Chapter 29: Organometallics

Organometallics consist of a transition metal bound to a carbon center. There are several transition metals that are considered precious that can assist with very important chemistry such as Pd, Au, Ag, Cu and Rh. [0]

Contents

Learning Objectices
29.1 Introduction to Organometallics
29.1.1 Organometallic Nomenclature
29.1.2 Background of Organometallic Chemistry
29.1.3 Structure and Bonding in Organometallic Complexes
29.1.4 Determining the Oxidation State of a Metal Ion
29.1.5 Electron Counting
29.1.6 Molecular Geometry
29.2 Reactions with Grignards and Alkyllithiums
29.2.1 Grignard and Organolithium Reagents: Nucleophilic Additions to Carbonyl Compounds
29.2.2 Grignard and Organolithium Reagents as Strong Bases
29.2.3 Limitations of Grignard and Organolithium Reagents
29.2.4 Synthesis of Acetylenic Organolithium and Grignard Reagents
29.2.5 Nucleophilic Ring-Opening of Oxiranes
29.2.6 Ring-Opening of an Asymmetrical Oxirane: Regioselective and Stereospecific
29.2.7 Reactions of Grignard Reagents with Oxiranes
29.3 Gilman Reagents (lithium diorganocopper reagents)
29.3.1 Formation and Synthesis of Gilman Reagents
29.3.2 Reactions of Gilman Reagents
29.4 Carbenes and Carbenoids
29.4.1 Methylene
29.4.2 Dichlorocarbene
29.4.3 The Simmons-Smith Reaction
29.5 Elementary Steps of Transition Metal Catalyzed Reactions
29.5.1 Oxidative Addition
29.5.2 Reductive Elimination
29.5.3 Migratory Insertion
29.5.4 Transmetallation
29.6 Cross-Coupling Chemistry
29.6.1 Selected Highlights in the History of Cross-coupling
29.6.2 Palladium-Catalyzed C-C Bond Forming Reactions
29.6.3 Suzuki, Stille, and Negishi Reactions
29.6.4 Sonogashira Chemistry
29.7 Olefin Metathesis

Learning Objectives

Understand the mechanism and predict the products produced in the nucleophilic addition of organometallic reagents to carbonyl compounds such as from Grignard reagents, alkyl lithium reagents, LiAlH₄, NaBH₄,Gilman reagents (organocuprates).

Understand carbenes, how they are made and how they are used in the Simmons-Smith reaction.

Determine the relative base strength of Grignard and lithium reagents and predict the products produced in acid-base reactions.

Recognize limitations of Grignard and alkyl lithium reagents.

Understand and write the mechanism for the nucleophilic ring-opening of oxiranes to produce alcohols and predict the regiochemistry and stereochemistry of the products in both basic and acidic conditions.

29.1 Introduction

29.1.1 Organometallic Nomenclature

When naming organometallic compounds, the metal is considered the parent group and the organic components are considered the substituent and should be identified by a prefix.

PhLi Et₂Zn Me₃Al

phenyllithium diethylzinc trimethylaluminium

If there is a substituent other than an organic fragment, then the substituent is named separately.

nBuMgBr Me₂AlCl

n-butylmagnesium bromide dimethylaluminium chloride

29.1.2 Background of Organmetallic Chemistry

The first synthesis of an inorganic compound was first reported in 1848 by Edward Frankland from zinc and ethyl iodide.

**Figure 29.1** A synthesis of diethyl zinc.

This reaction is particularly interesting as performed by Frankland as diethylzinc is extremely pyrophoric meaning that it reacts violently with air and moisture. To help facilitate this reaction, Frankland used a blanket of hydrogen gas to protect the diethyl zinc from air. This is an interesting choice as hydrogen gas itself is flammable which could have very easily compounded the problem of working with a flammable organometallic. Watch the video demonstration below to see an example of how undiluted diethylzinc reacts in air, in controlled conditions.

This choice of ‘inert’ atmosphere could have very easily compounded the problem of working with a flammable organometallic. Today, non-reactive gases such nitrogen or argon are typically used when these air and moisture sensitive reagents are being prepared and stored.

Despite diethylzinc (or DEZ, as it is sometimes called) being extremely reactive and dangerous to work with, it has several established uses in organic chemistry. It can be used as a source of ethyl carbanion in addition reactions for carbonyls and imines.

**Figure 29.2** The addition of ethyl carbanion to benzaldehyde using diethylzinc and a chiral ligand.

Additionally, it is commonly used in combination with diiodomethane as a Simmons-Smith reagent to convert alkenes into cyclopropyl groups (discussed later in this chapter). It is less nucleophilic than related alkyllithium and Grignard reagents, so it may be used when a "softer", less reactive nucleophile is needed.

29.1.3 Structure and Bonding in Organometallic Complexes

Introduction to d-orbitals. The organic chemistry that we have encountered thus far has relied only on s- and p-orbitals (and hybrid orbitals that arise from the mixing of these orbitals). We have seen many examples of reaction selectivity that arises because of predictable interactions of these simple orbitals. For example, we understand the backside attack in the S_N2 reaction as occurring due to the geometry of the C–X s* orbital of our electrophile (Figure 1).

**Figure 29.3** S_N2 reaction proceeds with backside attack due to favorable overlap of nucleophile and C–X s*.

Organometallic chemistry is the study of compounds and reactions that arise from interaction of carbon-based molecules with transition metal complexes. Transition metals are notable because the valence orbitals (thus the orbitals most involved in bonding and reaction chemistry) are d-orbitals. There are chemistries that are available to us with the presence of d-orbitals that are not available to elements that only have s and p orbitals. For example, we cannot accomplish substitution chemistry on sp²hybridized carbon centers. How then can we think about accessing products of these reactions? How can we add nucleophiles to olefins? How can we use simple molecules, like CO, to generate valuable products like carbonyl derivatives? These questions can all be answered by understanding the role that d-orbitals and transition metals play in organic reactions.

