Mea culpa - I hit Reply rather than Reply All and so only sent this to Greg...
On Tue, 23 Oct 2018 at 13:53, Chris Earnshaw <cgearns...@gmail.com> wrote: > Hi Greg > > Apologies again, I'm not trying to stir things up here. As we can see from > some of the the other discussion there's no clear view of what constitutes > aromaticity in these cases. I'm of the school which says that pyridone is > at least somewhat aromatic because, in crude terms, the electronegative > carbonyl oxygen 'steals' the electron from the carbon, the carbon provides > an empty p-orbital to the conjugated ring, and the ring nitrogen provides a > pair of electrons - hence 4n + 2 and aromatic. > > However, the thing that really worries me is that the 'iminopyridine' ring > in n12ccccc1=NCCC2 *should* be perceived in the same way as in > n12ccccc1=NC.CC2 but in practice that doesn't happen - one matches the > pyridine SMARTS c1ccccn1 and the other doesn't. This seems to be > potentially dangerous. The question of 'aromatic or not' is interesting, > but I'm actually more concerned with the consequences for compound > searching and filtering. > > As an approach, rather than simply checking if the exocyclic bond is in > another ring (of any type), would it be possible to check if that other > ring is fully conjugated? If it is, then the Huckel rule could/should be > applied to the fused system to determine aromaticity. If not, then the fact > the substituents form a ring is irrelevant and the potential aromatic > should be treated in the same way as the non-fused analogue. This would > avoid the current inconsistency, but there would no doubt still be some > challenging edge cases... > > Best regards, > Chris > > On Tue, 23 Oct 2018 at 12:43, Greg Landrum <greg.land...@gmail.com> wrote: > >> Dissent is fine, but it's important to remember that there are *always* >> going to be edge cases and that we're not trying to model something >> physically observable here. The concept of aromaticity is primarily there >> to make canonicalization easier. Section 3.4.2 here: >> http://www.daylight.com/dayhtml/doc/theory/theory.smiles.html has more >> info about this, as does the RDKit documentation: >> http://rdkit.org/docs/RDKit_Book.html#aromaticity >> >> I'm willing to change the current behavior, but someone would need to >> explain what it should be changed to in a way that is clear, unambiguous, >> and that would allow a human being looking at the structure to relatively >> easily figure out whether or not a given ring is aromatic. >> >> >> On Tue, Oct 23, 2018 at 1:17 PM Chris Earnshaw <cgearns...@gmail.com> >> wrote: >> >>> Sorry about this, but I think that 'perhaps sub-optimal' should be >>> replaced by 'definitely wrong'. The 'quasi-aromatic' system in these two >>> structures is identical and should behave as such, but in practice one of >>> them matches a pyridine SMARTS pattern and the other doesn't. That >>> shouldn't be affected by whether the saturated substituents form a ring or >>> not. I do appreciate that it gets messy to deal with as fused rings may be >>> fully conjugated, but the current behaviour seems to be disturbingly >>> inconsistent. It would be suboptimal to say that no exocyclic bond is >>> allowed to steal electrons, but that may be better than what's happening >>> here. >>> >>> Apologies for the dissent! >>> >>> Chris Earnshaw >>> >>> >>> >>> On Tue, 23 Oct 2018 at 11:57, Greg Landrum <greg.land...