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Enhanced stereochemistry representation
This document discusses enhanced stereochemistry representation in molecular structures, including absolute, and, and or labels. It explains that absolute labels indicate known exact stereochemistry, and labels indicate mixtures. Or labels signify a pure but unknown structure, while and labels represent mixtures where both configurations are present. Examples are given to illustrate how these labels can be used to define stereochemical mixtures and unknown structures. The document also demonstrates how chromatographic separation can be used to separate stereoisomer mixtures into pure components.
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Enhanced stereochemistry representation
- 1. Enhanced Stereochemistry Features -How to Use Them, and Handle Unknowns and Mixtures Jan Christopherson Zoltán Szabó 1
- 2.
- 3. Mol V3000 Format Thisversion of the .mol filetype includes 3 special atom properties or labels Absolute label And label Or label But what do they do? 3
- 4. When do Iuse Advanced Stereochemistry Labels? The labels allow you to describe a known mixture of stereochemical features, instead of drawing two separate structures They also allow you to describe structures where relative stereochemical information is known, but absolute information is not 4
- 5. Absolute Label The absolutelabel indicates that the stereochemistry is known exactly Whether an absolute label is required is somewhat context-dependent Absolute label 5
- 6. Absolute Label -According to Specification Both V2000 and V3000 molfiles were developed by MDL, with published specifications Officially, a Chiral Flag (V2000) or an Abs Label (V3000) must be added to indicated that a wedge bond is not racemic Absolute label 6
- 7. Absolute Label -In Practice Absolute label 7 In practice, it is common to assume that a wedge bond without a label represents a single enantiomer, while a flat bond represents a mixture of isomers, racemic or otherwise Most ChemAxon tools are set by default to “Assume Absolute Stereo” in case of wedge bonds to conform with these norms
- 8. And label And Label The“And#” label indicates both wedged bonds are valid at the stereocenter (it is a mixture) If the # (number) is the same, the two centers must change together 8
- 9. And label And Label Ifyou see only And (& Abs) labels on a structure, then you know the stereochemical composition That is - you know which stereoisomers are present in your sample We know that this example is a mixture of all four isomers 9
- 10. And Label Examples Thestructure to the left, indicates a mix of all 4 of the structures below Since one center is And1, and the other And2, the two stereocenters are independent of each other 10
- 11. And Labels Examples Thestructure to the left, indicates a mix of both of the structures below Since both centers are And1, they can only change relative to one another 11
- 12. Or label Or Label The“Or#” label indicates one or the other wedged bonds are valid at the given stereocenter (pure but unknown) If the # (number) is the same, the two centers must change together Whenever an Or label is visible, it means the composition of the structure is not fully known 12
- 13. Or Label Examples Thestructure to the left, indicates one of the 4 structures below The exact isomer is unknown, but we know that it is a pure sample of one of the four structures shown above Since one center is Or1, and the other Or2, the two stereocenters are independent of each other 13
- 14. Or Label Examples Thestructure to the left, indicates one of the two structures below The exact isomer is unknown, but we know that it is a pure sample of one of the two structures shown above Since both centers are Or1, they can only change relative to one another 14
- 15. Key Takeaways And labelsindicate a mixture at the stereocenter Or labels indicate an either/or at the stereocenter Numbering indicates whether labels are independent or relative And numbering is always independent of Or numbering 15
- 16. Exercise 1 To whatstructure(s) (pure or mixture) does the following depiction correspond? 16
- 17. Answer 1 Part1 To what structure(s) (pure or mixture) does the following depiction correspond? Either: A mixture of these 4 structures: 17
- 18. Answer 1 Part2 To what structure(s) (pure or mixture) does the following depiction correspond? OR: A mixture of these 4 structures: 18
- 19. Answer 1 Notes Thetwo possible variations at the Or atom mean that only one of the two structures is present - but we don’t know which. The two independent And centers mean that, with the confines of the Or, all 4 structures are present as a mixture. Recall that Or and And numbering is independent (And1 does not affect Or1). 19
- 20. Exercise 2 Draw aquery structure which would match in a search to the 4 structures on the left, but not the 4 structures on the right? 20
