A guide to stereochemistry labels and list headers

1. Enhanced Stereochemistry
Features - How to Use Them, and
Handle Unknowns and Mixtures
Jan Christopherson
Zoltán Szabó
1

2. Enhanced Stereochemistry
Representation
2

3. Mol V3000 Format
This version 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 I use 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 absolute label 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
If you 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
The structure 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
The structure 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
The structure 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
The structure 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 labels indicate 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 what structure(s) (pure or mixture) does the
following depiction correspond?
16

17. Answer 1 Part 1
To what structure(s) (pure or mixture) does the
following depiction correspond?
Either:
A mixture of these 4 structures:
17

18. Answer 1 Part 2
To what structure(s) (pure or mixture) does the
following depiction correspond?
OR:
A mixture of these 4 structures:
18

19. Answer 1 Notes
The two 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 a query 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 Part 1
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 the structures on the left correspond to:
Structures on the right are avoided
since the two right hand stereocenters must match
23

24. Answer 2
We can further 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 can further 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 for 2 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 for 2 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 the four 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, one can 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 first separation 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 for 2 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 for 2 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 separation exercise 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 separation exercise 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 separation exercise 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. Jan Christopherson
(jchristopherson@chemaxon.com)
Zoltán Szabó
(zszabo20@chemaxon.com)
38