Hi,
I raised the same issue that Francis raised on the RDKit Slack channel on
Jan 14, 1917, with a different example (c1c[nH]c2nccc-2c1). With the same
response. Of course, breaking the non-aromatic ring causes the remaining
aromatic ring to be perceived as aromatic, as Greg's response would imply.
Chemically, this is not an edge case.
I agree with Chris that this is just wrong. However, it might be some
consolation (if that's the word I want) that back when I had access to
other packages, I tried the same example in all of them and got the same
result in every case. Even Daylight's web-site depiction scheme gave the
same result. I would love to know what OpenEye does, and in any case, there
are a lot more SMILES implementations out there now than there were then,
and I'ld also love to know whether any of the others get it (to my mind,
and Chris's, and Francis's) right.
The usual response quotes Dave Weininger's comment in the Daylight Theory
manual:
It is important to remember that the purpose of the SMILES aromaticity
detection algorithm is for the purposes of chemical information
representation only! To this end, rigorous rules are provided for
determining the "aromaticity" of charged, heterocyclic, and electron
deficient ring systems. The "aromaticity" designation as used here is not
intended to imply anything about the reactivity, magnetic resonance
spectra, heat of formation, or odor of substances.
There are at least two reasonable responses:
1. What do we use SMARTS for? Is it not to locate compounds with common
substructures? Is that not predicated on the notion that at least to some
extent, common substructures will be correlated with common activity? An
implementation that fails to see these examples as aromatic will fail to do
find the aromatic substructure these compounds when an aromatic SMARTS is
used for the search.
2. If, per the quotation above, the only purpose is really
canonicalization, why do we to bother to aromatize pyrrole in SMILES? After
all, it's already unambiguous without doing so. Would an implementation
that did not perceive pyrrole as aromatic be considered acceptable? If not,
then why is this example acceptable? Perhaps because such examples are
rare. But are we not, in fact, usually looking for unusual examples of
compounds containing a desired substructure?
It's difficult to fault RDKit for making the same mistake that everybody
else blithely accepts; but it would be great, IMO, if it could do better
than everyone else in this regard.
-P.
On Tue, Oct 23, 2018 at 8:15 AM Francis Atkinson <fran...@ebi.ac.uk> wrote:
> Ian,
>
> I think the idea is that the (out-of-plane) p orbital on the carbonyl
> C is both part of the ring pi-system and the carbonyl pi-system. However,
> both pi-electrons in the carbonyl 'belong to' the oxygen because it's more
> electronegative, and they thus aren't counted in the 4N+2.
>
> I am sure that explanation would pain a theoretical chemist, but, as
> Greg has pointed out, this is as much an informatics issue as a chemistry
> issue.
>
> The RDKit aromaticity perception is quite an inclusive one: others (
> *e.g.* Biovia's) are less so and wouldn't count pyridone as aromatic.
>
> Francis
> On 23/10/2018 12:48, Ian Tickle wrote:
>
>
> Francis
>
> Sorry yes you're right, the C with the exocyclic d.b. doesn't contribute
> its p electron to the pi system, but then doesn't that break the
> aromaticity since a continuous ring of contributing p orbitals is surely a
> requirementI would say that 2-pyridone should not be classed as aromatic
> for the same reason but its tautomer 2-hydroxypyridine Oc1ccccn1 clearly
> is. In 2-pyridone the ring C-C bond lengths alternate between conjugated
> single (1.45) and double (1.34) whereas in 2-hydoxypyridine they are all
> around the aromatic C-C length (1.39).
>
>
> I guess it all depends on how you define 'aromatic' but as I understand it
> there are 4 necessary conditions:
>
> 1. Must be cyclic.
> 2. Every atom in the ring must be conjugated (i.e. contributes a p orbital
> to the pi system).
> 3. Must have 4n+2 pi electrons.
> 4. Ring must be planar (i.e. any stereochemical distortion breaks the
> aromaticity even if the other 3 conditions are fulfilled).
>
> You could add that bond lengths between like atom types should be about
> equal, but that follows from the other conditions.
>
> Cheers
>
> -- Ian
>
>
> On Tue, 23 Oct 2018 at 11:45, 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
>>
>> --
> 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
>
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