Reaction Stage Mechanisms

The following reaction types (mechanisms) are allowed in MACiE:

• Assisted Other Tautomerisations
• Assisted Keto-Enol Tautomerisations
• Ingold Mechanisms - These are described in the next section.
• Named Organic Reactions
• Colligation
• Coordination
• Electron Transfer
• Heterolysis
• Homolysis
• Hydride Transfer
• Hydrogen Transfer
• Isomerisation
• Other Tautomerisations
• Keto-Enol Tautomerisations
• Pericyclic reactions
• Photochemical Activation
• Proton Transfer
• Radical Formation
• Radical Propagation
• Radical Termination
• Redox
• Sigmatropic rearrangement

Named Organic Reactions

There are many reactions in organic chemistry that are named, often after the people who first carried them out, or elucidated their mechanisms. We do not have ontology entries for every single one of these, only those contained in MACiE. The named reactions currently catered for are:

• Aldol addition - a special case of nucleophilic addition and is described as the acid- or base-catalysed condensation of one carbonyl compound with the enolate/enol of another, which may or may not be the same, to generate a β-hydroxy carbonyl compound - an aldol.
  

  

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• Amadori rearrangement - Acid or base catalysed rearrangement of N-glycosides of aldoses to N-glycosides of the corresponding ketoses.
  

  

• Claisen rearrangement - a pericyclic reaction. It is a highly stereoselective thermally allowed [3,3]-sigmatropic rearrangement of allyl vinyl or allyl aryl ethers Usually intramolecular.
  

  

• Michael addition - a 1,4-nucleophilic addition. Occurs on addition of a soft nucleophile to an α-β unsaturated carbonyl compound.
  

  

Proton, Hydride, Hydrogen and Electron Transfers

Proton transfers are ubiquitous in MACiE, due to the acid/base nature of most enzyme reactions. Whilst a proton transfer may often occur in conjunction with another reaction, it may often appear on its own. Because a proton transfer is very difficult to place in the scheme of Ingold reaction mechanisms, it was decided to give it its own category. An example proton transfer is shown below

Example of a proton transfer

Hydride transfers are handled in a similar manner to proton transfers. However, a hydride transfer can also be described as an elimination and concurrent addition or substitution. Thus a hydride transfer will almost always be accompanied by an elimination type (e.g. E2), addition or substitution type (e.g. Michael addition) and the hydride transfer itself. A hydride transfer is usually made up of two components, an elimination (of the hydride) and an addition to the hydride acceptor. There are currently 6 types of hydride transfer in MACiE:

• Aromatic Elimination with Aromatic Nucleophilic Addition

  
  Example of a Hydride Transfer consisting of Aromatic Elimination with Aromatic Nucleophilic Addition

• Bimolecular Elimination with Aromatic Nucleophilic Addition

  
  Example of a Hydride Transfer Consisting of Bimolecular Elimination with Aromatic Nucleophilic Addition

• Aromatic Elimination with Michael Addition

  
  Example of a Hydride Transfer Consisting of Aromatic Elimination with Michael Addition

• Unimolecular Elimination by the Conjugate Base with Bimolecular Substitution and Allylic Rearrangement

  
  Example of a Hydride Transfer Consisting of Unimolecular Elimination by the Conjugate Base with Bimolecular Substitution and Allylic Rearrangement

• Aromatic Elimination with Nucleophilic Addition

  
  Example of a Hydride Transfer Consisting of Aromatic Elimination with Bimolecular Nucleophilic Addition

• Unimolecular Elimination by the Conjugate Base with Aromatic Nucleophilic Addition

  
  Example of a Hydride Transfer Consisting of Unimolecular Elimination by the Conjugate Base with Aromatic Nucleophilic Addition

Hydrogen and electon transfers are handled in a similar manner to proton transfers. They occur when a hydrogen atom (or electron) is transferred as part of a radical reaction. An example hydrogen transfer is shown in the figure below.

Example of a hydrogen transfer

Proton, hydrogen, hydride and electron transfers all have transfer from and transfer to. These fields take a list of the chemical species that donate (transfer from) and accept (transfer to) the species being transferred. Where there is more than one species in the chain, the transfer from and transfer to boxes take a comma separated list. E.g. In a proton transfer from species1 to species2 to species3, the transfer from field would take the form species1,species2 and the transfer to field would take the form species2,species3. The figure below shows the annotation script fields associated with proton transfer as an example of the further annotation expected.

Figure 6: Species transfer further annotation

Heterolysis and Coordination

This is the cleavage of a bond with the bonding electrons ending up on one of the atoms, thus generating X^- and Y⁺ from an X-Y bonded species. It is often the first step in an S_N1, S_E1 and E1 reaction. The reverse of heterolysis is coordination.

Homolysis and Colligation

This is the cleavage of a bond so that each of the molecular fragments between which the bond is broken retains one of the bonding electrons. It is often the first step in an unimolecular homolytic substitution reaction. The reverse of heterolysis is colligation.

Homolytic reactions involve the formation, propagation and termination of radical species. In a homolysis the pair of bonding electrons in the bond are equally split between the atoms forming the bond (see Figure 1). Radical reactions often proceed via chain reactions, which are often uncontrolled, e.g. the reaction between CFCs and ozone in the atmosphere. However, in enzymes these chain reactions are somewhat more controlled, but still follow the general principles of a chain reaction:

• A single initiation step.