**Figure 29.4** Examples or organic reactions that can be accomplished using transition metal catalysts.

29.1.4 Determining the Oxidation State of a Metal Ion

The oxidation state is dictated by 1) the identity of the ligands attached to the metal center and 2) by the charge of the transition metal complex.

1. The identity of the ligands attached to the metal:

X-type ligands: anionic donors that contribute +1 to the oxidation state of a metal, i.e. Cl^–, F^–, OH^–, CH₃^–.

L-type ligands: neutral donors that do not effect that calculation of the oxidation state of a metal, i.e. PPh₃, ethylene, ethers.

Z-type ligands: electron acceptors that contribute –1 to the oxidation state of a metal. Examples of z-type ligands would be the binding of a metal to the empty p-orbital of a borane. These are rarely encountered in organometallic chemistry and we will not examine them in this chapter.

2. The overall charge of the complex:

The overall molecular charge is also important to consider. A negative charge is –1 to the oxidation state. A positive charge is +1 to the oxidation state.

29.1.5 Electron Counting

When we learned about Lewis Dot structures for organic molecules, we were guided by the octet rule, which says that stable molecules have a filled octet. We can understand the requirement for eight valence electrons because the atoms that we were discussing at the time only had s- and p-orbitals in their valence shell; two electrons in each of these orbitals (one s orbital and three p orbitals) results in eight electrons. Because organometallic complexes have accessible d-orbitals, the octet rule no longer applies; typically stable organometallic complexes satisfy the 18-electron rule. Eighteen also can be rationalized by realizing that in addition to the s- and p-orbitals of the octet rule, organometallics also have five accessible d-orbitals and thus can accommodate 18-electrons in their valence shell. We will see several cases in catalysis when the 18-electron rule is not obeyed – for instance in reactive metal complexes – but it is helpful to spend a moment seeing how one determines the electron count of a transition metal complex.

To determine the valence electron count, we simply take the number of electrons supplied by the metal ion (d-electron count) and add the number of electrons that are supplied by the ligand set.

Determining the d-electron count

The group number of the group that the transition metal is in on the periodic table tells you how many d-electrons a metal has in its neutral electronic configuration.

**Figure 29.5** The transition metals occupy the d-block of the periodic table. [1]

To determine the d-electron count of a metal ion in a coordination complex, simply take the number of d-electrons a metal has in its neutral electronic configuration (the group number of the metal from the periodic table) and subtract the oxidation state. Remember that the oxidation state is dictated by the identity of the ligands attached to the metal center and by the charge of the transition metal complex as outlined in the previous section.

29.1.6 Molecular Geometry

Unlike organic molecules, which almost universally display molecular geometries predicted by VSEPR theory, coordination complexes frequently diverge from the geometrical predictions made based on steric minimization. This divergence arises because of crystal-field splitting, which is a topic you’ll have to wait until inorganic chemistry to understand fully. For our purposes, we will only need to know that the geometries of metal complexes with partially filled d-orbitals is not always what you might expect based on VSEPR. Simple geometrical models do hold for d⁰ and d¹⁰ metal complexes because these compounds are not subject to crystal field stabilization.

29.2 Reactions with Grignards and Alkyllithiums

29.2.1 Grignard and Organolithium Reagents: Nucleophilic Additions to Carbonyl Compounds

When an alkyl halide is added to magnesium or lithium metal in an ether solvent, an organometallic reagent is formed. If magnesium is used, the reagent is called a Grignard reagent. The reagent was named after Victor Grignard (1871-1935) who extensively determined the chemistry of the reagent. Grignard and organolithium reagents can be made from alkyl halides, aryl halides, and vinyl halides.

The preparation of the Grignard reactions begins with the use of dry glassware (glass that has been heated to >100 °C) under an inert atmosphere. Magnesium metal turnings are treated with ether solvents (usually THF, bp 67 °C) and the slow addition of an organohalide species (most often organobromides are used), the reaction mixture is usually heated until boiling to help promote the reaction. The reaction begins with the reaction of the oxides on the magnesium turnings and any traces of moisture that may be left in the reaction vessel (called an induction period) followed by an acceleration in the rate of reaction. Most often, when the reaction rate begins to accelerate a noticeable color change will occur.

**Figure 29.6** Synthesis of organolithium and Grignard reagents

Grignard and organolithium reagents are not simple structures. In the case of Grignard reagents, the ether solvent is essential and incorporates two solvent molecules into its structure.

**Figure 29.7** Schlenk equilibrium of a Grignard in diethyl ether.

The mechanism for the formation of the Grignard reagent is a free radical transfer reaction. The electrons are colored to help you visualize the movement of the electrons, shown below.

**Figure 29.8** The redical mechanism for the synthesis of a Grignard using magnesium and R-X.

Grignard reagents can be made with chloro, bromo, and iodoalkyl halides but not fluroalkyl halides.

Organolithium reagents are more complex than Grignard reagents. Organolithium reagents form oligomeric structures, which consist of a few monomer units. Depending on the size of the alkyl group, aggregates are formed.

**Figure 29.9** The synthesis of organolithiums.

However, when thinking about the chemical reactivity of these reagents, the structures can be simplified to RMgX and RLi. The most important feature about these reagents is that the bond between carbon and the metals is a highly polarized bond that is slightly ionic in character. This is because carbon is far more electronegative than Mg or Li and carbon withdraws electron density from the metals. The carbon-lithium bond has about 40% ionic character and the magnesium-carbon bond has 35%. We can characterize this strongly polarized bond by the resonance structures given below.

