marvin reports chiral center wrongly

Hi





Please check the attached image output from geometry plugin.


It reported that there is one chiral center on this structure, but other drawing tools such as chemdraw from chembridge disagree.





Thanks,

Nitrogens having three different ligands are tetrahedral because of the non-bonding electron pair. However, they are usually not chiral, due to the fast inversion among standard conditions.





One exception is the case of bridgehead nitrogens, in which this easy inversion is prohibited. So I think, that your molecule really contains one chiral center.

Gyuri wrote:

Nitrogens having three different ligands are tetrahedral because of the non-bonding electron pair. However, they are usually not chiral, due to the fast inversion among standard conditions. One exception is the case of bridgehead nitrogens, in which this easy inversion is prohibited. So I think, that your molecule really contains one chiral center.

The N in this compound is not a bridgehead, and resonance with the pi bonds will make it flat, so it should not be considered a stereocenter.

bobgr wrote:

Gyuri wrote: Nitrogens having three different ligands are tetrahedral because of the non-bonding electron pair. However, they are usually not chiral, due to the fast inversion among standard conditions. One exception is the case of bridgehead nitrogens, in which this easy inversion is prohibited. So I think, that your molecule really contains one chiral center. The N in this compound is not a bridgehead, and resonance with the pi bonds will make it flat, so it should not be considered a stereocenter.

I asked around my coworkers and they all agreed to what bobgr mentioned above. Is there any way to fix this?

Thank you for the useful information. I am sorry for the delay in answering, we are consulting and running some last calculations to clarify the situation before correcting the problem.

My colleague performed a quantumchemical geometry optimization (DFT b3lyp 6-31d,p) on this molecule. Though, it was not a perfect SP3 tetraeder on the nitrogen, it was not flat.





However, we will accept your proposal and change the parity identification function (the basis of the stereo center count calculation) if we can find a simple method for the detection of these cases. So, would you prefer to ignore all nitrogens with double bonded neigbours?

The problem with N is that whether it is considered a stereocenter depends on the time scale. Most organic chemists do not think of trivalent N as stereogenic, because inversion occurs rapidly on the laboratory time scale, indeed even on the NMR time scale. However, on the femtosecond or shorter time scale, a trivalent N is usually stereogenic, unless it is strongly conjugated to a neighboring group.





My recommendation would be that a N attached to three different groups should *not* be considered a stereocenter unless inversion produces an isomer that is extremely high in energy (for example, if it is a bridgehead N).





A N that is attached to four different groups (and has a +1 charge) should always be considered to be a stereocenter.





I think most of your users are interested in stereocenters because they want to know whether the compound has isolable diastereomers, and this rule will accommodate those users.





By the way, you should really stop using that term "chiral center". The term reflects chemical and mathematical misconceptions, and IUPAC discourages it. Use "stereocenter" instead.

Quote:

My recommendation would be that a N attached to three different groups should *not* be considered a stereocenter unless inversion produces an isomer that is extremely high in energy (for example, if it is a bridgehead N). A N that is attached to four different groups (and has a +1 charge) should always be considered to be a stereocenter.

This is exactly the way how it works now, though, this fast function does not calculate inversion energies. Alpha unsaturated bridgeheads can be ignored as well as you all proposed.





Regarding the question of chiral centers and stereo centers I admit, that this is a difficult to decide question too. Both expressions are used widely often in a mixed way even in IUPAC documents. Though, I think, that stereo center is a bit wider thing (not just tetrahedral), I am open to consider this change if IUPAC discourages it. Can you please send me a link to that document?





I found a not too fresh IUPAC document saying:





Chirality Centre


An atom holding a set of ligands in a spatial arrangement which is not superposable on its mirror image. A chirality centre is thus a generalised extension of the concept of the asymmetric carbon atom to central atoms of any element, for example N+abcd, Pabc as well as Cabcd.





Though it is not too fresh, it is part of the IUPAC gold book:


http://goldbook.iupac.org/C01060.html

Gyuri wrote:

Quote: My recommendation would be that a N attached to three different groups should *not* be considered a stereocenter unless inversion produces an isomer that is extremely high in energy (for example, if it is a bridgehead N). A N that is attached to four different groups (and has a +1 charge) should always be considered to be a stereocenter. This is exactly the way how it works now, though, this fast function does not calculate inversion energies. Alpha unsaturated bridgeheads can be ignored as well as you all proposed.

I don't think it's exactly the way it works now. In the example above, the N is at a ring fusion, not at a bridgehead. N at a ring fusion should not be considered stereogenic.





I'm not too sure of the mathematical definition of a bridgehead atom, but I'll try. Consider two rings that share three or more atoms (not just two). These two rings also define a third, larger ring. The bridgehead atoms are contained in all three rings.

