This is just to note that pyridones are considered aromatic by all SMILES kits I've seen (thought I've certainly not seen them all!), and pyridone itself is cited in the Daylight Theory Manual as an example of an exocyclic double bond which does not break aromaticity.
-P. On Tue, Oct 23, 2018 at 10:12 AM Chris Earnshaw <cgearns...@gmail.com> wrote: > 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 >>>>> >>>> _______________________________________________ > Rdkit-discuss mailing list > Rdkit-discuss@lists.sourceforge.net > https://lists.sourceforge.net/lists/listinfo/rdkit-discuss >
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