Frustrated Reactor User

Can someone tell me what reactivity rule I could write to exclude amides and sulfonamides from reacting like amines in a simple amidation reaction?  I've been using Reactor for well over a year to do library enumerations, and I thought the following rule would work:

!match(ratom(1), amide, 2) && !match(ratom(1), "[nH1]") && !match(ratom(1), sulfonamide, 3)

This rule worked for amides but not sulfonamides. 

I find the entire suite of programs developed by ChemAxon to be very non-intuitive to the working synthetic chemist.  I shouldn't have to know about smiles, UNIX commands etc to get my work done.  Your User Manuals are written for computer programmers, and not chemists and as such are impossible to read and understand, much less find an answer to a simple question.

Thanks for reading.

Dear Edvard,

Thank you for your honest opinion. Many chemists work with Reactor within Excel sheets (JChem for Excel) or Instant JChem database and usually do not face with the tough task of reaction rule design.

Though, many computational scientists and cheminformaticians love their efficiency and flexibility, you truly speak from my heart, synthetic chemists should not need to waste their time by learning SMARTS (not even SMILES) or command line tools to be able to create virtual reactions.

However, synthetic chemistry problems are complex as well, and it is quite difficult to formulate them. It is easy to draw atoms that are needed, but it is more difficult to specify something that you would like to exclude, especially if you have further dependencies and conditions as well. It is not simple to intuitively display something that should NOT be present in the neighbourhood of a reaction site. We introduced a dictionary of functional groups hiding the corresponding SMARTS expressions. You use that dictionary when you refer to functional groups by names like amide, sulfonamide, but there are certainly lots of places for improvements. I would gladly welcome any examples or ideas for visually simple and intuitive specification of complex reaction sites.

(Minor issue, but it would have improved the readibility of your expression if you used  and instead of &&. We support both forms of this logical operator)

Besides, we develop a reaction library ourselves and provide it with Reactor hoping that we can ease your life by providing the most important set of classical synthetic reactions in the near future. Any bug reports, suggestions and contributions are appreciated.

You are right, many parts of the documentation are programmer oriented and often difficult to locate. We are aware of that and I am glad to see that that our new application scientists having chemistry background have started to review and rewrite the documentation. It s a longlasting task and will take some time to notice their work due to the release cycles as well, but they are on the problem.

Regarding the concrete case, please send your generic reaction scheme and some example reactions you expect and would like to avoid (screenshots will do), and we will try to help to find a suitable solution.

Best wishes,

Gyorgy

Hello Gyorgy,

Thank you for your quick response.  I appreciate your concern and the time.  I too have used ChemAxon products a lot with Excel but every so often, I need to use Reactor to prepare reaction templates to be used in high speed automated synthesis.  Fortunately we already have a number of Reactor schemes saved which we can use and easily modify if needed.  When some new chemistry is being introduced, a new reaction scheme needs to be prepared.

The general reaction scheme and screen shots are in the attached Word Doc.  It's essentially an amidation reaction of a Boc-protected amino acid followed by deprotection.  I've included in the example, the sulfonamide which reacts twice.  I've also attached the files from Reactor, and the structure files for your use.

Thanks again.  If you need additional information, let me know,

Sincerely,

Edward Fritzen

Thanks for the files. I am on the road at the moment, so I will be able to respond next week. Is that OK?

No problem.  Let me know if you need more information.

Ed

Please see the attached reaction, it contains your example, so you can easily test it within Reactor or the Reaction Editor. Basicaly you would just need a simple Reactivity rule:

match(ratom(1), amine, 2)

but the "amine" definition did not pay attention to the N-methyl-sulfonamido case, so I just added the enhanced definition in SMARTS that seems to work.

match(ratom(1), "[#6X4:1][NX3;!$(NC~[!#1!#6]);!$(N[!#1!#6]):2]", 2)

I will review and enhance our related functional group definitions. Is this the behaviour you expected?

Hi Gyuri,

I tried the file you sent and there is something wrong with that file.  I've captured the screen shots and have attached a Word Doc which describes the behavior I see when attempting to use your file. 

In any event, I devised a work-around which avoids the use of the rule.  I've attached the revised Reactor scheme for your information.  Essentially, I excluded a sulfur atom at one of the atoms in the reactants and this scheme behaves like it should, exluding any sulfonamides from undergoing the reaction.

Thanks for you all your help.  I've tried to learn more about Reactor and some of other ChemAxon products, but I find the online user manuals very difficult to understand. 

Thanks again,

Ed

When we design a new reaction, we first fill the reaction examples list in the Examples page of the Reaction Editor. Those are used as a test set
during the reaction design. The first example is a typical one, since
it is displayed on the reaction selection page (when available). Other examples are for testing the reaction scheme and the rules. If anything goes wrong, one or more examples will fail during the tests. When no reaction is present, the generic scheme is displayed in the reaction selection page. So, the behaviour you mentioned is intentional, chemists usually
prefer to see a real reaction example in our reaction library not an ugly reaction scheme
(sometimes they look really ugly) ;)

I sent you a reaction containing several examples (Example page), even additional properties (Properties page). It is a generic acylation of amines that works with acid halides, carboxylic acids, anhydrides and esters as well. I added your reaction example to the list of the examples, it is the last one. You can test the reaction scheme in two ways. Either press the test button on the Test page of the Reaction Editor, or you can import the example reactants with a toolbutton on the second page of the Reactor wizard to see reactions performed with the examples. It seems that all of the examples including your one works properly.

No doubt, the documentation should be better, my colleaues are aware of our fair comments, and will work on the improvements.

Gyuri,

Thanks for the help.  Now I understand what's going on.  You're right, the reaction you sent does work fine.  I still have a lot to learn about using Reactor.

 

Ed

Hi,

This is a complex task, and I really appreciate that you take your time to design new reacion rules. The reaction editor interface should be more intuitive, not mentioning the documentation issues again. If you have any more problems you know how to reach me.

Best wishes,

Gyuri