{"id":9711,"date":"2016-03-10T18:06:13","date_gmt":"2016-03-10T23:06:13","guid":{"rendered":"https:\/\/www.masterorganicchemistry.com\/?p=9711"},"modified":"2025-07-03T06:04:25","modified_gmt":"2025-07-03T11:04:25","slug":"the-heck-suzuki-and-olefin-metathesis-reactions","status":"publish","type":"post","link":"https:\/\/www.masterorganicchemistry.com\/2016\/03\/10\/the-heck-suzuki-and-olefin-metathesis-reactions\/","title":{"rendered":"The Heck, Suzuki, and Olefin Metathesis Reactions (And Why They Don’t Belong In Most Introductory Organic Chemistry Courses)"},"content":{"rendered":"

The Heck, Suzuki, and Olefin Metathesis Reactions Are Really Cool. [But They Don’t Belong In (Most) Introductory Courses]<\/strong><\/p>\n

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\u00a0are palladium catalyzed coupling reactions<\/strong> (Suzuki and Heck reactions in particular) and olefin metathesis<\/strong>.<\/p>\n

I generally think this is a bad idea for most courses.\u00a0\u00a0In my opinion, covering transition metal catalysis introduces an excessive number of “open loops” \u00a0– new reactions, reagents, \u00a0mechanisms, and concepts – that simply cannot be closed in any satisfactory manner given the limited time available. \u00a0More on that at the bottom of the post.<\/p>\n

However, the fact remains that the material is often covered, and students have to deal with it. Rather than completely ignore this topic, I’ve chosen to provide a condensed overview of three important reactions involving “organometallics” – the Suzuki reaction, the Heck reaction, and olefin metathesis.<\/p>\n

First, let’s look at things from the 50,000 foot perspective.<\/p>\n

\"summary<\/a><\/p>\n

Table of ContentsRemove featured image<\/a><\/strong><\/p>\n

    \n
  1. Why Transition Metal Catalysis Is Important<\/a><\/li>\n
  2. The Suzuki Reaction<\/a><\/li>\n
  3. The Heck Reaction<\/a><\/li>\n
  4. Olefin Metathesis<\/a><\/li>\n
  5. Should These Reactions Be Covered In Introductory Courses? Pros and Cons<\/a><\/li>\n
  6. Conclusion<\/a><\/li>\n
  7. Notes<\/a><\/li>\n
  8. Quiz Yourself!<\/a><\/li>\n
  9. (Advanced) References and Further Reading<\/a><\/li>\n<\/ol>\n
    \n

    <\/a>1. Transition Metal Catalysis Is Vital To Modern Drug Discovery and Fine Chemical Synthesis<\/strong><\/h2>\n

    Take a look at this excellent chart of the Top 200 Pharmaceutical Products by US Volume<\/a>. Here are three examples.<\/p>\n

    \"celebrex<\/p>\n

    Each of these drugs represents the end result of incredibly expensive multi-year projects by major pharmaceutical companies and have generated untold billions of dollars in revenue. These are the “needles” found after searching through extremely<\/em> large haystacks (10,000 molecules or more) in a process we call\u00a0drug discovery.\u00a0<\/em><\/p>\n

    This isn’t the place to cover drug discovery in detail (although if you’re curious, Derek Lowe’s<\/span> In The Pipeline <\/a>does that job admirably<\/em>). \u00a0I merely want to make the point here that organic chemists\u00a0involved in this endeavour:<\/p>\n

      \n
    1. \u00a0need access to\u00a0a large number of molecules (sometimes called “libraries”) that they can screen for biological activity (e.g. killing a certain cancer cell line, inhibiting a specific enzyme, etc.)<\/li>\n
    2. often need to make small adjustments to “tune” or modify a molecule’s pharmacological properties (such as its fat-solubility, bioavailability, metabolic profile, and several other factors).<\/li>\n<\/ol>\n

      If you look at the molecules above, you’ll note that each of them contain aromatic rings and other sp2\u00a0<\/sup>hybridized carbons<\/strong>. This is a very common structural feature of drugs and drug-like molecules.<\/p>\n

      All this lead-up is merely to say that certain transition-metal catalyzed reactions are extremely useful for rapidly, predictably, and cheaply forming new bonds between sp2<\/sup>– hybridized carbons<\/strong> (e.g. aromatic rings) and thus have become an indispensable part of the modern organic chemists’ toolkit. They can be used to rapidly generate analogues of molecules for the purpose of improving their pharmacological properties.<\/p>\n

      [Just in case you need some perspective on the importance of small differences in structure, \u00a0I should note that the mere presence or absence of a simple methyl group <\/a>(CH3<\/sub>) has been known to\u00a0sometimes make a 100-fold difference in the potency of a drug! ]<\/em><\/span><\/p>\n

