Looking At The Heck Reaction Biology Essay

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Palladium catalysis is a powerful tool for both common and modern organic synthesis. The Heck reaction is a palladium-catalyzed cross coupling reaction of organyl halides to alkenes and is a very important yet somewhat unpredictable carbon-carbon bond forming process. Unlike most catalytic organic reactions, the Heck reaction is not well defined and specific for particular reagents and catalysts with optimal conditions, solvents, ligands, etc. Instead, the scope of the reaction is changing, expanding, and being improved on frequently. Therefore, fine-tuning this reaction entails thousands of variations and involves learning about palladium catalysis as a whole.1 Among the different types of palladium-catalyzed reactions, the Heck reaction was one of the first to be developed by Mizoroki and Heck in the early 1970's. Mizoroki and co-workers reported the reaction with aryl iodides and potassium acetate in methanol at 120ï‚°C independently of Heck and co-workers. However, Heck and co-workers reported the reaction under more opportune laboratory conditions by reacting organyl halides with olefinic compounds in the presence of a hindered amine base and catalytic palladium to form substituted olefins.2 Due to the Heck reaction being a reasonably simple way to synthesize substituted unsaturated compounds, its application is widely used in polymerization chemistry, UV screens, pharmaceuticals, preparation of hydrocarbons, and in advanced enantioselective synthesis of natural products. 1 The Heck reaction has become one of the most useful catalytic carbon-carbon bond forming processes in organic synthesis. Scheme 1 shows the general Heck reaction in which aryl, benzyl and styryl halides react with olefins at high temperatures in the presence of an amine base and a catalytic amount of Pd(0) to form substituted olefins. 3

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R1-X + R2 R4 R3 H Pd(0) (catalytic) ligand, base, solvent heat R2 R4 R3 R1

Scheme 1

Even though the reaction is somewhat unpredictable, there are certain general features of the reaction. For instance, the Heck reaction works best for preparation of disubstituted olefins from monosubstituted ones. Also, the electronic nature of the substituents on the olefins has a limited influence on the reaction; however, electron poor olefins tend to give higher yields. In addition, a wide variety of functional groups can be present on the olefin such as esters, ethers, carboxylic acids, nitriles, phenols, dienes, but allylic alcohols tend to rearrange.3 An important aspect of the Heck reaction is the generation of the active palladium species. The active palladium catalyst can be formed in situ from precatalysts such as Pd(OAc)2 and Pd(PPh3) 4. Usually the reaction is carried out with mono and bidentate ligands.3 However, the reaction can work with or without phosphine ligands, but the phosphine ligands stabilize the palladium in its zero oxidation state. The utilization of phosphine ligands is the common and well-established approach that gives optimal results in a majority of cases.1 It has also been found that the reaction rate depends on the degree of substitution of the olefinic compound. Generally, more substituted olefins progress at a slower rate the less substituted olefins. Also, the X group on the aryl or vinyl substituent has a large impact on the rate of the reaction. Typically the order of X from fastest to slowest rate is I > Br ~ OTf >> Cl. It is typically difficult in catalysis to execute a coupling reaction with an aryl or vinyl chloride and remains a challenge to have it work as well or better than other halides. It is also worth noting that usually unsymmetrical olefins undergo substitution at the least substituted carbon.3 4

The Heck reaction has been utilized in hundreds of works and still remains a mystery as to the exact scope of the reaction. Small variations such as substrate structure, nature of the base, ligands, temperature, pressure, etc. lead to mixed results. Sometimes more sophisticated ligands for more advanced organic transformations will be unsuccessful for the simplest cases of the Heck reaction. On the other hand, much advancement has been made in its mechanistic detail and flexibility as a catalytic carbon-carbon bond forming reaction, which will be discussed in this review.1

