Heck Reactions

[Dhara Lyford]

Thepalladium-catalyzed C-C coupling between aryl halides or vinyl halides and activated alkenes in the presence of a base is referred as the "Heck Reaction". Recent developments in the catalysts and reaction conditions have resulted in a much broader range of donors and acceptors being amenable to the Heck Reaction.

An efficient and simple protocol for phosphine-free Heck reactions in water in the presence of a Pd(L-proline)2 complex as the catalyst under controlled microwave irradiation conditions is versatile and provides excellent yields of products in short reaction times. The reaction system minimizes costs, operational hazards and environmental pollution.

B. K. Allam, K. N. Singh, Synthesis, 2011, 1125-1131.

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The datasets generated during and/or analysed during the current study are included in this Article (and its Supplementary Information) or are available from the corresponding authors upon reasonable request. If possible, datasets will also be deposited in public repositories of the UPV and CSIC. Source data are provided with this paper.

F.G.-P. performed the synthesis and characterization of Pd catalysts and the corresponding reactions. R.G. carried out and interpreted the computational studies. J.O.-M. performed and interpreted the synchrotron studies and the in-flow reactions. R.P.-R. and M.C.J. designed and supervised the investigations on photoredox-catalysed coupling between aryl bromides and 1,1-diphenylethylenes. M.L.-H. and J.C.H.-G. carried out and interpreted HR STEM measurements, image analysis and simulations. M.B. carried out and supervised the computational studies. J.C.-S and R.P.-R. performed the photoredox-catalysed reactions together with the isolation, purification and characterization of TAEs. A.L.-P. performed the synthesis and characterization of Pd catalysts and the corresponding reactions, supervised the whole study and wrote the manuscript (all authors contributed to the manuscript).

There has been a trend in recent years towards including transition metal catalyzed reactions in the introductory organic chemistry curriculum. The reactions most common covered are palladium catalyzed coupling reactions (Suzuki and Heck reactions in particular) and olefin metathesis.

[Just in case you need some perspective on the importance of small differences in structure, I should note that the mere presence or absence of a simple methyl group (CH3) has been known to sometimes make a 100-fold difference in the potency of a drug! ]

Pd-catalyzed cross coupling allows one to snap together complimentary pieces together like Lego blocks. For bonus points, you might imagine how you could use the Suzuki to build the crucial sp2-sp2 bond in Valsartan, for example.

A third important transition metal catalyzed reaction often covered in introductory organic chemistry is olefin metathesis or sometimes ring-closing metathesis. The transition metal catalyst generally employed here incorporates ruthenium (Ru) as the active metal rather than palladium.

In the example below, some labelling will help to keep track of what bonds are being formed and broken. Note that we break the double bond between C-1 and C-2 as well as the double bond between C-7 and C-8, while forming a new double bond between C-2 and C-7 (labelled in red). Since there are 4 carbons between C-2 and C-7 we will end up forming a 6-membered ring. [Note: Ring closing metathesis works well for 5, 6, and 7 membered rings (as well as larger ones) but fails if we try to make strained 3- and 4-membered rings]

There are also cases where the reverse reaction (ring-opening metathesis) can be employed, but it generally requires a cyclic alkene with some ring strain present (norbornene is a perfect example). [For the curious, you can read about ring-opening metathesis polymerization (ROMP) here.

One application of olefin metathesis has been to utilize unsaturated alkenes from plant sources (linseed oil, for example) and convert them into terminal alkenes via cross-metathesis with ethene, CH2=CH2. These terminal alkenes are commercially important: Elevance recently built a $40 million production facility to process plant oils via cross metathesis. The advantage with using a feedstock like linseed oil is that it is a renewable resource; until now, petrochemicals have typically been the hydrocarbon source for these products.