  Whilst homolysis (Figure 1) of a bond is the classical method for generating a free radical, it is not the only one. Radicals may also be formed in a single electron transfer from a metal centre (see Figure 2). When this is the case we simply call the reaction a radical formation.

  
  Single Electron Transfer Radical Initiation

• Multiple propagation steps

  Propagation proceeds mostly via Ad_H2 or S_H2, however it may also proceed via an eliminative mechanism.

  
  Radical Propagation via Substitution

  
  Radical Propagation via Addition

  
  Eliminative Radical Propagation

• and a single termination step

  Radicals can be terminated via an Ad_H2 reaction, or single electron transfer from the radical species to, for example, a metal centre.

  
  Single Electron Transfer Radical Termination

  
  Radical Termination via Addition

We have found that the classification of radical reactions is far from trivial, and thus have created more generic classifications of formation, propagation and termination for those reactions. These generic classifications are also useful given the fact that an Ad_H2 reaction may be either a termination or propagation.

Pericyclic Reactions

A reaction that occurs by the concerted cyclic shift of electrons. Thus a concerted reorganisation of bonding takes place throughout a cyclic array of continuously bonded atoms.

There are three basic types of pericyclic reaction:

1. Electrocyclic reaction - an intramolecular reaction of an acyclic π-electron system in which a ring is formed with a new σ bond, and the product has one fewer π bonds than the starting material. This reaction type is not currenly included in the MACiE annotation.

   
   An example of an electrocyclic reaction

2. Cycloaddition - a reaction of two separate π-electron systems in which a ring is formed with two new σ bonds, and the product has two fewer π bonds than the reactants. The Diels-Alder reaction is an example of a cycloaddition. This reaction type is not currenly included in the MACiE annotation.

   
   An example of a Diels-Alder reaction

3. Sigmatropic reaction - a reaction in which an allylic σ bond at one end of a π-electron system appears to migrate to the other end of the π-electron system. The π bonds change positions in the process, and their total number ios unchanged. The Claisen rearrangement is an example of a sigmatropic reaction.

   
   An example of a Claisen rearrangement

Isomerisations and Tautomerisations

Isomerisation is a parent definition, and is used to define all isomerisations. This includes the Amadori rearrangement and tautomerisations. Whilst the scripts currently don't contain other types of isomerisation, it would be trivial to add them in as and when needed. An isomerisation reaction is defined as a reaction in which the principal product is isomeric with the principal reactant. An isomer is one of several species (or molecular entities) that have the same atomic composition (molecular formula) but different line or stereochemical formulae, thus they have different physical and/or chemical properties.

Tautomerisation is the isomerisation by which tautomers are inter-converted and is a reaction type which requires the user to input further data. When a tautomerisation is present, the user must specify the type of tautomerisation. We currently offer four types of tautomerisation:

• Keto-enol tautomerisation
• Assisted keto-enol tautomerisation
• Other tautomerisation
• Assisted other tautomerisation

The IUPAC Gold Book specifies tautomerisations as isomerisms of the general form shown in the figure below, where the isomers are readily inter-convertible.

General Form of a Tautomerisation

The most common form of tautomerisation is that of keto-enol tautomerisation is shown in the figure below, in which G = hydrogen, X = carbon, Y = carbon and Z = oxygen. However, the X, Y and Z are not limited to carbon and oxygen, and G is not limited to hydrogen.

Example of a Keto-Enol Tautomerisation

In MACiE there are many cases where the tautomerisation only occurs with external help, e.g. a base abstracts the proton and an acid donates another proton at the end, for example in the figure below.

Fully Assisted Keto-Enol Tautomerisation

Or the tautomerisation starts from neutral state (or negative state) and proceeds, with proton transfer to (or from) an external source, to a negatively charged (or neutral) state, The example below shows the neutral to negative state.

Partially Assisted Keto-Enol Tautomerisation

In both of these cases the tautomerisation is termed an assisted tautomerisation, where the bonding patterns of X, Y and Z are the same as in a "true" tautomerisation, but the G group is variable and can take the form of either a proton or a negative charge.

Keto-enol tautomerisation, whilst the most common form, is not the only type of tautomerisation found in MACiE, thus we allow for a category of "Other" tautomerisations, i.e. any tautomerisation which is not a keto-enol tautomerisation.

Radical Formation, Propagation and Termination

Radical formation is used when there is either homolytic cleavage of a bond, or a single electron transfer. This reaction type is necessary due to the fact that a single electron transfer isn't handled well by any other reaction type, unless it were to be described as a redox reaction. However, this is less than ideal.

Radical termination may also occur in other ways than homolytic addition, thus it was decided that there should be a category to deal with terminations of alternative mechanisms. The same is true for radical propagation.

Redox

A redox reaction is one in which a one electron transfer occurs to generate a radical. This reaction type requires the user to specify the species reduced and oxidised. The figure below shows the annotation script fields associated witha redox reaction as an example of the further annotation expected.

Redox further annotation

Activation of Reactant Species

Although not a reaction mechanism per sae, this is the term given to a step in which one of the reactant species is activated by a means other than the enzyme's active site. Currently the only type of activation allowed in MACiE is photochemical activation.

Photochemical activation is the actviation of a chemical species through the absorption of light, thus exciting the molecule.