Multiple substitution with the same reagent on one molecule

Hi. I would like to generate differently substituted porphyrins with two lists of substituents(for example, list #1 contains -F, -Cl, -Br and list #2 contains phenyl, trifluoromethyl and methyl). There are 4 "meso" and 8 "beta" positions on this molecule. The beta position can only be substitued with a group from list #1 and meso from list #2. I couldn't figure out how to generate a library in which every porphyrin's meso substituents (and beta) are from the same group. In the above example the desired output would be 9 different molecules:

4 meso phenyl and 8 beta fluorine

4 meso phenyl and 8 beta chlorine

4 meso phenyl and 8 beta bromine

4 meso methyl...

In my every attempts the molecules had different substituents in the same kind of positions( for example 3 -F and 1 -Cl) or the reactor added extra R-groups to these positions(making them hipervalent(5) carbons) or only one atom were substitued and the other 3 or 7 remained R. What should I do differently?

Thank you for your help in advance

Zoltán

Please attach your input molecules and the expected output as molecule files (in any format we support). Attach also the reactions which didn't generate the expected output. 

Zsolt

The files:

reactor_1.xml : reaction resulting in hypervalent carbons
reactor_2.xml : reaction resulting in only one substitution
reactor_3.xml : half-success, I had to completly ignore the starting macrocycle. Because of this, this cannot be applied to substitute the resulting molecules in another position.
reactor_betaposition.mrv : a set of substituents for "beta" substitution
reactor_mesoposition.mrv : a set of substituents for "meso" substitution
reactor_macrocycle.mrv : a set of starting macrocycles. If this library generation works, I would like to substitute related macrocycles in a similar manner.
reactor_mesoporphyrin_reactor_1.mrv The : results of reactor_1.xml
reactor_mesoporphyrin_reactor_2.mrv The : results of reactor_2.xml
reactor_mesoporphyrin_reactor_3.mrv The : results of reactor_3.xml Examples of (only) meso substitution in a desired way.
example.mrv : examples of desired substitution pattern.

Hi,

Will you always have the same input, phorphyrin? If not, what similar compounds would you like to use as input?

Thanks, Anna

There are two examples in the attached file: the first is a corrole, the second is a porphyrinogen.

Hi Zoli,

I do apologize for the delay in getting back to you. 

You will be able to generate the desired products in two single steps: 
1. First step is going to be the halogenation,
2. the second step is going to be the aromatic substitution.
The output of the first step should be the input of the second step.

Scheme in SMARTS for the first reaction: [H:3][c:1](:c):c.[Se:4][#17,#35,#53:2]>>[#17,#35,#53:2]-[c:1](:c):c
Reactiviry rule: smallestAtomRingSize(ratom(1)) > 6

Scheme in SMARTS for the second reaction: [H:3][c:1]1c[#6][#7]c1.[#6;a:2][Se:4]>>[#6;a:2]-[c:1]1c[#6][#7]c1 
(No reactivity rule is required this case)

Hope this answeres your question.

Cheers,
Anna 

Hi,

I've tried the halogenation and it didn't work. The result is halogenation.mrv(ratio= 1:2, combinatorical) and the reactivity rule had no effect on the output. The reaction wasn't selective for the beta positions and if the ratio was higher than 1:1, some products had different halogens on them. 

I've also experimeted with an another reaction(dimethyl_reaction.mrv, the result is in dimethyl.mrv). The two molecules generated are exactly the same. This means that the double bonds indicating the aromaticity of the porphyrin makes the symmetric porphyrin "look like less symmetric" for reactor.

I am trying to regenerate your issue, but it works for me.

Are you using Reactor for reaction enumeration? If so, which version? What parameters are you using while enumerating products? Can you attach a screenshot of your settings?

Anna

Reactor version number is 5.12 201303201150-301163
After the screenshot I found out that the reactor doesn't remembers the reactivity rules, but I don't know why(so after clicking on 'OK' on the  reaction rules' dialog box and then on the 'Reaction rules' button again it shows a blank text field with the grey 'type your chemical terms here...' text).

I see, you are using Reactor within Instant JChem. I would suggest you to use tha latest version, 5.12.4, although this should not be a proble. 
I tried the same reaction, I think it works. I had no issues with reaction rules.

I attached a screenshot and I also attached the reactants I used and products I got after reaction enumeration in combinatorial mode using 1:2 ration. These are the products you would like to get?

Anna

Yes, this should be correct with an appropriate 1:4(1:3 in case of the corrole) reagent ratio.

Hi Zoli,

Is the reaction working?
I attached the reaction file I am using to generate proper products. Let me know how it goes.

Cheers,
Anna

I've tried the previous settings with a halogen ratio of 8 and I wasn't able to stop the reactor. After restarting IJChem I found the three correctly substituted porphyrinogens, so the attempt to substitute the corrole chrashed it. I tried the reaction again with only the porphyrin as a substrate, but the result was the same crash without generating any molecules. Reactor still won't remember the reaction rules.

I ran this reaction in IJC, using 1:8 ratio. Please take a look at the attached file, is this what you are looking for? 

Did you intall all the licenses properly? Is Instant JChem running well otherwise?

I installed the academic research licence and it was only one file. I haven't actually used the trial licence on the computer that I use. IJC is working without any problems, despite this.

Could you give me a brief, step by step overview how are you generating those products in IJC?