**Figure 29.10** Ionic character of M-C bonds.

Thus Grignard and organolithium reagents are essentially carbanions and are very strong bases.

For comparison, the structure of a carbocation, carbon radical, and a carbanion are given below. Because of charge repulsion, carbanions are tetrahedral in structure.

**Figure 29.11** A comparison of a carbocation, carbon radical, and carbanion.

They are also strong nucleophiles that are capable of attacking electrophiles, including the carbonyl group of aldehydes, ketones, and esters.

Organolithium reagents are prepared in a similar fashion to Grignard reagents, by treating an alkyl, aryl or vinylhalide with at least two equivalents of lithium metal. The formation of organolithium compounds is exothermic and will proceed at room temperature.

**Figure 29.12** The synthesis of butylltihum.

Organolithiums are formed much the same was as the Grignard reactions through a radical process. Organolithium species are very polarized (their bonds are described as polar covalent) and can almost be thought of as a stabilized anion (shown below).

**Figure 29.13** Graphical representation of the reactivity of organolithiums, tand the highly ionic character of the C-Li bond.

Because the electronegativities of lithium and magnesium are so much lower than carbon, these species exhibit high partial ionic character, that is to say that they are reactive and do not behave as salts. Organolithium species can therefore be easily dissolved in non-polar solvents such as pentane, in which they form complex yet well-ordered aggregates.

**Table 29.1** Percent Ionic Character with carbon and several other elements.

Click here to see the answer to Question 29.11.

What is the mechanism of a Grignard Reagent attacking a carbonyl group?

As seen from the question above, the first step in the mechanism is a nucleophilic attack by the negatively charged carbon of the Grignard (or organolithium) reagent on the partially positive carbonyl carbon (negative goes to positive) to form a halomagnesium alkoxide. To complete the synthesis and produce the alcohol, diluted acid or water is added to the halomagnesium alkoxide.

**Figure 29.14** Protonation of the alkoxide generated from a Grignard reaction.

General Reactions to Produce 1°, 2° and 3° Alcohols and Carboxylic Acids

When a Grignard or organolithium reagent is reacted with formaldehyde, a primary alcohol is produced.

**Figure 29.15** Addition of a Grignard to formaldehyde.

When a Grignard or organolithium reagent is reacted with an aldehyde a secondary alcohol is produced.

**Figure 29.16** Addition of a Grignard to an aldehyde.

When a Grignard or organolithium reagent is reacted with a ketone, a tertiary alcohol is produced.

**Figure 29.17** Addition of a Grignard to a ketone.

When a Grignard or organolithium reagent is reacted with carbon dioxide, a carboxylic acid is produced. This is not an alcohol but is included here to show the full scope of the organometallic reagent. The carboxylate anion that is created is too unreactive to react further with the Grignard.

**Figure 29.18** Addition of a Grignard to carbon dioxide.

When a Grignard or organolithium reagent is reacted with an ester, a tertiary alcohol is formed and interestingly the tertiary alcohol produced has the alkyl group of the reagent added twice to it. The reason for this is the ketone that is generated as an intermediate is more electrophilic than the ester and reacts with a second equivalence of the Grignard reagent, as shown in the mechanism below.

The first step is the nucleophilic addition of the reagent to form a tetrahedral intermediate.

**Figure 29.19** Addition of a Grignard to an ester.

In the second step, an alkoxide leaves to form a ketone. Typically, alkoxides are not good leaving groups, however the tetrahedral intermediate itself is an alkoxide and loss of RO^- produces a more thermodynamically stable carbonyl compound.

**Figure 29.20** Loss of an alkoxide from a tetrahedral intermediate.

The above reaction is in equilibrium and the alkoxide can act as a nucleophile and reverse the process. However, once the ketone is formed, the stronger nucleophile, which is the Grignard reagent, will preferentially react with the ketone to form a new C-C bond and convert the ketone into a tertiary alcohol.

**Figure 29.21** Addition of a Grignard to a ketone and protonation of the alkoxide.

The final step is not in equilibrium since a leaving group is not present.

Simplifying the Mechanism (Nucleophilic Addition to a Carbonyl Carbon)

Notice that all of the reactions involve a nucleophilic attack on the carbonyl carbon to form an alkoxide.

**Figure 29.22** Addition of a nucleophile to a carbonyl group.

Thus for all Grignard and organolithium reactions follow the simplified mechanism.

Identify the carbanion of the reagent. It is the carbon bonded to the metal.

Draw an arrow from the carbanion to the carbonyl’s electrophilic carbon. This forms the new carbon–carbon bond.

Draw another arrow from the π bond to the oxygen. This forms a negatively charged alkoxide ion.

Step 2 protonates the alkoxide to form the desired alcohol.

If the carbonyl is an ester or acyl chloride, the nucleophile adds twice.

**Figure 29.23** Addition of a Grignard or organolithium to an ester or acid chloride.

Identify the carbanion of the reagent. It is the carbon bonded to the metal.

Draw an arrow from carbanion to the carbonyl’s electrophilic carbon. This forms the new carbon-carbon bond.

Draw another arrow from the π bond to the oxygen. This forms a negatively charged alkoxide ion.

The alkoxide leaving group leaves to form a ketone.

Draw an arrow from carbanion to the carbonyl’s electrophilic carbon. This adds the alkyl group for the second time.

Draw another arrow from the π bond to the oxygen. This forms a negatively charged alkoxide ion.

Step 2 protonates the alkoxide to form a tertiary alcohol with the alkyl group from the reagent added twice.