Mechanism

The Heck reaction is similar to the "textbook" mechanism of cross coupling reactions except that the carbon-carbon bond forming reaction is established by migratory insertion instead of reductive elimination. The process is driven by the ability of Pd(0) complexes to undergo oxidative addition to C-X bonds followed with their addition to olefinic compounds. The reaction can precede though a neutral mechanism (Scheme 2) or a cationic mechanism (Scheme 3).4,5 In general, the reaction undergoes a cationic mechanism when X is OTf, OAc, or when Ag+, TI+, quaternary ammonium and phosphonium salts are used to help displacement from halides. It is also predominate when chelating ligands are used for catalysis. For the Heck reaction to undergo a neutral mechanism, X is usually a strong -donor such as Cl, Br, or I. 6 5

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Scheme 2: Neutral Mechanism L4Pd -2L L2Pd0 PdII L R' XL R PdII L R' X R PdII L X R' H RH H PdII X L R R' H migratory insertion internal rotation B-H elimination PdII X L H R' R R R' LPdII HX Base HBX oxidative addition R'X L reductive elimination 6

Scheme 3: Cationic Mechanism L4Pd -2L L2Pd0 PdII L R' XL R PdII L R' L R PdII L L R' H RH H PdII L L R R' H migratory insertion internal rotation B-H elimination PdII L L H R' R LPdII HL oxidative addition R'X AgX AgN O3 +NO3- +NO3- + + NO3- NO3- + reductive elimination AgCO3- AgHCO3 R' R

For the neutral or cationic mechanism, it is imperative to reduce Pd(II) to Pd(0) in order to generate the active species. Primary reduction is most likely accomplished by phosphine, and the reduction is assisted by hard nucleophiles. Usually the most common approach to obtain the 7

active Pd(0) is generated in situ from Pd(OAc)2 and PPh3 to form anionic Pd(0). Most likely the nucleophile attacks the coordinated phosphine by a nucleophilic substitution at the phosphorus atom. Contrary to the belief that donor phosphines are more susceptible to oxidative oxidation, in this reaction electron-withdrawing groups on phosphine increase the rate of the reaction. Also, at high temperatures, the most likely active species is Pd nanoparticles.1 The incorporation of an amine base has a beneficial effect in that it is involved in the primary reduction of Pd(II), but the base has no influence on the reduction rate in the presence of phosphine. However, it is notable that the Pd(0) species must have a proper coordination shell in order to undergo oxidative addition. No more that two strongly bound ligands are allowed, which leads to a restriction on the choice of ligands and their concentration in the Heck reaction.6 The first step of the catalytic cycle is the oxidative addition of usually a 14-electron complex (Pd(0)L2). The oxidative addition to C-X bonds is usually the rate determining step and proceeds through a concerted type mechanism. The cis-geometry is formed first, but the trans geometry is preferred because phosphine ligands prefer to be opposite one another. The oxidative addition step of the Heck reaction has been investigated further by studying the kinetics of this step. The active anionic Pd(OAc)2 species was measured with an amperometry at a rotating disk electrode polarized on the plateau of the oxidation wave of the Pd(0) complex. They found that the addition of PhI led to rapid decay of oxidation current, but at longer times, the oxidation current rose again. This meant that iodide ions were released into solution upon oxidative addition and the reaction proceeds through a short lived anionic pentacoordinated complex. In addition, Jutand and Amatore found that the reaction is zero order in [PPh3] and first order in [Pd(OAc)2]. Therefore, it was established that the oxidative addition was the rate-determining step of the Heck reaction.6 8

