Question about CIP labeling

[shubbey]

ELIKOB.zip

I've attached a molecule that has the two nitrogen centers labeled as "S" via Rule 3 (at least according to the jsmol integration: https://chemapps.stolaf.edu/jmol/jsmol/cip.htm

I'm wondering why these aren't assigned via Rule 1a, since the three branches aren't symmetric. I'm assuming that your labeling is correct and I'm misunderstanding how the official assignment works. Thanks

[Edit] Actually now I'm seeing inconsistent results. I was under the impression that jsmol was built on the same code as Centres but when I drop that SDF into the above evaluator I get the aforementioned results. When I run centres.jar I get a "no chiral" situation for this same file. Any ideas what is correct here? I am trying to implement these rules in-house and was under the impression that bridgehead nitrogens should be chiral contenders but by my logic these would be assigned via rule 1A and not rule 3 (Looking at the molecule itself makes me think that "no chiral" is correct since its basically planar but I didn't think dihedral angle was checked as part of the evaluation).

[johnmay]

Hmm, well that nitrogen is aromatic (if it's the one I think it is) so would be flat. Indeed it looks that way in the 3D file you provided. The other nitrogen would invert.

Easy to work with SMILES since the configurations are explicit- is this the one:

CCCCCN1C2=NC(=C([N@]2c2cc(ccc12)C(=O)OC)C(=O)c1ccccc1)c1ccccc1
CCCCCN1C2=NC(=C([N@@]2c2cc(ccc12)C(=O)OC)C(=O)c1ccccc1)c1ccccc1

[johnmay]

Paste in here: https://www.simolecule.com/cdkdepict/depict.html

C(%3DO)c1ccccc1)c1ccccc1&w=-1&h=-1&abbr=on&hdisp=bridgehead&showtitle=false&zoom=1.25&annotate=cip&r=0) C(%3DO)c1ccccc1)c1ccccc1&w=-1&h=-1&abbr=on&hdisp=bridgehead&showtitle=false&zoom=1.25&annotate=cip&r=0)

[johnmay]

In-fact all Nitrogen are aromatic, just need to draw the fused benzene in an alternate Kekúle form.

[shubbey]

Thank you for the quick response. But is there actually a chiral center here despite the labeling? As noted, these are aromatic nitrogens and the ring system is flat. It seems to me that even tetrahedral nitrogens have such a low energy barrier that they would never be labeled chiral. But all that said, if there is a standard I would like to be sticking to it. So I'm just not sure here!

[johnmay]

Yes that’s what I’m saying. Sorry didn’t see your edit.

There are two separate things, what things should be labelled and what is the label. I can’t comment too much on JMol since I work mainly on SMILES and 2D where everryrhing is nicely labelled. Coming from 3D if there is the slightest angle then it may be define. It sounds like maybe JSMol needs to be tweaked.

[johnmay]

I do have the bridge head code somewhere in CDK. As I said I mainly focused on SMILES and 2D in which case the input defines it. e.g.

[N@]1(CC2)CC[C@H]2C(O)C1

[shubbey]

Thanks again John. I think I get it. The issue here is more in the 3D-to-stereochemistry assignment than it is the CIP labeling (which in your examples is going off SMILES-provided chirality). It seems to me that JMol has an issue because they are calling these planar nitrogens chiral (and also from what I can tell using the wrong CIP rule). I suspect that N is a tricky case because it really will only be chiral in these bridgehead situations as you've just posted. But I guess SMILES can call anything chiral as part of the designation.

[johnmay]

Correct. Interesting in the bridged example I posted, InChI does not considered that nitrogen chiral.

Here is the logic in the CDK: https://github.com/cdk/cdk/blob/9c95df9cf2d7fddbe393f805946ef57bd2faadbe/base/standard/src/main/java/org/openscience/cdk/stereo/Stereocenters.java#L523-L531

[shubbey]

Excellent! That stereochemistry assignment info is very useful.