Insertion reaction: Difference between revisions

An insertion reaction is a chemical reaction where one chemical entity (a molecule or molecular fragment) interposes itself into an existing bond of typically a second chemical entity e.g.:

A + B–C → B–A–C

The term only refers to the result of the reaction and does not suggest a mechanism. Insertion reactions are observed in organic, inorganic, and organometallic chemistry. In cases where a metal-ligand bond in a coordination complex is involved, these reactions are typically organometallic in nature and involve a bond between a transition metal and a carbon or hydrogen.^[1] It is usually reserved for the case where the coordination number and oxidation state of the metal remain unchanged.^[2] When these reactions are reversible, the removal of the small molecule from the metal-ligand bond is called extrusion or elimination.

There are two common insertion geometries— 1,1 and 1,2 (pictured above). Additionally, the inserting molecule can act either as a nucleophile or as an electrophile to the metal complex.^[2] These behaviors will be discussed in more detail for CO, nucleophilic behavior, and SO₂, electrophilic behavior.

Organic chemistry

Homologation reactions like the Kowalski ester homologation^[3] provide simple examples of insertion process in organic synthesis. In the Arndt-Eistert reaction,^[4][5] a methylene unit is inserted into the carboxyl-carbon bond of carboxylic acid to form the next acid in the homologous series. Organic Syntheses provides the example of t-BOC protected (S)-phenylalanine (2-amino-3-phenylpropanoic acid) being reacted sequentially with triethylamine, ethyl chloroformate, and diazomethane to produce the α-diazoketone, which is then reacted with silver trifluoroacetate / triethylamine in aqueous solution to generate the t-BOC protected form of (S)-3-amino-4-phenylbutanoic acid.^[6]

Mechanistically,^[7] the α-diazoketone undergoes a Wolff rearrangement^[8][9] to form a ketene in a 1,2-rearrangement. Consequently, the methylene group α- to the carboxyl group in the product is the methylene group from the diazomethane reagant. The 1,2-rearrangement has been shown to conserve the stereochemisty of the chiral centre as the product formed from t-BOC protected (S)-phenylalanine retains the (S) stereochemistry with a reported enantiomeric excess of at least 99%.^[6]

A related transformation is the Nierenstein reaction in which a diazomethane methylene group is inserted into the carbon-chlorine bond of an acid chloride to generate an α-chloromethyl ketone.^[10][11] An example, published in 1924, illustrates the reaction in a substituted benzoyl chloride system:^[12]

Perhaps surprisingly, α-bromoacetophenone is the minor product when this reaction is carried out with benzoyl bromide, a dimeric dioxane being the major product.^[13] Organic azides also provide an example of an insertion reaction in organic synthesis and, like the above examples, the transformations proceed with loss of nitrogen gas. When tosyl azide reacts with norbornadiene, a ring expansion reaction takes place in which a nitrogen atom is inserted into a carbon-carbon bond α- to the bridge head:^[14]

The Beckmann rearrangement^[15][16] is another example of a ring expanding reaction in which a heteroatom is inserted into a carbon-carbon bond. The most important application of this reaction is the conversion of cyclohexanone to its oxime, which is then rearranged under acidic conditions to provide ε-caprolactam,^[17] the feedstock for the manufacture of Nylon 6. Annual production of caprolactam exceeds 2 billion kilograms.^[18]

Carbenes undergo both intermolecular and intramolecular insertion reactions. Cyclopentene moieties can be generated from sufficiently long-chain ketones by reaction with trimethylsilyldiazomethane, (CH₃)₃Si–CHN₂:

Here, the carbene intermediate inserts into a carbon-hydrogen bond to form the carbon-carbon bond needed to close the cyclopentene ring. Carbene insertions into carbon-hydrogen bonds can also occur intermolecularly:

Carbenoids are reactive intermediates that behave similarly to carbenes.^[19] One example is the chloroalkyllithium carbenoid reagent prepared in situ from a sulfoxide and t-BuLi which inserts into the carbon-boron bond of a pinacol boronic ester:^[20]

CO Insertion

The insertion of carbon monoxide across a metal-carbon site to form an acetyl group is the oldest-known and most-studied metal-ligand insertion reaction. It proceeds by a 1,1 reaction coordinate, attaching the carbonyl carbon to both the metal and the ligand. The first CO insertion was discovered in 1957 by the reaction of CO with Mn(CO)₅CH₃, forming Mn(CO)₅COCH₃.

