September 16, 2021
by Charis Lam, Marketing Communications Specialist, ACD/Labs
What’s a Markush structure?
A Markush structure is a chemical structure representation that defines a group of related compounds.
The name Markush comes from patent-law history, but the structures are used in many other contexts. From the first R-group you saw in an organic chemistry textbook, or the first structure you drew with variable repeats, you’ve worked with Markush structures.
You might use them:
- On patent claims, to cover a wide class of related compounds.
- When elucidating structures, to identify areas where exact structure (e.g., a methyl attachment point) is still unknown.
- When identifying metabolites. For example, dehydroxylation is a common modification, but indicating that a hydroxyl has been removed is sometimes easier than identifying which Markush structures allow you to mark that ambiguity.
- To represent mixtures. For instance, polymerization might create compounds of variable chain length, which you could indicate using bracket notation.
ACD/Labs’ software supports Markush structures for all use cases, including within metabolite biotransformation maps.
Types of structural variation
Markush structures represent four main types of structural variation: substituent, positional, frequency, and homology.
The functional group or substituent at a particular attachment point varies.
This Markush structure could represent either toluene or phenol.
The attachment point for a defined substituent varies.
The hydroxyl group could be attached to any of the four highlighted carbons.
The number of repeats of a substructure varies.
The number of repeats (n) is variable or undefined.
Homology variation is similar to substituent variation, but here the R group is a broader class of homologous substructures, rather than a set of explicitly defined possibilities.
Here the R-group could be any alkyl (methyl, ethyl, isobutyl, etc.).
How to draw compounds with structural variation in ChemSketch
You can draw compounds with structural variation in your chemistry drawing software, including in ChemSketch.
Drawing Markush structures with substituent and homology variation
Drawing an R-group is similar to drawing an atom, except with the Radical Label tool rather than the Oxygen, Fluorine, or other atom tools. In ChemSketch, you can find the Radical Label tool in the bottom half of the left-hand toolbar.
Use the Radical Label tool to draw R groups. Then define R with a Text label.
Drawing Markush structures with frequency variation
Use the Brackets Tool in ChemSketch’s horizontal toolbar. Select the tool and drag over the atoms and bond(s) you wish to enclose. The Brackets Properties dialog box allows you to customize the bracket style and indices.
Use the Brackets Tool to add brackets to your structure.
The Brackets Properties dialog contains options for customizing brackets.
Drawing Markush structures with positional variation
Select the atoms where the substituent may be attached. Then click the Markush Bond button in ChemSketch’s horizontal toolbar.
Use the Markush Bond tool to label positional variants.
ChemSketch has four styles for positional variants:
- Ordinary Markush bond without a shadow
- Ordinary Markush bond with a shadow (useful for specifying exactly which atoms the substituent might be attached to, if ambiguity is possible)
- Addition/loss of a mass/fragment (fragments specify the atoms involved, while masses are numbers only)
- Addition/loss of a mass/fragment with a shadow
From left to right: Markush bond, Markush bond with shadow, addition/loss of fragment/mass, addition/loss of fragment/mass with shadow
From left to right: Markush bond, Markush bond with shadow, loss of mass, and loss of a fragment with shadow.
To generate the distinct structures represented by a position-variant Markush structure, use the Enumerate Markush Structures add-on. (Install Add-Ons by going to Options > Add-On Organizer. Search for new Add-Ons in your ACD/Labs installation folder.)
Running Enumerate Markush Structures creates a tiled display of all variants, allowing you to compare and consider the possible structures.
The inset Markush structure represents four different chemical entities, which are generated by the Enumerate Markush Structures add-on.
Markush structures are useful in many places within chemistry, and creating them with chemistry drawing software takes no more time than regular chemical drawing. Add Markush structure drawing to your skillset to accurately communicate your science.
This blog post features ChemSketch, a chemistry drawing package from ACD/Labs. ChemSketch is free for personal and academic use, and available by license for commercial use. Learn more about ChemSketch here.