      Let’s walk through the first and arguably most important transition metal catalyzed reaction we’ll cover: the Suzuki reaction.<\/p>\n

      <\/a>2. The Suzuki Reaction<\/strong><\/h2>\n

      The Suzuki reaction is a palladium-catalyzed reaction for forming a new C-C bond between two coupling partners:<\/p>\n

      \u2022 an alkenyl or aryl halide<\/strong> (Br, Cl, or I) [or sometimes triflate (OTf)]<\/sub><\/p>\n

      \u2022 an alkenyl or aryl boronic acid<\/strong> R-B(OH)2 \u00a0 \u00a0 \u00a0[or sometimes boronic ester, R\u2013B(OR)2]<\/sub><\/p>\n

      The reaction is catalyzed by a\u00a0palladium<\/strong> compound, which comes in many varieties (see below) but for simplicity, we’ll use Pd(PPh3<\/sub>)4<\/span><\/span>. Base (such as NaOH or KOH) is also essential to the reaction.<\/p>\n

      The product of the reaction contains a new C\u2013C bond<\/strong> between the carbon attached to the halogen and the carbon attached to the boronic acid. The halogen and the boronic acid are removed.<\/p>\n

      You can think of palladium as acting as a “matchmaker” in this reaction – it brings the two partners together, but is itself not incorporated in the reaction product.<\/p>\n

      \"basics<\/p>\n

      We can control where the bonds form by employing the appropriate\u00a0precursors. For instance, in the second example above, note that our aryl bromide [1-bromo-4-methylbenzene] has a bromine “para” (opposite) the CH3<\/sub> group on the aromatic ring. \u00a0Had we used the “meta” isomer [1-bromo-3-methylbenzene] the new C-C bond would likewise have formed “meta” to the methyl group.<\/p>\n

      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<\/sup>-sp2<\/sup>\u00a0<\/sup>bond in Valsartan, for example.<\/p>\n

      \"valsartan<\/p>\n

      For further reading and background on the Suzuki, I recommend the resources of Myers<\/a> and White<\/a>, and of course Mike Evans’ Organometallic Reader<\/a><\/strong> provides a general background for the key concepts of organometallic chemistry.<\/p>\n

      <\/a>3. The Heck Reaction<\/strong><\/h2>\n

      A second important palladium-catalyzed C\u2013C bond forming reaction\u00a0is actually the great-granddaddy of them all, known as the Heck reaction<\/em>.<\/p>\n

      Just as in the Suzuki, one of the coupling partners is an alkenyl or aryl halide (Br, Cl, I) [or sometimes OTf]<\/sub><\/p>\n

      Unlike the Suzuki, there is no boronic acid employed. [The names of cross-coupling reactions tend to get assigned based on the identity of the “organometallic” coupling partner]<\/span><\/em>. In the Heck, the coupling partner is a mere alkene.<\/p>\n

      Here’s an example. Pay close attention to the bonds that form and break here:<\/p>\n

      \"the<\/p>\n

      The Heck reaction ends up forming a new C\u2013C bond between the aryl halide and the alkene, and we break both a C-Br and C\u2013H bond (that C-H bond breaking can be tricky to see!).<\/p>\n

      No doubt by looking at this one example you might find yourself coming up with questions, such as, “what’s up with all those reagents under the arrow such as Pd(OAc)2\u00a0<\/sub>, NEt3<\/sub>\u00a0\u00a0and P(o-tol)3<\/sub>\u00a0?”, and “why did the bond form specifically on THAT part of the alkene when there could be two other C-H bonds to break?”. I understand<\/em>. More on that below.<\/p>\n

      <\/a>4. Olefin Metathesis\u00a0<\/strong><\/h2>\n

      A third important transition metal catalyzed reaction often covered in introductory organic chemistry is\u00a0olefin metathesis<\/strong> or sometimes\u00a0ring-closing metathesis<\/strong>. The transition metal catalyst generally employed here\u00a0incorporates ruthenium (Ru) as the active metal rather than palladium.<\/p>\n

      Unlike coupling reactions, which involve alkenyl or aryl halides along with “organometal” coupling partners, the key functional group involved in olefin metathesis are very simple: alkenes.<\/p>\n

      Simply put, olefin metathesis stitches two alkenes together<\/strong>. It can be done between two individual alkenes (“intermolecular” or “cross-metathesis”) but is more commonly used to form rings from a molecule containing two alkene functional groups.<\/p>\n

      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).\u00a0\u00a0Since there are 4 carbons between C-2 and C-7 we will end up forming a 6-membered ring. \u00a0[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<\/em><\/span>]<\/p>\n

      \"olefin<\/p>\n

      The reaction is catalyzed by a ruthenium compound which has come to be known as “Grubbs’ Catalyst”, after its discoverer, olefin metathesis pioneer (and Nobel Prize winner) Robert H. Grubbs<\/a>. [I’ve taken a liberty with the structure of this Grubbs catalyst, showing the form of the catalyst when it’s active in the catalytic cycle here and not the commercially available “precatalyst”.]<\/em><\/span><\/p>\n

