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Should reactions Smarts be aromatized ?
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Reply to topic    Home -> Forums -> Support -> Structure manipulation: Reactor & Fragmenter -> Should reactions Smarts be aromatized ?

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creisser
Joined: 26 Apr 2006
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Post subject: Should reactions Smarts be aromatized ?
Link to postPosted: Thu May 01, 2008 11:54 am  Reply with quote
Good morning,

I have the following query.
We have a small set of Reactions which we use to enumerate Combinatorial Libraries.
So far, I have automatically aromatised the Smarts and used them directly.
However, a recent example has shown that this sometimes causes problem.

This is the example Smirks un-aromatised, the reaction produces the expected product.
select jc_react('[#1,#6]-[#7-:2][N+:3]#[N:4].[#1,#6][C:5]#[C:1][#1,#6]>>[#1,#6][N:2]1[N:3]=[N:4][C:5]([#1,#6])=[C:1]1[#1,#6]','C[N-][N+]#N.CC#CC','method:n reverse:n unambiguousReactionsOnly:n allowDuplProdLists:n ignoreErrors:y')
as product from dual;
CN1N=NC(C)=C1C

However, when using the aromatised Smirks, the product is different and a double-bond is missing.
select jc_react('[#1,#6]-[#7-:2][N+:3]#[N:4].[#1,#6][C:5]#[C:1][#1,#6]>>[#1,#6]-[c:5]1[n:4][n:3][n:2](-[#1,#6])[c:1]1-[#1,#6]','C[N-][N+]#N.CC#CC','method:n reverse:n unambiguousReactionsOnly:n allowDuplProdLists:n ignoreErrors:y')
as product
from dual
Cc1[nH][nH]n(C)c1C, which after de-aromatisation gives CN1NNC(C)=C1C (I have lost a double-bond in the product)

What do you recommend?
Aromatise the reagents but not aromatising the Reaction? My aim is to apply the same rules to all reactions if possible.

Thanks
Catherine
creisser
Joined: 26 Apr 2006
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Post subject:
Link to postPosted: Thu May 01, 2008 1:35 pm  Reply with quote
The examples from my previous post were running on 5.0.2

I have just done a quick comparison with 3.2.6 and I get the result below

select jc_react('[#1,#6]-[#7-:2][N+:3]#[N:4].[#1,#6][C:5]#[C:1][#1,#6]>>[#1,#6]-[c:5]1[n:4][n:3][n:2](-[#1,#6])[c:1]1-[#1,#6]','C[N-][N+]#N.CC#CC','method:n reverse:n unambiguousReactionsOnly:n allowDuplProdLists:n ignoreErrors:y')
as product
from dual
Product = Cc1nnn(C)c1C

select jc_react('[#1,#6]-[#7-:2][N+:3]#[N:4].[#1,#6][C:5]#[C:1][#1,#6]>>[#1,#6][N:2]1[N:3]=[N:4][C:5]([#1,#6])=[C:1]1[#1,#6]','C[N-][N+]#N.CC#CC','method:n reverse:n unambiguousReactionsOnly:n allowDuplProdLists:n ignoreErrors:y')
as product from dual;
Product = CN1N=NC(C)=C1C

With 3.2.6, the aromatisation of the reaction does not seem to make a difference.

Thanks
Catherine
Zsolt
Joined: 11 Jan 2006
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Post subject: Re: Should reactions Smarts be aromatized ?
Link to postPosted: Mon May 05, 2008 11:33 am  Reply with quote
Hi,
creisser wrote:
I have the following query.
We have a small set of Reactions which we use to enumerate Combinatorial Libraries.
So far, I have automatically aromatised the Smarts and used them directly.
However, a recent example has shown that this sometimes causes problem.

This is the example Smirks un-aromatised, the reaction produces the expected product.
select jc_react('[#1,#6]-[#7-:2][N+:3]#[N:4].[#1,#6][C:5]#[C:1][#1,#6]>>[#1,#6][N:2]1[N:3]=[N:4][C:5]([#1,#6])=[C:1]1[#1,#6]','C[N-][N+]#N.CC#CC','method:n reverse:n unambiguousReactionsOnly:n allowDuplProdLists:n ignoreErrors:y')
as product from dual;
CN1N=NC(C)=C1C
Yes, this is the correct result.
Quote:
However, when using the aromatised Smirks, the product is different and a double-bond is missing.
select jc_react('[#1,#6]-[#7-:2][N+:3]#[N:4].[#1,#6][C:5]#[C:1][#1,#6]>>[#1,#6]-[c:5]1[n:4][n:3][n:2](-[#1,#6])[c:1]1-[#1,#6]','C[N-][N+]#N.CC#CC','method:n reverse:n unambiguousReactionsOnly:n allowDuplProdLists:n ignoreErrors:y')
as product
from dual
Cc1[nH][nH]n(C)c1C, which after de-aromatisation gives CN1NNC(C)=C1C (I have lost a double-bond in the product)
This result is not correct. The results should be the same whether the molecules in the reaction are aromatized or not. We will fix this bug in the next version.

Regards,
Zsolt
Gyuri
Joined: 21 May 2004
Posts: 704
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Post subject:
Link to postPosted: Mon May 05, 2008 2:48 pm  Reply with quote
The problem seems to related to a bug in the handling of aromatic nitrogens in reactions. The problematic aromatized product SMILES contains implicit hydrogens, which is invalid in this case. Those hydrogens should not appear in the products. My colleagues will check the error and will get back to you soon.
creisser
Joined: 26 Apr 2006
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Post subject:
Link to postPosted: Fri May 09, 2008 8:20 am  Reply with quote
Thanks
Catherine
Gyuri
Joined: 21 May 2004
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Link to postPosted: Wed May 28, 2008 3:22 pm  Reply with quote
The source of the error has been identified and corrected in the latest (5.0.4) JChem release.
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