Also, Amatore and Jutand knew that the cationic complex [PhPd(PPh3)2+BF4-] reacts with styrene, but the reaction is slower than that with PhPd(OAc)(PPh3)2. This is the case because the solvated cationic species gives a trans-adduct that requires isomerization to allow syn-insertion of the olefin into the Ph-Pd bond (Scheme 4). They found that the trans-PhPd(OAc)(PPh3)2 did not react fast unless acetate ions were added, which established that PhPd(OAc)-(PPh3)2 is the key reactive intermediate in Heck reactions. Its reaction with olefins is the rate-determining step of the catalytic cycle.6 Scheme 4 Migratory insertion is the product-forming step of the Heck cycle where the new C-C bond is formed. It is this step that can explain regio- and stereoselectivity as well as substrate selectivity. For both mechanistic approaches (cationic and neutral) studies found that the reaction of the active intermediate is inhibited by excess phosphine, which establishes that a free coordination site is required for olefin coordination. Computational data has shown that by addition of a cationic carbene complex in the migratory insertion stage of the reaction, the degree of charge transfer from Pd to the olefin is negligible and there was no charge build-up in the transition state. This confirmed that the migratory insertion step takes place through a concerted process, not an Sn2 type mechanism.7 Pd+ LL S Ph + Ph -S Pd+ LL Ph Ph Pd+ L L Ph Ph trans cis

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The stereochemistry of the product makes the Heck reaction an appealing reaction for organic synthesis. Generally, the Curtin-Hammet principle is the controlling factor for E and Z product ratio, where the E isomer is usually obtained unless R is very small.1 However, steric 9

and electronic factors play major role in controlling the outcome of the insertion process. Migratory insertion can place the aryl group on either carbon of the alkene. Electronic factors can control this placement. In the case of electron deficient alkenes and styrene derivatives, the aryl group is placed on the most electrophilic carbon  to the Ph or electron withdrawing group. With electron rich alkenes, the opposite regiochemistry is usually obtained with the aryl group  to the electron donating group, but with the aryl group still placed on the most electrophilic carbon. With neither electron rich nor electron deficient alkenes, a mixture of products can be produced with steric factors controlling the outcome.8 Following migratory insertion, -Hydride elimination occurs. The elimination must occur through a syn-coplanar geometry between the Pd and the  hydrogen atom. The process is concerted and goes through a strong agostic interaction between the Pd and -hydride. After the syn-elimination, the PdH is scavenged by base and Pd(0) is released back into the catalytic cycle.7

Disadvantages

There are a few drawbacks to the Heck reaction as a useful tool in organic synthesis. Substrates used in the reaction cannot have  hydrogens because they will undergo rapid -Hydride elimination to give olefins. Also, as with many cross coupling reactions, aryl chlorides are not usually good substrates because they tend to react very slowly if at all.3 Chemists are continually researching to find new ligands for the Heck reaction. This is the case because phosphine ligands are expensive, toxic, and unrecoverable. For large-scale industrial purposes, the phosphines can be a bigger economical issue than palladium because palladium can be recyclable. Also, to achieve the favorable rates of reaction, higher catalyst loadings are needed because fully ligated complexes of palladium have low reactivity. Ultimately, finding ligands to 10

enhance the efficiency of the palladium would lead to higher rates and lower cost. Also, even though Palladium can be recyclable, it is usually lost at the end of the reaction. This is a huge expense factor, especially on a large scale.1

Novel Research

An important reaction to the synthesis of natural products has been the development of catalytic asymmetric intramolecular Heck reactions. This has been done with a relatively small number of ligands, while current research is being done to find new ligands such as chiral ones to be utilized in the asymmetric Heck reaction.9 Due to the major problem of losing the palladium catalyst at the end of the reaction, extensive research has been done to solve this problem. Carmichael and co-workers have found a number of low melting point ionic liquids that the Heck reaction can be performed in. The high solubility of the Pd catalyst in ionic liquids and their low solubility in organic solvents allows the products of the reaction to be separated from the ionic liquid and catalyst by solvent extraction with an organic solvent or by fractional distillation.10 Due to the unpredictable, flexible character of the Heck reaction, research is continual, and advances are still being made. Its complexity and sometimes-surprising results leads to interest from many research groups and facilities to try to completely understand the reaction. However, such extensive and abundant research is done only because the Heck reaction is such a powerful carbon-carbon bond forming reaction with many uses for synthetic organic chemistry in the academic and industrial world. 11