29.2.2 Grignard and Organolithium Reagents as Strong Bases

Grignard and organolithium reagents behave like carbanions and are much more basic than amides and alkoxides, because carbon is less electronegative than either nitrogen or oxygen. Because alkylmetals are strong bases, organometallic reagents are sensitive to moisture and react rapidly with water. It is very important that all reagents are dry when using organometallic reagents. If water is present in the reaction vessel, the yield of the desired alcohol will be dramatically decreased because the reagent will react as a Brønsted-Lowry base and abstract a proton from water to generate an undesired alkane. The example below depicts the undesirable side reaction with water that would decrease the yield of 1-phenylethanol.

**Figure 29.24** Quenching side-reaction between a Grignard and water.

This can be turned into a useful reaction if the desired product is a deuterated compound.

**Figure 29.25** Synthesis of deuterated compounds by reaction of a Grignard and deuterated water.

Click here to see the answer to Question 29.17.

29.2.3 Limitations of Grignard and Organolithium Reagents

Grignard and organolithium reagents are strong bases. Because of this, they cannot be prepared from compounds that contain acidic groups (-OH, -NH₂, -NHR, -SH, -C≡CH, RCO₂H) or compounds that have carbonyl groups.

Click here to see the answer to Question 29.18.

29.2.4 Synthesis of Acetylenic Organolithium and Grignard Reagents

Magnesium acetylides can be readily made by using an alkyl Grignard reagent because the sp hybridized ≡C-H bond is more acidic than the sp² hybridized C-H bond.

**Figure 29.26** Synthesis of alkynyl Grignard reagents from alkynes.

Lithium acetylides can be made by the addition of lithium metal or using strong bases such as butyllithium (LiCH₂(CH₂)₂CH₃).

**Figure 29.27** Synthesis of alkynyl lithium reagents.

29.2.5 Nucleophilic Ring-Opening of Oxiranes

Ring-opening of an oxirane with a nucleophile follows a S_N2 pathway. The nucleophile attacks the electrophilic carbon and displaces the leaving group. What is slightly unusual is that the leaving group is a strong base, an alkoxide ion, and the leaving group remains attached to the alkyl chain. After acid work-up, an alcohol is produced that is two carbons away from the nucleophile.

**Figure 29.28** Ring-opening of oxirane (an epoxide) by a nucleophile.

Ethers are unreactive towards nucleophiles because alkoxides are very poor leaving groups. However, oxiranes (epoxides) are far more reactive than ethers because of the ring strain in the three membered ring. The ring-opening of an epoxide with a nucleophile is both kinetically and thermodynamically favored as shown in the Potential Energy Reaction Coordinate diagram given below. In contrast, the nucleophilic attack by a strong nucleophile on a dialkyl ether is kinetically and thermodynamically unfavorable.

**Figure 29.29** Reaction coordinate diagram of a nucleophile reacting with an epoxide and acyclic ether.

A number of strong nucleophiles can be used for this reaction including Grignard reagents and LiAlH₄.

**Figure 29.30** Ring opening of expoxides by different nucleophiles.

Epoxides and sex pheromones

Epoxides are commonly seen in naturally occurring molecules and compounds that possess biological activity. In nature, epoxides are made from alkenes using a class of enzymes called oxygenases.

**Figure 29.31** The strucute of Periplanone B.

One fun example of an epoxide-containing molecule is Periplanone B. Periplanone B is an exceptionally potent sex pheromone produced by female American cockroaches. It serves as an excitant to male periplaneta americana cockroaches.

Although sex pheromones are common for many organisms, especially insects, the existence of sex pheromones for humans remains a topic of modern interest and debate.

Nonetheless, a battery of supposed pheromone-containing products are available, along with many references for such products in pop culture. Check out the classic scene from Anchorman where Brian (Paul Rudd) attempts to seduce Veronica Corningstone (Christina Applegate). “60% of the time, it works every time”!

29.2.6 Ring-Opening of an Asymmetrical Oxirane: Regioselective and Stereospecific

Regioselective: As stated above, ring-opening of the oxirane by a nucleophile follows an S_N2 mechanism. If the oxirane is asymmetrical, the reaction will occur at the least hindered or least substituted carbon because of steric interaction between the nucleophile and electrophile.

Stereospecific: This reaction is stereospecific since the stereochemistry of the reactant determines the stereochemistry of the product. This is demonstrated in the following question.

29.2.7 Reactions of Grignard Reagents with Oxiranes

Due to the angular and torsional strain of oxirane molecules, they will undergo ring openings reactions with several nucleophiles including Grignard and organolithium reagents. Treatment of ethylene oxide with isopentylmagnesium bromide initiates a ring-opening event. Upon treatment of dilute acid in the workup, 5-methylhexanol is produced.

**Figure 29.32** Synthesis of an alcohol by ring-opening an epoxide with a Grignard.

29.3 Gilman Reagents (lithium diorganocopper reagents)

29.3.1 Formation and Synthesis of Gilman Reagents

Henry Gilman (1893-1986) of Iowa State University was the first to develop the synthesis and use of diorganocopper reagents from the treatment of an organolithium (alkyl, aryl or vinyllithium) with copper (I) salts such as copper iodide, an example is shown below.

**Figure 29.33** Synthesis of a Gilman reagent.

In the above example, isobutyllithium is reacted with copper (I) bromide to form diisobutylcopper and an equivalent of lithium bromide salt. Gilman reagents consist of two organic fragments ligated to copper forming a negatively charged species which is charge balanced with a lithium ion.