Quote:

Regarding the question of chiral centers and stereo centers I admit, that this is a difficult to decide question too. Both expressions are used widely often in a mixed way even in IUPAC documents. Though, I think, that stereo center is a bit wider thing (not just tetrahedral), I am open to consider this change if IUPAC discourages it. Can you please send me a link to that document? I found a not too fresh IUPAC document saying: Chirality Centre An atom holding a set of ligands in a spatial arrangement which is not superposable on its mirror image. A chirality centre is thus a generalised extension of the concept of the asymmetric carbon atom to central atoms of any element, for example N+abcd, Pabc as well as Cabcd. Though it is not too fresh, it is part of the IUPAC gold book: http://goldbook.iupac.org/C01060.html

I can't seem to find a quote more recent than that, either, but I'll keep my eyes out for it. Meanwhile, even the term "asymmetric center" is more acceptable than "chiral center". The problem with "chiral center" is that you can have an achiral center at the center of a chiral compound, and you can have a chiral center at the center of an achiral compound. Consider the various stereoisomers of 1,2,3,4,5-pentanepentaol, and you'll see what I mean.

Code:

In the example above, the N is at a ring fusion, not at a bridgehead.

Ah yes, you are right!

Dear all,





Are you sure that fused N should not be considered as stereocenter?


I think if there are no double bonds in a molecule similar to the upper one then the N can be stereocenter.


So I think the rule that only bridgehead N can be stereocenter if the N is in ring is not good.


Andras

Again, whether trivalent N is considered a stereocenter depends on the time scale, but when most organic chemists refer to a stereogenic N, they mean that it has a very high barrier to inversion. The fused N does not have a high barrier to inversion.

Hi,





We will change our stereocenter detection algorithm to detect only bridgehead Nitrogen atom as stereocenter if the Nitrogen atom is in ring.





Andras

volfi wrote:

Hi, We will change our stereocenter detection algorithm to detect only bridgehead Nitrogen atom as stereocenter if the Nitrogen atom is in ring. Andras

Hi

Is this the side effect of the change made in the latest release?  I tested in 5.2.0/5.2.2 marvin sketch, and it seems that chiral center is wrongly reported.

I tested with chemdraw and it does not report the existence of chiral center and asked around chemists and they say no chiral center for this compound.

Could you check?

Thanks,

 

Hi,

This bug is not connected to the latest release.

It seems that the bug exist for a long time:

MarvinSketch 5.1.5

MarvinSketch 5.1.0

are buggy.

 

Andras

volfi wrote:

Hi, This bug is not connected to the latest release. It seems that the bug exist for a long time: MarvinSketch 5.1.5 MarvinSketch 5.1.0 are buggy.   Andras

Thanks Andras for the info, but could you clean these existing bugs?  We are thinking to push marvin to chemsits to replace an existing/expensive drawing tool, but these bugs are a serious broker.

 

 

The compound you drew has allene-like symmetry.  JChem does not handle stereocenters in such compounds very well.

However, you should be happy to know that the StereoisomerPlugin correctly generates just one stereoisomer of this compound.  If JChem really thought that the compound had two stereocenters, it would generate four "stereoisomers."  

We will correct this issue very soon, we need to improve the asymmetry recognition of stereo center determination in these cases.
Bob, thank you for your comment. The stereisomers are generated correctly, because of an extra duplication filtering using the generated isomers.

Gyuri wrote:

We will correct this issue very soon, we need to improve the asymmetry recognition of stereo center determination in these cases. Bob, thank you for your comment. The stereisomers are generated correctly, because of an extra duplication filtering using the generated isomers.

Thanks for your help. We are looking forward to hearing from you for the fix.

Our chemists generate a lot of compounds with sterechemistry/tautomers as part of their job and we have a special internal processes in-place for these compounds.  Therefore, it is one of minimum requirements for the tool to be able to deal with chrial center properly.

We made marvin available to over 200 chemists  April 2008, so we did a survey how many chemists are using marvin after a year later. It turned out that no one was using  marvin at all.  So, we want to chnage it in the future.

Thanks again,

yasushi

 

 

 

 

Hi,

 

I  think it is important to point out that this problem does not affect
the handling of chiral centers at any other parts of our software.

All other parts (e.g. import, export, structure search, duplicate search, clean, etc ...) handle chiral information correctly (including MDL enchanced stereo).

 

Szilard

Szilard wrote:

Hi,   I  think it is important to point out that this problem does not affect the handling of chiral centers at any other parts of our software. All other parts (e.g. import, export, structure search, duplicate search, clean, etc ...) handle chiral information correctly (including MDL enchanced stereo).   Szilard

Hi Bob,

Let me rephrase:

I  think it is important to point out that this problem does not affect the handling of chiral centers at any other parts of our software (e.g. import, export, structure search, duplicate search, clean, etc ...).

Your example seems to be a different case with an intersting interaction of two types of stereo information (might be known thing) ... now I let the real experts asnwer this one (maybe in the JChem forum) :)

Best regards,

Szilard

 

Bob, we can solve now the problem of the ChiralCenterCount function reported by Yokubo. From the technical point of view, the problem you mention is a bit different, but we will support allenene-like stereochemistry as well in the future.

Dear Yasushi and Bob,

Thank you for reporting these problems, your comments helped us a lot to recognize that the chiral center count calculation was not correct. The fixed calculation is available now in the latest release (5.2.3_2). We plan to extend this function further in the future by the detection of more complex special chirality cases, like the axial chirality of certain allenes and biphenyls.

Best regards

Gyuri