      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<\/strong><\/a> is a perfect example). [For the curious, you can read about ring-opening metathesis polymerization (ROMP) here<\/strong><\/a>.<\/p>\n

      One application of olefin metathesis has been to utilize unsaturated alkenes from plant sources (linseed oil,<\/a> for example) and convert them into terminal alkenes via cross-metathesis with ethene, CH2<\/sub>=CH2<\/sub>. These terminal alkenes are commercially important: Elevance recently\u00a0built a $40 million production facility\u00a0to process plant oils via cross metathesis<\/a>. 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.<\/p>\n

      If the above seems like an overly brief coverage of three key transition metal catalyzed reactions, I agree. I actually don’t think these reactions belong in most courses, and here’s why.<\/p>\n

      <\/a>5. Should Transition Metal Catalyzed Reactions Be Covered In Introductory Organic Courses? Pros and Cons<\/h2>\n

      First, by “cover”, I really mean, “should this be\u00a0tested”.\u00a0<\/em>\u00a0It’s one thing to tell the class to put the pens down and just have a look at these reactions which have revolutionized organic chemistry. It’s quite another to expect students to study, learn, and most importantly , understand these reactions such that they can reasonably answer questions about them on an exam.<\/p>\n

      Let’s cover the reasons “Pro” first, and then address the “Con”.<\/p>\n

      Pro: It\u2019s reflective of modern organic chemistry.\u00a0<\/b><\/em><\/p>\n

      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.<\/p>\n

      Pro: Nobel Prizes were awarded for this work.<\/strong><\/em><\/p>\n

      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.<\/p>\n

      Pro: If it replaces a reaction that gets little use today, like the Canizarro reaction, what\u2019s the loss?<\/strong><\/em><\/p>\n

      From a teaching perspective, spending a lecture or two on these reactions necessitates dropping some other course material. If it means skipping the\u00a0Canizarro and Sandmeyer (as previously mentioned), or the malonic ester synthesis, Robinson annulation, \u00a0the Ruff degradation, Hofmann elimination, and so on – is that really such a huge loss?<\/p>\n

      Also: It’s more fun to teach advanced stuff<\/strong><\/em><\/p>\n

      Cross couplings and olefin metathesis represent one of the few additions to the core organic chemistry curriculum in the past 20 years. \u00a0 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.<\/p>\n

      Looking at the other side:<\/p>\n

      Con\u00a0–\u00a0The mechanisms are completely disconnected from\u00a0the rest of the course<\/em><\/strong><\/p>\n

      As instructors, we value and teach the importance of\u00a0understanding<\/em> reactions and electron flow, not merely memorizing what is going on.<\/p>\n

      One of the fun things about teaching organic chemistry is showing students how concepts and skills that they learn in the first few weeks of class are\u00a0still relevant<\/em> at the very end of the course.<\/p>\n

      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.<\/p>\n

      \"curved<\/p>\n

      Where do transition metal mechanisms fit into any of this? Yes, of course they can be understood, given enough time, and of course they do follow the core tenets of chemistry in a broad sense.<\/p>\n

      However the mechanisms themselves are so foreign to a new observer that they require a tremendous amount of work filling in the background if they are to be understood properly.<\/p>\n

      Try identifying the nucleophile and electrophile in the reaction below. How do the electrons flow?<\/p>\n

      \"in<\/p>\n

      There actually\u00a0is\u00a0<\/em>an electrophile and a nucleophile here, but not in any sense that students are accustomed to seeing.<\/p>\n

      And this is just oxidative addition, to say nothing of other key organometallic mechanisms – reductive elimination, transmetallation, beta-hydride abstraction and so on. Covering this material is a huge diversion from the main goal of an introductory organic chemistry course: understanding electron flow.<\/p>\n

      Con: There isn’t enough time to cover the key concepts<\/strong><\/em><\/p>\n

      Say you want to give students an understanding of how these reactions work. Where do you start?<\/p>\n

      In the case of the Suzuki, it’s one thing to\u00a0say<\/em>\u00a0that it starts with oxidative addition of Pd into the C-X bond, followed by “transmetallation”, and then followed by reductive elimination. It’s another thing entirely to try to\u00a0teach\u00a0<\/em>it in a course where students have had zero previous exposure to transition metal reaction mechanisms.<\/p>\n

      And no, putting up a slide which describes the catalytic cycle of the Suzuki is not<\/em> the same thing as teaching it.<\/p>\n

      Here’s a partial list of some other concepts that will be unfamiliar to someone trying to learn cross coupling reactions in the context of an introductory organic chemistry course:<\/p>\n