29.3.2 Reactions of Gilman Reagents

As with Grignard reagents and organolithiums, Gilman reagents are used for forming C-C bonds in coupling reactions with organohalides. Gilman reagents are best prepared from two equivalents of primary alkyl, vinylic, allylic and arylhalides from the respective organolithium reagent. Poorer conversions to the alkyl Gilman reagent occur when secondary or tertiary alkylhalides are used.

**Figure 29.34** Synthesis of a Gilman reagent.

With the Gilman reagent in hand it can be used in the subsequent coupling reaction (shown below).

**FIgure 29.35** Reaction of a Gilman reagent and a vinyl bromide.

With the treatment of two equivalents of bromoisobutane with Li wire and copper (I) bromide salt, lithium diisobutylcopper (Gilman reagent) is formed. Further treatment of the diorganocuprate species with a bromo (E)-alkene in ethereal solvent produces a new carbon bond with retention of configuration. Because the retention of configuration is completely maintained, we can state that this reaction is stereospecific. Using Gilman reagents, the coupling of a vinylbromide occurs. Vinylic halides are typically unreactive towards displacement, thus this technique is a unique approach to bond formations of this type. Futhermore, only one equivalent of the organic fragment is coupled in the reaction shown above, however the organocuprate species can transfer the second organic fragment in a subsequent coupling reaction with (E)-1-bromobut-1-ene.

**Figure 29.36** Ring-opening of an epoxide with a Gilman reagent.

More recently, an alternative method was used to produce the Gilman reagents that uses a catalytic amount of copper (I) bromide. This reaction variation is preferred for use on large scale in manufacturing as the amount of chemical waste produced by companies is always an environmental and financial concern.

**Figure 29.37** The copper-catalyzed coupling of an alkyl halide with a Grignard.

29.4 Carbenes and Carbenoids

Surrounded by only six valence electrons, the general formula for carbene is R₂C. They are a neutral yet electron deficient molecule, thus they behave as electrophiles. Their most notable reactions occur with alkenes in a process called cyclopropanation to give a three-membered ring called a cyclopropane.

29.4.1 Methylene

Of the carbene family, the simplest carbene contains one carbon atom. The reaction to produce this carbene species called methylene. Methylene is most often formed by one of two ways: photolysis (cleavage by light) and thermolysis (cleavage by heat). A common synthetic pathway to acquire access to methylene carbene is through the gentle heating or exposure to light of diazomethane (note: the rapid evolution of nitrogen gas makes this reaction very dangerous to perform without the proper precautions).

**FIgure 29.38** Photolysis of diazomethane to generate methylene.

The carbon central to the carbene is sp² hybridized in the lowest energy state, in fact, its electronic state is very similar to that of a carbocation and a carbanion as it shares similar features from each. It has both a vacant p orbital and a lone pair of unshared electrons in an sp² orbital. A plane created by three sp² orbitals lies perpendicular to an unhybridized 2p orbital. Methylene in this lower energy electronic state will be reactive towards all alkene and C-H bonds. Unfortunately, its synthetic utility is limited for reasons of non-specificity.

**FIgure 29.38** In the ground state, methylene (a carbene) has an electron deficiency and a lone pair, meaning that it shares some characteristics of carbocations and carbanions.

29.4.2 Dichlorocarbene

The synthesis of dichlorocarbene is performed by treating chloroform with the strong base potassium tert-butoxide.The synthesis of dichlorocarbene is performed by treating chloroform with the strong base potassium tert-butoxide.

**FIgure 29.39** Synthesis of dichlorocarbene.

Although methylene is very unspecific in its reactivity towards alkenes and C-H bonds, dichlorocarbene is stable and chemoselective. This stabilization feature is attributed by its resonance stabilization with the lone pairs from chlorine which helps to partially satisfy carbon's electron deficiency and its tendency to exist with a filled octet.

**Figure 29.40** Resonance structures of dichlorocarbene.

We think of chlorine as electron-withdrawing, the above resonance structure shows an example in which chlorine can behave as an electron-donor. Upon addition to an alkene functional group, cyclopropanation will occur (as shown below).

**Figure 29.41** Cyclopronantion of an alkene with dichlorocarbene.

29.4.3 The Simmons-Smith Reaction

Howard Simmons and Ronald Smith, both American chemists developed a useful protocol for the addition of methylene to an alkene. The procedure calls for the use of diiodomethane and a zinc-copper couple to create a compound called iodomethylzinc iodide known as the “Simmons-Smith” reagent.

**Figure 29.42** Synthesis of the Simmons-Smith reagent.

This compound is used in the reaction of methylenecyclohexane to produce spiro[2.5]octane, a bicyclic compound.

**Figure 29.43** Cyclopropanation of an alkene with a Simmons-Smith reagent.

29.5 Elementary Steps of Transition Metal Catalyzed Reactions

Just like the chemistry of carbon, transition metal ions participate in a set of well-defined transformations. Just like the chemistry of carbon, if you understand what the individual steps are, you can string them together to accomplish your synthetic goals. Here, instead of writing multi-step organic synthesis schemes, we will be writing multi-step catalysis cycles.

29.5.1 Oxidative Addition

Oxidative addition is the simple addition of a small molecule to a metal center. The metal provides two electrons, which are donated to an anti-bonding orbital of the substrate. In so doing, the A–B bond is broken, the metal is oxidized by two electrons, and new M–A and M–B bonds are formed.

**Figure 29.44** Oxidative addition is a transformation in which a metal ion inserts into an A–B bond and results in the formation of new M–X and M–C bonds in the product.

**Figure 29.45** Insertion of Mg⁰into a C–Br bond to generate a Grignard reagent is an example of an oxidative addition. Another common reaction step that will be important to this course is the insertion of Pd⁰into the C–X bond of aryl electrophiles.

