Homogeneous Catalysis in Fine Chemicals and Polymer Synthesis

Reaction Mechanisms  

C-C and C-heteroatom coupling reactions are one of the most powerful synthetic tools in organic chemistry. The selective building of new C-C bonds is generally a key step in both the synthesis of high added value compounds in industry and the manufacture of commodity and special polymers.

 

 

C-C coupling reactions in fine chemistry.

 

The Heck reaction (1st equation)¹ and the Stille reaction (2nd equation)² are two of the most used C-C coupling processes for the synthesis of useful molecules, often with a complicated architecture.

 

 

Both are catalyzed by palladium complexes. The Heck reaction was discovered in the late sixties and since then it has developped in one of the most important reactions in organic synthesis. The application of the intramolecular Heck reaction to the synthesis of cyclic derivatives has been a major advance.¹ New catalytic systems have been reported that efficiently carry out the reaction in very small amounts (0.001% or less).³ The Stille reaction involves a transmetalation step, a transfer of an organic group R² from Sn to Pd, along with the coupling of two groups R¹-R². It is the most extensively used coupling reaction. There are other coupling processes which are also catalyzed by Pd compounds and involve a transmetalation step, as shown in equation 3. The Kharasch (M = MgX), Negishi (M = ZnX), Suzuki (M = B(OH)₂)⁴ and Hiyama (M = SiR₃)⁵ reactions are examples of this type of coupling.

 

   

  

Understanding the mechanism of a reaction is crucial to improve its efficiency and find more convenient conditions for application. When carried out for catalytic reactions, the study of mechanisms comprise the isolation of intermediates and study of separate steps of the reaction. We have shown in recent years that the use of perhaloaryl derivatives (mainly C₆F₅ and C₆Cl₂F₃) has many advantages both for the isolation of intermediates and for the study of kinetics by ¹⁹F NMR. We have applied this methodology to the study of the Heck reaction with classic catalysts, and to other processes of crucial importance in Pd-mediated reactions: Olefin insertion, Pd-migration along carbon chains, cyclization, etc. Reaction intermediates have been isolated and their evolution studied.⁶ We have also studied the mechanism of aryl exchange between Pd atoms, and the oxidative addition and transmetalation steps in the Stille reaction.⁷ As a consequence of these studies a more complete and correct mechanism for the Stille reaction, including stereochemical aspects, has been proposed and is shown in Scheme 1.

Scheme 1

 

 

The mechanistic studies of these reactions have been extended to several types of substrates presenting special difficulties in the reaction. Thus, a new catalytic system has been found that is active in the Heck reaction applied to perfluorinated substrates.⁸ The Stille reaction for allyl substrates has been studied in detail and the mechanism, ascertained by the isolation of relevant intermediates like the one shown here. As a result a more efficient reaction for allyl derivatives has been developed.⁹ 

 

 

 

New C-C coupling reactions are being studied in our group that could be eventually developed and applied in organic synthesis such as the migratory insertion of aryl and carbene groups in the coordination sphere of palladium as shown in scheme 2.¹⁰ The study of the transmetalation of a carbene group from a group 6 metal carbene to palladium and the migration step are current subjects of our work.

  

Scheme 2

  

References :

1.- a) A. de Meijere and F. E. Meyer, Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. b) I. -P. Beletskaya, A. V. Cheprakov, Chem Rev. 2000, 100, 3009-3066.

2.- (a) J. K. Stille, Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) P. Espinet, and A. Echavarren. Angew. Chem. Int. Ed., 2004, 43, 4704-4734. (c) V. Farina, Pure Appl. Chem. 1996, 68, 73. (d) Farina, V.; Krishnamurthy, V.; Scott, W. J.; The Stille Reaction. Ed.;Wiley: New York, 1998.

3.- a) M. Ohff, A. Ohff, D. Milstein Chem. Commun. 1999, 357. b) W. A. Herrmann, C. Brossmer, C.-P. Reisinger, T. H. Riermeier, K. Ofele, M. Beller Chem. Eur. J. 1997, 3, 1357. -

4.- S. P. Stanforth Tetrahedron 1998, 54, 263 and references therein..

5.- K. A. Horn Chem. Rev. 1995, 95, 1317.

6.- A. C. Albéniz, P. Espinet, Y. -S. Lin J. Am. Chem. Soc., 1996, 118, 7145-7152 ().

7.-A. L. Casado, P. Espinet, A. M. Gallego -.J. Am. Chem. Soc., 2000, 122, 11771-11782.

8.-A. C. Albéniz, P. Espinet, B. Martín-Ruiz, D. Milstein. -J. Am. Chem. Soc., 2001, 123, 11505-11505.

9.-A. C. Albéniz, P. Espinet, B. Martín-Ruiz, Chem. Eur. J. 2001, 7, 2481-2489.

10.- a) A.C. Albéniz, P. Espinet, R. Manrique, A. Pérez-Mateo, Angew. Chem. Int. Ed. Engl. 2002, 41, 2363; b) A.C. Albéniz, P. Espinet, R. Manrique, A. Pérez-Mateo, Chem. Eur. J. 2005.