Mechanism

The mechanism for the apparent CO insertion into a metal-alkyl bond is actually a migratory insertion, with a migration of the alkyl group to another bound CO, followed by addition of a free CO (see figure below).^[21] This can be demonstrated by ¹³C-labeling the incoming CO ligand, which results in 100% of the labeled CO residing cis- to the acetyl group.

The CO insertion mechanism is not always a migration. The reaction of CO with (Cp)MeLFeCO, where L is a nucleophilic group such as PPh₃, yields a mix of both alkyl migration products and products formed by true insertion of bound carbonyls into the methyl group, which is controllable by the choice of solvent.^[22]

Square planar complexes can also undergo CO insertions. Insertion reactions in square planar complexes are of particular interest because their structure allows additional reaction mechanisms to occur. While just like octahedral complexes, square planar complexes can undergo in-plane migration, their lack of out-of-plane steric hindrance renders them much more open to nucleophilic attack of the metal by the CO. Since square planar groups usually form 16 electron species, the 5-coordinate intermediate that forms is stabilized by the 18-Electron rule, and undergoes migratory insertion readily.^[22] In most cases the in-plane migration pathway is preferred, but, unlike the nucleophilic pathway, it is inhibited by an excess of CO.^[23]

Effects on reaction rates

• Steric strain – Increasing the steric strain of the chelate backbone in square planar complexes pushes the carbonyl and methyl groups closer together, increasing the reactivity of insertion reactions.^[23]

• Oxidation state – Oxidation of the metal tends to increase insertion reaction rates. The main rate-limiting step in the mechanism is the migration of the methyl group onto a carbonyl ligand, oxidizing the metal by imparting a greater partial positive charge on the acetyl carbon, and thus increasing the rate of reaction.^[2]

• Lewis acids – Lewis acids also increase the reaction rates, for reasons similar to metal oxidation increasing the positive charge on the carbon. Lewis acids bind to the CO oxygen and remove charge, increasing the electrophilicity of the carbon. This can increase the reaction rate by a factor of up to 10⁸, and the complex formed is stable enough that the reaction proceeds even without additional CO to bind to the metal.^[2]

• Electronegativity of the leaving group - Increasing the electronegativity of the leaving alkyl group stabilizes the metal-carbon bond interaction and thus increases the activation energy required for migration, decreasing the reaction rate.^[24]

• Trans-effect – Ligands in an octahedral or square planar complex are known to influence the reactivity of the group to which they are trans-. This ligand influence is often referred to as the trans-influence, and it varies in intensity between ligands. A partial list of trans-influencing ligands is as follows, from highest trans-effect to lowest:^[22] aryl, alkyl > NR₃ > PR₃ > AsR₃ > CO > Cl. Ligands with a greater trans-influence impart greater electrophilicity to the active site. Increasing the electrophilicity of the CO group has been shown experimentally to greatly increase the reaction rate, while decreasing the electrophilicity of the methyl group slightly increases the reaction rate. This can be demonstrated by reacting a square planar [(PN)M(CO)(CH₃)] complex with CO, where PN is a bidentate phosphorus- or nitrogen-bound ligand. This reaction proceeds in much greater yield when the methyl group is trans-P and the CO trans-N, owing to the higher trans-influence of the more electronegative nitrogen.^[23]

Reverse reaction

Decarbonylation of aldehydes, the reverse of CO insertion, is much more difficult to perform than the associated carbonylation as it requires both a cis- empty site and enough energy to break a carbon-carbon bond. Additionally, such reactions are usually not catalytic, as the extruded CO binds too tightly to the metal centre to be dissociated even under the high heats required for this reaction.^[25] Extrusion of CO from an organic aldehyde is most famously demonstrated using Wilkinson's catalyst, which undergoes oxidative addition of the aldehyde C–H instead of H–H, and then undergoes CO extrusion to form an octahedral product.^[26]