A variety of mechanisms are available for oxidative addition reactions, and differentiation depends on the trajectory of interaction between the metal center and the incoming substrate. Both S_N2 and three-centered transition states are common. Others are possible (i.e. radical reactions), but we will not see these processes in this course.

29.5.2 Reductive Elimination

Reductive elimination is the chemical reverse of oxidative addition. Overall the metal center is reduced by two electrons and a new A–B bond is formed. It is the product-forming step in many catalytic cycles.

**Figure 29.46** Reductive elimination is a transformation in which a bond (A–B) is eliminated from a transition metal ion. The metal ion is reduced by two electrons during the bond-forming reaction.

**Figure 29.47** C–C reductive elimination from a diaryl metal complex is an important product-forming step in many transition-metal-catalyzed reactions.

Similar to oxidative addition, the term reductive elimination does not imply a reaction mechanism. Both S_N2 and concerted three-centered reactions are common and radical pathways are possible.

With only oxidative addition and reductive elimination reactions, we have no opportunity to develop useful catalysis; these steps are simply the reverse of one another. In order to develop catalysis, we need methods for ligand exchange chemistry. The two major approaches that we will encounter are migratory insertion reactions and transmetallation reactions.

29.5.3 Migratory Insertion

A migratory insertion is a reaction in which an unsaturated ligand inserts itself into an M–X bond. The reaction is redox neutral at the metal and decreases the coordination number of the metal by one. In addition, the valence electron count of the metal decreases by two. There are two common migratory insertion reactions: 1,1- and 1,2-insertion.

1,1-Migratory Insertion In a 1,1-insertion, the same atom of the migrating ligand forms new bonds with both the M and the X of the M–X bond that is involved.

**Figure 29.48** 1,1-Migratory insertion of a carbonyl ligand into an M–C bond.

Using just the steps we have seen so far – oxidative addition, reductive elimination, and migratory insertion – we can already develop some important catalytic reactions. For example, the Monsanto process combines MeOH and CO under the action of Rh catalysis to generate acetic acid. Historically, the Monsanto process was an important industrial approach to the synthesis of acetic acid.

**Figure 29.49** Catalytic cycle for the Monsanto acetic acid synthesis.

1,2-Migratory Insertion In a 1,2-insertion, the two atoms of the unsaturated ligand form bonds to the M and the X ligands. A 1,2-migratory insertion reaction of an olefin complex results in the formation of an empty coordination site and a new metal alkyl complex.

**Figure 29.50** 1,2-Migratory insertion of an olefin into an M–H bond.

Olefin migratory insertion reactions are critical steps in olefin hydrogenation. An early seminal report of olefin hydrogenation was disclosed by Sir Geoffrey Wilkinson, who showed that homogeneous Rh coordination complexes are efficient catalysts for olefin hydrogenation. Wilkinson’s work resulted in the Nobel Prize in 1973 and chemists still refer to RhCl(PPh₃)₃ as Wilkinson’s catalyst.

**Figure 29.51** Rh-catalyzed olefin hydrogenation chemistry.

Hydrogenation with Wilkinson’s catalyst commences with dissociation of a phosphine ligand from Rh to generate 14-electron intermediate that reacts with H₂ (Figure 29.51). Olefin binding to metal, 1,2-migratory insertion, and reductive elimination afford the hydrogenated organic product and regenerate the reactive 14-electron catalyst intermediate.

**Figure 29.52** Catalysis cycle for olefin hydrogenation using Wilkinson’s catalyst.

1,2-Migratory insertion reactions are reversible. The reverse of a migratory insertion is a β- elimination reaction. The β-hydride elimination is a ubiquitous version of the β-elimination and results in the formation of a metal hydride and an olefin (Figure 29.50). 1,2-Migratory insertion and β-hydride elimination reactions are important elementary reaction steps in a variety of metal-catalyzed olefin functionalization reactions. A classic olefin functionalization reaction, and an important synthetic method, is the Heck reaction, in which an aryl halide and an olefin are combined with a Pd catalyst.

**Figure 29.53** A Heck olefination reaction between an aryl halide and an electron deficient olefin is a powerful method for olefin arylation.

The mechanism of the Heck reaction is pictured in Figure 29.54. The key steps of a Heck reaction are 1) oxidative addition of Pd(0) into the C–X bond of an aryl halide to generate an organometallic Pd(II) intermediate, 2) 1,2-migratory insertion of an olefin to generate a Pd(II) alkyl intermediate, 3) β-hydride elimination to generate an olefin and a metal hydride, and 4) HX reductive elimination from the Pd(II) catalyst intermediate to regenerate the Pd(0) species that is required to engage with the next equivalent of substrate.

**Figure 29.54** The catalytic cycle of a Heck reaction.

Importantly, Pd(PPh₃)₄, which is a common catalyst for cross-coupling reactions, is an 18-electron complex and coordinatively saturated. In order to participate in oxidative addition, two phosphine ligands must dissociate from the metal center to afford a 14-electron PdL₂ intermediate that is then poised to react with aryl halides.

29.5.4 Transmetallation

Besides migratory insertion of unsaturated ligands, transmetallation is the other major organometallic transformation that allows introduction of new ligands to transition metal complexes. In a transmetallation reaction, two metals swap ligands. Transmetallation can proceed between many metals and typically proceeds under thermodynamic control (i.e. reversible). The R group tends to migrate from the more electropositive element to the less electropositive element.

**Figure 29.55** Transmetallation reactions involve the exchange of ligands between two metals.

29.6 Cross-Coupling Chemistry

29.6.1 Selected Highlights in the History of Cross-coupling

The formation of carbon-carbon bonds via nucleophilic substitution is a fundamental process in organic chemistry. The Wurtz reaction (ca. 1855), which involves two alkyl halides in the presence of sodium to form an alkane, is the oldest reported protocol to form a bond between two sp³-hybridized carbon centers.

