route [35-38]. Despite its wide applications in the preparation of small molecules and linear polymers containing diyne moieties, its mechanism remains unclear [38-40]. It has been proposed that a dimeric copper acetylide complex is involved, whose collapse leads to the formation of the diyne product (Scheme 9). 

Although copper acetylides seem to be able to perform a nucleophilic substitution reaction at the sp-carbon atom of a bromo- or iodoacetylene (Cadiot-Chodkievicz reaction), this reaction has only rarely been used for the preparation of cyclic 1,3-diacetylenes. Copper-mediated oxidative coupling reactions (Glaser, Hay and Eglinton coupling) are more popular in this area and have attracted much attention in the construction of carbon-rich cyclic and polycyclic systems (see Chapter 13). One of the earliest carbon-rich systems of this type was the CzoHg system 19 [11,16] [Eq. (5)]. 

In a study by Pomposo and coworkers, SCNPs were constructed from all ne-functionalized polymers using the copper-catalyzed Glaser-Hay allq ne coupling reaction. Interestingly, the allq ne-bearing polymer was synthesized without necessity of protection using redox-initiated RAFT polymerization. While not traditionally considered a click reaction, the tetrazine-norbornene reaction enjoys fast, quantitative conversions at room temperature without the need for a catalyst. O Reilly and coworkers exploited the benefits of this reaction for SCNP synthesis. ... 

The Castro-Stephens reaction is the cross coupling of a copper acetylide (1) and an aryl or vinyl halide (2) to give a disubstituted alkyne (3). The reaction, which shares some common elements with the Sonogashira, Cadiot-Chodkiewicz, Rosenmund-von Braun, Hay, and Glaser coupling reactions, was discovered by Stephens and Castro in the early 1960s and has found some applications in synthesis. " ... 

Several minor variations and practical improvements on the Glaser and related acetylenic coupling reactions have been developed. For example, when Cul is substituted for CuCl in the standard Hay conditions (TMEDA, O2, acetone) a greatly improved yield of 12 is obtained, which was ascribed to the more soluble CuI-2TMEDA in acetone. The homocoupling of 2-ethynyl-l-methylpyrrole (13) only proceeds in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), which may be due to the decreased acidity of the acetylenic hydrogen. ... 

The most useful approaches to the synthesis of di- and poly-ynes from terminal alkynes are undoubtedly the copper-catalyzed couplings discovered by Glaser (CuCl, NH4OH, EtOH, 02)," Eglinton [Cu(OAc)2, hot pyridine or quinoline, 02], and Hay [Cu(I), tmed, 02]. Some of the many applications of these reactions are discussed in the following. 

For Glaser couplings the Hay modification, requiring a minimum quantity of cuprous salt complexed with N,N,N ,N -tetramethylethylenediamine and passage of oxygen, is recommended [20]. Figure (1.13) illustrates a reaction sequence leading to a hexadeca-acetylene (17) [20,21]. 

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