What is organometallic chemistry?

What is organometallic chemistry?

Organometallic chemistry is the area of chemistry that deals with compounds containing a metal–carbon bond. As such, this area combines aspects from both organic and inorganic chemistry.

An organometallic compound is characterised by the presence of one or more carbon–metal bonds.

It is important to note that the metal can either be a member of the s or p block on one hand or a d-block metal (transition metal) on the other. There are no real direct pharmaceutical applications known for group 1 and 2 organometallic compounds, as they are very reactive reagents, except that they are commonly involved in the synthesis of modern medicines. Examples of such synthetic reagents include sodium cyclopentadienide (NaCp, NaC₅H₅) and butyl lithium (BuLi) compounds.

Cyclopentadienyl or Cp⁻ (C₅H₅⁻) is a commonly used ligand in organometallic chemistry, which is ver-satile in the number of bonds it can form to a metal centre (M). There are different ways of representing these interactions (see also Figure 8.1).

NaCp is an organometallic agent that is mainly used to introduce a cyclopentadienyl anion (C₅H₅⁻) to a metal centre in order to form a so-called metallocene (see Chapter 8 section 2 for a definition of metallocenes). NaCp can be synthesised by the reaction of either sodium with cyclopentadiene or from dicyclopentadiene under heating. Sodium hydride (NaH) can also be used as a base, instead of sodium, to deprotonate the acidic CH₂ group of the cyclopentadiene (Figure 8.2).

It is interesting to look at the bonding in this Cp ligand. First of all, it is important to understand the formation of the cyclopentadienyl anion, the Cp⁻ ligand. Cyclopentadiene is surprisingly acidic, which is a result of the resonance stabilisation of the resulting cyclopentadienyl anion (Cp−). 

The cyclopentadienyl anion follows Huckel’s rule (4n + 2, n = 0, 1, 2, etc.), which means that the Cp⁻ anion is a planar carbocycle of aromatic nature.

An aromatic molecule has to be a cyclic and planar molecule with an uninterrupted network of electrons.

Furthermore, it has to fulfil the Huckel rule, which states it has (4n + 2) electrons.

Organolithium compounds (Li—C bond) are probably the best known organometallic agents. In organic synthesis and drug design, they can be used as either an extremely potent base or as nucleophile; in the latter case, the organic moiety will be introduced to the target molecule. They are typically synthesised by reacting an organohalide (RX) with elemental lithium. The best known examples are n-butyllithium (n-BuLi), sec-butyllithium (s-BuLi) and tert-butyllithium (tert-BuLi), with tert-BuLi being the most reactive (Figure 8.3).

Figure 8.3 Chemical structures of (a) n-BuLi, (b) s-BuLi and (c) t-BuLi. Note that these compounds can form complex structures in the solid state and in solution

Alkali metal organometallics are more or less pyrophoric, which means they combust spontaneously on contact with air. They have to be handled under the exclusion of air, humidity and oxygen and are mostly stored in hydrocarbons. The solvent plays an important role and can be responsible for potential decomposition processes or an increased or reduced reactivity. 

The heteroatoms of solvents can potentially also coordinate to the alkali metal and therefore influence potential cluster formation of the organometallic compound. Alkali metal organometallics are known to form relatively complex clusters in solution and in the solid state, which influences their reactivity.

Organometallic compounds, containing d-block metals, are currently under intense research within the pharmaceutical chemistry area in order to find new treatment options for cancer and diabetes, amongst others. d-Block organometallics are generally fairly stable complexes, which in contrast to alkali metal organometallics can be handled in the presence of air. Whilst s- and p-block organometallics form and bonds between the metal and the organic group, in d-block organometallics the number of bonds, which is called hapticity, can be further increased.

The most common ligands for d-block organometallics include carbon monoxide (CO) in the form of the carbonyl group, phosphanes (PR₂H) and derivatives of the cyclopentadienyl (Cp⁻) ligand. A characteristic example is the bonding of the metal with the carbonyl ligand, which can be described as one M—CO interac-tion. A vacant (hybridised) orbital of the metal centre forms a bond with the CO ligand, which means that electronic charge is donated from the CO ligand to the metal centre. As CO is also a π-acceptor ligand, a back donation of electronic charge from the metal centre can occur. This donation/back donation interplay results in a strengthening of the metal–carbon bond and a weakening of the carbon–oxygen bond. CO is classified as a σ-donor and π-acceptor molecule.

The chemistry of d-block organometallic chemistry covers a vast amount of material and therefore we will concentrate on the area of so-called metallocenes, which are complexes containing typically a d-block metal and two Cp⁻ ligands. This area encompasses the most promising drug-like candidates so far.