@gmail.com> >>> wrote: >>> >>>> The current implementation requires "exocyclic" bonds to actually be >>>> *non-ring* bonds in order to be recognized as such. >>>> This is perhaps sub-optimal, but it's clearly defined and avoids >>>> arguments about when exactly an "exocyclic" bond starts stealing electrons. >>>> >>>> -greg >>>> >>>> On Tue, Oct 23, 2018 at 12:46 PM Francis Atkinson <fran...@ebi.ac.uk> >>>> wrote: >>>> >>>>> Ian, >>>>> >>>>> I make it 6 electrons: two from the N, none from the C double >>>>> bonded to the exocyclic N, and one each from four other carbons in the >>>>> ring. It's isoelectronic with *e.g.* pyridone, which is aromatic in >>>>> RDKit... >>>>> >>>>> In [1]: from rdkit import Chem >>>>> >>>>> In [2]: Chem.MolToSmiles(Chem.MolFromSmiles('O=c1[nH]cccc1')) >>>>> Out[2]: 'O=c1cccc[nH]1' >>>>> >>>>> The protonated/tautomerised version are indeed aromatic >>>>> (interconverting bewteen these species was actually how I came across this >>>>> issue), but I still reckon the unprotonated bicyclic should be aromatic >>>>> too... >>>>> >>>>> Francis >>>>> On 23/10/2018 11:18, Ian Tickle wrote: >>>>> >>>>> >>>>> Hi, it seems to me that neither is aromatic since the N-substituted >>>>> hetero ring breaks the Huckel rule by having 7 e- (2 from the N and 1 each >>>>> from the 5 Cs). If you remove 1 e- from the N (so it's [n+]) and also >>>>> make >>>>> the external double bond into a single (picking up a proton on the other >>>>> N) >>>>> it becomes pyridinium which is certainly aromatic. >>>>> >>>>> [n+]12ccccc1NCCC2 >>>>> >>>>> [n+]12ccccc1NC.CC2 >>>>> >>>>> What does it make of those? >>>>> >>>>> Cheers >>>>> >>>>> -- Ian >>>>> >>>>> >>>>> On Tue, 23 Oct 2018 at 10:37, Francis Atkinson <fran...@ebi.ac.uk> >>>>> wrote: >>>>> >>>>>> Hello, >>>>>> >>>>>> In the following pair of molecules, the bicyclic is >>>>>> non-aromatic, >>>>>> whereas the 'ring-opened' analogue is aromatic... >>>>>> >>>>>> In [1]: from rdkit import Chem >>>>>> >>>>>> In [2]: Chem.MolToSmiles(Chem.MolFromSmiles('n12ccccc1=NCCC2')) >>>>>> Out[2]: 'C1=CC2=NCCCN2C=C1' >>>>>> >>>>>> In [3]: Chem.MolToSmiles(Chem.MolFromSmiles('n12ccccc1=NC.CC2')) >>>>>> Out[3]: 'CCn1ccccc1=NC' >>>>>> >>>>>> Notebook version: >>>>>> >>>>>> https://nbviewer.jupyter.org/gist/flatkinson/b88eb42510a79594a9e37042eeb7e224 >>>>>> >>>>>> This seems counter-intuitive to me: I don't see why the pyridine in >>>>>> the >>>>>> first molecule shouldn't be aromatic, just as it is in the second. >>>>>> >>>>>> Am I missing something here? >>>>>> >>>>>> Thanks, >>>>>> >>>>>> Francis >>>>>> >>>>>> -- >>>>>> Dr Francis L Atkinson >>>>>> >>>>>> Chemogenomics Group >>>>>> European Bioinformatics Institute (EMBL-EBI) >>>>>> European Molecular Biology Laboratory >>>>>> Wellcome Genome Campus >>>>>> Hinxton >>>>>> Cambridge CB10 1SD >>>>>> United Kingdom >>>>>> >>>>>> (01223) 494473 >>>>>> >>>>>> >>>>>> >>>>>> _______________________________________________ >>>>>> Rdkit-discuss mailing list >>>>>> Rdkit-discuss@lists.sourceforge.net >>>>>> https://lists.sourceforge.net/lists/listinfo/rdkit-discuss >>>>>> >>>>> -- >>>>> Dr Francis L Atkinson >>>>> >>>>> Chemogenomics Group >>>>> European Bioinformatics Institute (EMBL-EBI) >>>>> European Molecular Biology Laboratory >>>>> Wellcome Genome Campus >>>>> Hinxton >>>>> Cambridge CB10 1SD >>>>> United Kingdom >>>>> >>>>> (01223) 494473 >>>>> >>>>> _______________________________________________ >>>>> Rdkit-discuss mailing list >>>>> Rdkit-discuss@lists.sourceforge.net >>>>> https://lists.sourceforge.net/lists/listinfo/rdkit-discuss >>>>> >>>> _______________________________________________ >>>> Rdkit-discuss mailing list >>>> Rdkit-discuss@lists.sourceforge.net >>>> https://lists.sourceforge.net/lists/listinfo/rdkit-discuss >>>> >>>
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