Industrial applications

The most widely known application of migratory insertion of carbonyl groups is the Monsanto acetic acid process, which uses an rhodium-iodine catalyst system to transform methanol into acetic acid under relatively mild, catalytic conditions. It has been more recently superceded by the Cativa process which uses the cis-dicarbonyldiiodoiridate(I) anion [Ir(CO)₂I₂]⁻ (1) as catalyst.^[27][28] By 2002, worldwide annual production of acetic acid stood at 6 million tons, of which approximately 60% is produced by the Cativa process.^[27]

The catalytic cycle for the Cativa process, shown above, begins with the reaction of methyl iodide with the square planar active catalyst species (1) to form the octahedral iridium(III) species (2), the fac-isomer of [Ir(CO)₂(CH₃)I₃]⁻. This oxidative addition reaction involves the formal insertion of the iridium(I) centre into the carbon-iodine bond of methyl iodide. After ligand exchange, the migratory insertion of carbon monoxide into the iridium-carbon bond, step (3) to (4), results in the formation of a square pyramidal species with a bound acetyl ligand. The active catalyst species (1) is regenerated by the reductive elimination of acetyl iodide from (4), a de-insertion reaction.^[27]

SO₂ Insertion

SO₂ is an electrophilic species. When SO₂ encounters a transition metal with alkyl ligands, it acts like a Lewis acid towards the alkyl ligand.^[1]

Mechanism

The mechanism of SO₂ insertion is shown in the figure below.^[29] First, the sulfur coordinates to the ligand with the electronegative oxygens pointing away from the complex. Then, two different pathways can occur to “insert” the sulfur dioxide between the metal and the alkyl ligand. The top pathway shows the creation of an ionic complex, O,O’-sulphinate where the metal has a positive charge and the ligand has a negative charge. The bottom pathway shows the creation of an O-sulphinate, which can be a stable product. Also, either of these intermediates can form an S-sulphinate, the most common SO₂ insertion species and a 1,1 type geometry. IR spectroscopy and NMR can determine the type of compound.^[29] S-sulphinate has sulfur-oxygen stretching frequencies from 1250–1000 cm⁻¹ and 1100–1000 cm⁻¹. The O, O'-sulphinate and O-sulphinate are difficult to distinguish as they have stretching frequencies from 1085–1050 cm⁻¹ and 1000–820 cm⁻¹ or lower. The pathway involving the O, O' sulphinate can generally be ruled out if the original metal complex fulfilled the 18 electron rule because the two metal-oxygen bonds would exceed the 18 electron rule.^[2]

When SO₂ is inserting into a square planar complex that does not have 18 electrons, it inserts slightly differently. Since the metal is coordinatively unsaturated, the SO₂ can pre-coordinate with the metal. Then, it inserts itself between the metal and the alkyl group as shown in the example below.^[30]

Effects on reaction rates

The ability of SO₂ to insert depends upon the electronic interactions between the metal and the ligand. If there is pi bonding between the ligand and metal, the SO₂ will not insert. When steric effects are negligible, the ability of SO₂ to insert increases with an increase in the electron donating capacity of the ligand and decreases with the electron withdrawing capacity of the ligand. These trends highlight the electrophilic nature of SO₂ insertion.^[29]

Reverse reaction

The insertion of SO₂ is rarely reversible.^[1] Often, in trying to desulfinate a compound, the whole compound is destroyed.^[29] Some exceptions include: thermal/photochemical extrusion in [CpFe(CO₂{S(O)₂C₆F₅}] in toluene and thermal extrusion from [CpFe(CO){P(OPh)₃}{S(O)₂CH(Ph)(SiMe₃)}] under vacuum.^[2] The reason that desulfination does not easily occur may be that when there is ligand expulsion, instead of the alkyl group migrating as happens in the case of CO, the SO₂ bonds again with the metal to form an O,O’ sulphinate.^[2]