- 21. Answer 2 Part1 There are two possible answers: 21 or
- 22. Answer 2 Notes Typically,when running a (substructure) query against a structure database, ALL variations that could match part of the provided structure will be returned. This can depend upon the query settings 22
- 23. Answer 2 All thestructures on the left correspond to: Structures on the right are avoided since the two right hand stereocenters must match 23
- 24. Answer 2 We canfurther our understanding of this structure. It corresponds to: Either a mix of the two structures on the left Or a mix of the two structures on the right 24
- 25. Answer 2 We canfurther our understanding of this structure. It corresponds to: A pure sample of one of these four structures 25
- 26. Enhanced Stereochemistry Representation &Chiral Separation Example 26
- 27. Separation exercise for2 stereocenters In case of separating a 4 component mixture by chromatography we obtain two pairs of two in the first step. The separation of the obtained isomeric pairs results in the stereochemically pure individuals. 27
- 28. Separation exercise for2 stereocenters The “separation-tree” on the right shows how the appropriate isomers relate to each other. 28 “Separation-tree”: enantiomers diastereomers Mix of 4 28 2 pairs of 2 4 individuals enantiomers
- 29. Relationships of thefour possible stereoisomers This image represents another view of the stereochemical relationships of the individual stereoisomers 29 diastereomers enantiomers diastereomers enantiomers diastereomers diastereomers
- 30. In practice, onecan often encounter a case when a compound with two stereogenic centers is separated to obtain pure individuals, but the absolute configurations of neither the intermediary mix of 2, nor the the products are known. In this case the use of up and down wedged bonds can show a difference between the products. Separation exercise for 2 stereocenters - unknown stereocenters 30
- 31. In the firstseparation step, by performing achiral chromatography the cis-pairs are separated from trans-pairs of compounds. In this case, we assume that the first eluted pair is the cis-pair. Separation exercise for 2 stereocenters - unknown stereocenters 31 supposedly cis supposedly trans achiral separation
- 32. Separation exercise for2 stereocenters - unknown stereocenters 32 and supposedly cis supposedly trans chiral separation The isomeric pairs are separated further in chiral chromatography to obtain the stereochemically pure compounds. In all cases the label will be Or1 because the samples are pure, but the stereocenters aren’t known nor independent from each other. The orientation of wedged bonds can clearly indicate which compound is obtained from either the cis or the trans pair. However, it is difficult to unequivocally indicate the difference between the cis separated and trans separated isomers. and chiral separation
- 33. Separation exercise for2 stereocenters - unknown stereocenters 33 Several conventions can be imagined, e.g. from left to right on the molecule we can use the up-wedged bond for the first isomer and the down wedged bond for the second isomer (also considering whether it was cis or trans one step before). To make the situation extra clear we can use additional attached data (see Slide 36) to highlight which isomer was obtained. and supposedly cis supposedly trans chiral separation and chiral separation achiral separation
- 34. intensity tR Mix of 4- achiral intensity tR intensity tR Mix of 2 intensity tR 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 intensity tR “trans” 1 2 3 4 5 6 4 individuals - chiral “cis” “cis” “trans” “cis-1” “cis-2” “trans-1” “trans-2” achiral chiral chiral and and Demonstration of Chromatographic Separation
- 35. Reaction and separationexercise for 2 stereocenters An example with a hypothetical reaction. The stereocenter at C-F bond is known. Mix of 2 Separated diastereoisomers Containing Containing either one 35 and
- 36. Reaction and separationexercise for 2 stereocenters To further specify naming of isomers according to either analytical or preparative chromatography text data can be attached. Separated diastereoisomers... Containing either one 36 ...with attached data and Even with the enhanced stereochemistry representation, it may not be possible to unequivocally label all the stereogenic centers in the separated isomers. In such cases, it may be desirable to attach additional text labels to the structures based on the order of elution (or other company convention) to identify each isomer. This function is available as Chemically Significant Text (CST) in ChemAxon’s Compound Registration System.
- 37. Reaction and separationexercise for 2 stereocenters An example with a hypothetical reaction. The stereocenter at C-F bond is unknown, but it represents a single isomer. Mix of 2 Separated diastereoisomers (2 structurally different samples of): Containing Each containing either: and 37 or
- 38.