As I described earlier, transition metal catalyzed coupling reactions (the Suzuki and Heck, among others) and Ru-catalyzed olefin metathesis are powerful reactions that get a tremendous amount of use in modern synthetic organic chemistry. By including these reactions in an introductory course, we can convey to students some of the incredible inventiveness and creativity of cutting edge organic chemists and also show them reactions that are more relevant than, say, the Cannizarro reaction or the Sandmeyer reaction, which rarely get any use these days.

Along the same lines, the fact that these reactions have recently won Nobel Prizes for their developers (Suzuki, Heck, Negishi in 2010 for palladium-catalyzed cross-coupling; Grubbs, Schrock, and Chauvin in 2005 for olefin metathesis) is noteworthy and drives home their relevance.

Cross couplings and olefin metathesis represent one of the few additions to the core organic chemistry curriculum in the past 20 years. As unfair as it might sound, adding this material thus provides an opportunity to alleviate some instructor boredom, as well as to challenge students abilities to think through new material. Along the same lines, research-oriented professors often relish the opportunity to teach material that is closer to the heart of modern organic chemistry rather than spend time covering reactions advanced students are unlikely to ever encounter in the lab.

In every reaction from the simplest acid-base reaction to the end of the course in peptide synthesis, students can identify curved arrows and point out nucleophiles and electrophiles. The tools that are useful in chapter 4 on acid-base chemistry are still useful in chapter 24 on peptide synthesis.

Preaching the importance of understanding concepts on one hand, and teaching the Suzuki and Heck reactions (or some watered down versions thereof) in a single day on the other, completely goes against this philosophy.

These reactions, which are based on fundamental organometallic and inorganic chemistry principles, are indeed challenging to teach in a traditional undergraduate introductory organic chemistry course. That being said, they are commonly included in most curricula nowadays and they are more or less here to stay.

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A new efficient protocol for the nickel-catalyzed Heck reaction of aryl triflates with vinyl ethers is presented. Mild reaction conditions that equal those of the corresponding palladium-catalyzed Heck reaction are applied, representing a practical and more sustainable alternative to the conventional regioselective arylation of vinyl ethers. A catalytic system comprised of Ni(COD)(2) and 1,1'-bis(diphenylphosphino)ferrocene (DPPF) in combination with the tertiary amine Cy(2)NMe proved effective in the olefination of a wide range of aryl triflates. Both electron-deficient and electron-rich arenes proved compatible, and the corresponding aryl methyl ketone could be secured after hydrolysis in yields approaching quantitative. Good functional group tolerance was observed matching the characteristics of the analogous Pd-catalyzed Heck reaction. The high levels of catalytic activity were explained by the intermediacy of a cationic nickel(II) complex potentially responsible for the successive β-hydride elimination and base promoted catalyst regeneration. Although these elementary reactions are normally considered challenging, DFT calculations suggested this pathway to be favorable under the applied reaction conditions.

Transition metals have played an important role in synthetic organic chemistry for more than a century, and offer catalytic transformations that would have been impossible with classical chemistry. One of the most useful and versatile of the transition metals is palladium, which over the years has catalyzed many important carbon-carbon forming reactions. Popular cross-coupling reactions such as the Suzuki, Stille and the Heck reaction are all catalyzed by palladium, or more correctly, by palladium in its ground state, Pd(0).

Recently, interest in palladium(II)-catalyzed transformations has started to grow, partly due to the development of the vinylic substitution reaction, commonly called the oxidative Heck reaction, presented in this thesis. This Pd(II)-catalyzed, ligand-modulated reaction occurs under air at room temperature, and for the first time a general protocol employing a wide range of olefins and arylboronic acids was obtained. Ligand screening showed that the bidentate nitrogen ligand, 2,9-dimethyl-1,10-phenanthroline (dmphen), was the most suitable ligand. Dmphen is believed to facilitate regeneration of active Pd(II), increase catalytic stability and improve the regioselectivity in the reaction. A mechanistic investigation was conducted using electrospray ionization mass spectrometry (ESI-MS), making it possible to observe cationic intermediates in a productive oxidative Heck arylation. The results obtained are in agreement with the previously proposed catalytic cycle.

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