Industrial applications

There are few examples of SO₂ insertion in industry due to the low reactivity of SO₂ insertions and the low stability of the created products, but SO₂ insertion can be a step in production of sulfolanes.^[31][32]

Olefin Insertion

Olefin insertions are insertion reactions involving alkenes and alkynes and they can insert into metal-carbon as well as metal-hydrogen bonds. Many of olefin insertions' features are similar to those of carbonyl insertion in terms of the mechanism, however key differences are present. One of these is the potential to perform multiple insertions in tandem providing a mechanism for polymerization.^[33]

Mechanism

The mechanism for olefin insertions into metal-carbon or metal-hydrogen bonds converts an olefin complex into an alkyl complex, forming a bond between the carbon or hydrogen with the carbon at the β position. This insertion at the same time forms a bond between the metal and the carbon at the α position. When a metal has sufficient electrons for π-backbonding,^[34] the olefin can be coordinated to the metal before insertion. Depending on the ligand density of the metal, ligand dissociation may be necessary to provide a coordination site for the olefin.

Fundamental features of olefin insertions include the mechanism's dependance on the electron density of the metal complex it is inserting into. For instance, a coordinatively saturated 18-electron metal complex will likely require ligand dissociation to provide a vacant coordination site for the insertion to occur (this is also true for the β-elimination^[35]). In the case of coordinatively unsaturated metal complexes with lower electron counts (such as the 14-electron Cp*₂ScCH₃ complex), there are already vacant coordination sites available for olefin insertion without the need for ligand dissociation.

Effects on reaction rates

Factors affecting the rate of olefin insertions include the formation of the cyclic, planar, four-center transition state involving incipient formation of a bond between the metal and an olefin carbon.

From this transition state, it can be seen that a partial positive charge forms on the β-position carbon with a partial negative charge formed on the carbon or hydrogen initially bonded to the metal. This explains the subsequently observed formation of the bond between the negatively charged carbon/hydrogen and the positively charged β-carbon as well as the simultaneously formation of the metal-α-carbon bond.

This transition state also allows for consideration of the two most contributing factors to the rate of olefin insertion reactions. These include the orbital overlap of the alkyl group initially attached to the metal and the strength of the metal-alkyl bond. With greater orbital overlap between the partially positive β-carbon and the partially negative hydrogen/alkyl group carbon, the formation of a bond between them is facilitated and the insertion reaction rate is increased. With increasing strength of the metal-alkyl bond, the breaking of the bond between the metal and the hydrogen/alkyl carbon bond to form the two new bonds with the α-carbon and β-carbon (respectively) is slower, thus decreasing the rate of the insertion reaction.^[36]

Reverse reaction

The reverse mechanism for olefin insertion into a metal-hydrogen bond is β-elimination, which can only occur if a vacant orbital and a vacant coordination position are available in addition to the presence of a hydrogen at the β position.^[37] If these conditions exist, the decomposition of the metal alkyl complex can take place resulting in a hydride/olefin complex that can subsequently dissociate the olefin.

Industrial applications

As mentioned previously, a fundamental feature of olefin insertion is the opportunity for multiple insertions, providing a mechanism for polymerization. An industrial application of this is ethylene polymerization, which is catalyzed heterogeneously by titanium(III) salts and aluminum alkyls (also known as Ziegler-Natta catalysts).^[38] In these reactions, ethylene is coordinated to a vacant site on the titanium metal followed by its insertion. This can be repeated multiple times, potentially leading to high molecular weight polymers.

Other Insertion reactions

CO₂ insertion could be important for use in feedstocks. CO₂ prefers insertion into metal-nitrogen bonds rather than metal-carbon bonds. Most CO₂ extrusion reactions can occur thermally. Isocyanides (RNC) and nitrosyls (NO) insert similarly to CO in many ways including the same reaction mechanism for insertion into a square planar complex. Insertions of unsaturated species such as O₂, S, carbenes, and nitrenes have also been observed.^[2]

References