The primary drawbacks for this transformation are that significant amounts of homo-coupled and elimination products are observed. However, a variant of this process called the Wurtz-Fittig reaction, which involves an alkyl and aryl halide in the presence of sodium metal, does not lead to the same by-product formation.

**Figure 29.57** The Wurtz-Fittig reaction.

In the time that followed the work by Wurtz, the organometallic reagents investigated for C-C bond formation included those of lithium and potassium. However, the reactivity of organometallic reagents was overshadowed by their tedious preparation and handling along with their tendency to decompose upon exposure to the conditions typically encountered when working out on the bench, making their use less practical. Much later, in 1954, Kharasch began experimenting with the use of organo-alkalis together with transition metals. He developed a coupling reaction that featured an organomagnesium and an organohalide, which at the time was considered to be the best route for alkyl-alkyl coupling. The application of this method for synthetic purposes presents yet another limitation because the coupling partner to the Grignard reagent must be activated, such as allylic or benzylic halides or some unhindered primary alkyl halides. Kochi was successful in developing a modified procedure involving primary alkyl halides and Grignard reagents in combination with Li₂CuCl₄. Although it generates negligibly small quantities of homo-dimers and functional group compatibility continued to be a concern with these types of reactions.

**Figure 29.58** Copper-catalyzed reaction of an alkyl halide and alkyl Grignard.

The S_N2 reaction between an organometallic such as an organolithium or organomagnesium is limited to unhindered alkyl halides and are subject to many undesirable side reactions such as non-selective metal-halogen exchange, disproportionation, and β-hydride elimination (BHE). As one might expect, the high propensity of organolithium and organomagnesium reagents to engage most electrophilic functional groups such as ketones, esters, and aldehydes limits the scope of the coupling reactions. Kumada, Tamao, and Corriu discovered a more promising route to achieving alkyl-alkyl cross-coupling using a Ni-based catalyst that offered improved selectivity over other methods. However, concerns for substrate tolerance for particularly electrophilic functional groups remained unaddressed. Nonetheless this work was pivotal in leading cross-coupling down a fruitful path over the last 40 years.

**Fig 29.59** A nickel-catalyzed Kumada coupling.

The gradual movement from nickel to palladium as the catalytic metal improved the generality of cross coupling, leading to seemingly limitless applications in the synthesis of natural products, pharmaceuticals and materials. These efforts in cross-coupling culminated when the Nobel prize was awarded to Richard F. Heck, Ei-ichi Negishi and Akira Suzuki for "palladium-catalyzed cross-couplings in organic chemistry” in 2010. New and innovative variations of this pivotal transformation continue today.

29.6.2 Palladium-Catalyzed C-C Bond Forming Reactions

Cross-coupling reactions combine organohalide electrophiles with organometallic nucleophiles in the presence of a transition metal catalyst (Figure 29.60). Pd(0)/Pd(II) catalytic cycles have emerged as an extremely robust strategy to accomplish cross-coupling chemistry and a wide variety of organometallic reagents can be used in cross-coupling reactions. There are an enormous number of named reactions which are all fundamentally the same cross coupling sequence. They are differentiated only by the metal from which transmetallation proceeds.

**Figure 29.60** Cross-coupling reactions are a powerful method for building new C–C bonds from aryl halides and organometallic nucleophiles. The organohalide coupling partner is also commonly vinyl or alkynyl. The organometallic coupling partner can also be aryl, vinyl, or alkynyl.

The typical cross coupling catalytic cycle involves oxidative addition of the aryl halide to generate an aryl Pd(II) intermediate, transmetallation to introduce a second M–C bond to the Pd complex, and reductive elimination to generate the targeted C–C bond and regenerate the Pd(0) catalyst (Figure 29.61). Cross-coupling chemistry is particularly important of the formation of C–C bonds between sp² hybridized carbon centers (aryl and vinyl substrates) because these reactions do not present the opportunity for undesired β-hydride elimination reactions to be accomplished. Recent progress has begun to support alkyl cross-coupling reactions using special ligands that retard β-hydride elimination.

**Figure 29.61** Canonical cross-coupling catalysis cycle.

Similar to the Heck reaction, PdL₂ intermediates are needed in order to achieve oxidative addition to Pd(0). A major thrust of modern organometallic research is the development of new, extremely sterically bulky ligands that stabilize PdL₂ intermediates.

29.6.3 Suzuki, Stille, and Negishi Reactions

Suzuki reactions are particularly important synthetic reactions because aryl boronic acids are widely available and, unlike many organometallic reagents like Grignard and organozinc species, are stable to air and water. Figure 29.62 illustrates an interesting reaction sequence in which hydroboration is utilized to generate an organoboron species that is a competent reaction partner in subsequent Suzuki coupling.

**Figure 29.62** Hydroboration-Suzuki cascade

Stille couplings are similar to the Suzuki couplings, but utilize organostannanes to transmetallate alkyl or aryl groups to palladium. A wide variety of organostannes can be prepared by reliable methods and are generally stable molecules that are suitable for storage. The main drawback is the high toxicity of organotin compounds and the potential for transmetallation of other alkyl groups on tin.

**Figure 29.63** A Stille coupling forms a new sp²-sp²C-C bond.

The Negishi coupling uses organozinc coumpounds to couple the same electrophiles as the Suzuki and Stille couplings. The reactivity of organozinc compounds is higher than the boron and tin counteprarts, but less than the alkyllithium and Grignard reagents that they are prepared from. The result is cross-coupling reactions that display moderate functional group tolerance (e.g., compounds containing an ester can be coupled) with higher reactivity than the equivalent Suzuki coupling (i.e., faster reactions and lower temperatures). Secondary alkyl groups may be coupled if special ligands are used to mitigate migratory insertion and β-hydride elimination that result in isomerization from the secondary to the primary coupling product.

**Figure 29.64** A Negishi coupling allows for the coupling of alkyl groups with aryl halides containing sensitive functional groups like the ester above.

29.6.4 Sonogashira Chemistry

The Sonogashira reactions is an important cross-coupling reaction that directly couples aryl halides with alkynyl C–H bonds.

**Figure 29.65** The Sonogashira reaction provides an approach to the direct coupling of aryl halides and terminal alkynes.

The mechanism of the Sonogashira reactions is very similar to that of the aforementioned cross-coupling reactions, except the reaction does not use a pre-formed organometallic nucleophile and thus we need to determine the identity of our transmetallating reagent. Alkynes are not acidic enough to be directly deprotonated by the weak bases employed in Sonogashira reactions (i.e. tertiary amines). Instead, interaction with a Cu(I) salt, via a π-complex, sufficiently depresses the pK_a of the alkynyl C–H such that it can be deprotonated in the reaction conditions. There are two catalytic cycles that are simultaneously involved in the Sonogashira reaction – one for the cross coupling and the other to generate alkynyl copper reagents that are responsible for the observed transmetallation reaction.

**Figure 29.66** Dual catalysis cycles that are responsible for Sonogashira coupling.

29.7 Olefin Metathesis

Olefin metathesis is an incredibly useful reaction in which C=C bonds are cleaved and new C=C bonds are formed. In the presence of many transition metals, the olefin exchange reaction pictured in Figure 29.67 is observed. The extent of olefin scrambling is typically thermodynamically controlled; a mixture of all available olefins is obtained from these reactions.

**Figure 29.67** Olefin metathesis results in the scrambling of the termini of C=C bonds.

The importance of olefin metathesis is related to the ubiquity of olefins in organic molecules. Olefin metathesis chemistry has applications in fine chemical synthesis and in large scale commodity chemical synthesis, which we will explore below. The potential utility of olefin metathesis reactions has motivated an enormous effort to develop highly active and highly selective catalysts for application to various metathesis reactions. Figure 29.68 illustrates some common metathesis catalysts.

**Figure 29.68** Common olefin metathesis catalysts.

Molybdenum catalysts were popularized by Prof. Dick Schrock and ruthenium-based catalysts were popularized by Prof. Robert Grubbs, who, along with Prof. Yves Chauvin, were awarded the Nobel Prize in chemistry in 2005.

Chauvin’s major contribution to the development of olefin metathesis was the suggestion that cycloaddition reactions, and metallacyclobutane intermediates, were involved in the reaction mechanism of olefin metathesis. These metallacycles have subsequently been isolated in some cases and shown to be relevant intermediates in the chemistry.

**Figure 29.69** Olefin metathesis reactions proceed via a series of [2+2] cycloadditions between olefins and alkylidene complexes to generate metallocyclobutane intermediates and subsequent retro-cycloaddition reactions which afford olefins and alkylidene complexes; in this figure the Grubbs I catalysts is abbreviated as [Ru]=CHPh.

Olefin metathesis reactions proceed by initial binding of olefins to the metal center to form a p-complex. Subsequent [2+2] cycloaddition generates a metallocyclobutane intermediate. You may recall from our studies of pericyclic reactions and cycloadditions that a [2s+2s] cycloaddition is thermally forbidden. This example is a beautiful illustration of the kind of reaction that can take place easily when the d-orbitals are involved in reaction chemistry! The metallocyclobutane that is generated can break down via a retro-[2+2] cycloaddition to either regenerate the starting reactants (reverse of original cycloaddition in Figure 29.69) or can break down to generate a new olefin and a new alkylidene complex. Via the intermediacy of metallocyclobutane intermediates, olefinic substrates swap the carbon atoms of the C=C bond.

Olefin metathesis chemistry is thermodynamically controlled and in many cases mixtures of olefins are obtained. There are certain cases in which olefin metathesis chemistry can be controlled and can be directed to generate a single product. For example, Figure 29.70 illustrates two examples of ring-closing metathesis (RCM) chemistry. In these examples, diene substrates undergo an olefin metathesis reaction which generates an equivalent of ethylene. While under equilibrating conditions, the ethylene could participate in a reverse olefin metathesis reaction, it is a gaseous substrate and can be removed by either vacuum or a flow of inert gas through the reaction vessel. These approaches take advantage of Le Chatelier’s principle to achieve high-yielding olefin metathesis reactions.

**Figure 29.70** Ring-closing metathesis can be used to generate a variety of ring sizes. These reactions can be selectively driven to completion by removing the evolved ethylene from the reaction vessel.

Another major application of olefin metathesis chemistry is in ring-opening metathesis polymerization (ROMP) chemistry. The driving force to selectively generate polymer and not intractable mixtures of olefins in these reactions is provided by ring strain in the monomers that are used to generate the polymer. For example, in the ROMP of dicyclopentadiene illustrated below, the strained olefin that is part of the norbornene unit is selectively cleaved first. Metathesis of this double bond leads to long polymer chains that are decorated by bicyclic units. Following consumption of the more strained olefin, subsequent cross-metathesis reactions between the remaining cyclopentene groups leads to substantial polymer cross-linking that generates very robust plastics.

**Figure 29.70** Ring opening metathesis polymerization (ROMP) of dicyclopentadiene.

Synthetic Problems

Synthesis Question 1

Devise a synthesis for the following compound, your answers should contain a commercially available starting material, any intermediates and reaction conditions: