ACE Reaction Network
********************

Reaction network generation ACE reaction Reaction discovery

The Amsterdam Modeling Suite has several tools available to create
reactions networks:

* ACE reaction (this tutorial),

* PES Exploration, and

* ChemTrayzer2

Out of these, **ACE reaction is the fastest tool**, and can be used
for quick initial guesses of a network.

ACE Reaction generates a reaction network from  user-specified
reactants and products. It creates initial guesses for intermediates
based only on molecular graphs, and then confirms the validity of the
intermediates using geometry optimization.

In this tutorial you will learn to use ACE reaction to generate a
network, and interpret the results.

We will use the following addition reaction as our example.

[image]

**ACE reaction needs a selection of active atoms as input**, and the
set should never be larger than 11 atoms. The red atoms in the above
figure are the atoms we expect to be involved in bond-breaking or
forming.

We can use our chemical intuition to predict a reaction mechanism, and
then see if ACE reaction indeed suggests this reaction as a likely
option.

The expected reaction mechanism would involve

* deprotonation of the diketone (the negative charge will be
  stabilized by conjugation with the two oxygen atoms), followed by

* electrophilic addition to the protonated cyclohexenone molecule, and

* finalized by a proton jump to recreate the ketone from the enol.

[image]


Set up the ACE reaction network computation
===========================================

   **1.** Start **AMSinput**
   **2.** In AMSinput, select the **ACE Reaction Network** panel: [image: ADFPanel][image] → [image: ACErxnNetworkPanel][image]
   **3.** In the Main panel, select **Mopac** from the **Engine** dropdown menu

Now the reactant and product structures can be either imported or
drawn. In the drawing panel on the left of the window, the bar at the
bottom shows that the reactant is selected and can now be created.

Tip:

  The SMILES strings for these molecules are:

  * Reactant 1: "O=C1C=CCCC1"

  * Reactant 2: "CC(=O)CC(C)=O"

  * Product: "CC(=O)C(C(C)=O)C1CCCC(=O)C1"

   **4.** Download the xyz files "here" and save and unpack
   **5.** Use **Import System** from the **File** menu to import the file reactant1.xyz into the **Reactant** block in the drawing panel
   **6.** Click on the **+** next to the **Reactant** entry in the main panel
   **7.** Select **New Molecule** in the dropdown menu of the newly appeared reactant entry
   **8.** In the drawing panel, change the name of the new molecule block from Mol-1 to Reactant2, and use **Import System** from the **File** menu to import the file reactant2.xyz.
 [image]

   **9.** Click on **Product** at the bottom of the drawing panel
   **10.** Import the product molecule (product.xyz)
 [image]

   **11.** Select the active atoms in the reactant molecules and add them by clicking on the **+** button next to  **Active Atoms**

* Reactant 1 should have **5** active atoms (2 H, 2 C, 1 O)

* Reactant 2 should have **6** active atoms (3 H, 3 C)

* Total number of active atoms: **11**

See the figure below for the exact atoms to select:

[image]

The active atoms are the only atoms allowed to be involved in bond-
breaking and bond-forming processes.

   **12.** Select the **Fragments** panel from the **Model** menu, and wait a few seconds for the fragments to be created
 [image]

These fragments are the smallest possible fragment, based on the
selection of active atoms. **It is good practice to check the guessed
fragment charges**, to see if they will lead to the correct charges
for any intermediate molecules we expect.

In this case, we can see that all the active H-atoms have a charge of
+1, which is compensated by the fragments they are coordinated to.

The first step of our proposed reaction indeed involves a proton
transfer, which requires the transferred H-atom to have a positive
charge. Therefore the expected charges of the proposed intermediates
match the guessed fragment charges, and we can accept them as
reasonable guesses.

All fragments are estimated to be non-stable, which means that
intermediates that contain a pure fragment as one of its submolecules
will not be accepted.

We are now ready to run our ACE reaction job. An ACE reaction
calculation always consists of three steps.

1. Intermediate generation by iteratively breaking and forming bonds
   in the reactant molecules.

2. Creating a reaction network by determining which pairs of newly
   created intermediates are connected by an elementary reaction.

3. Minimizing the reaction network by eliminating paths that involve
   to many bond-breaking and forming processes.

By default these three steps will all be performed, but the user also
has the option to select only one of the steps. If only step 2 or 3 is
selected, a restart directory needs to be provided. In this case we
keep the default selection of **All**.

[image]

There is a final option **Analyze Network**, which also requires a
restart directory to be specified. This option reads a network from
the restart directory, and allows the 'min number of shortest paths
written' (default is 5) to be adjusted. The selection of shortest
paths will then be written to a separate RKF file. The setting 'min
number of shortest paths written' can be found in the main panel.


Running an ACE reaction job
===========================

   **1.** Use the **File** → **Run** command
   **2.** When asked to save your input, save it with a name of your choice.
   **3.** The AMSjobs window comes to the front and your job starts running.

It will take a few minutes for the job to finish.

Note:

  ACE reaction jobs may not show in AMSjobs by default. You can make
  them visible by checking the option for **Filter** → **Other**.

   **4.** When the job has finished, select the job in AMSjobs and click on **SCM** → **Movie**

This will open the five shortest paths found from reactant to product.

[image]

It is also possible to view the full reaction network in AMSmovie, but
this will be difficult to interpret.

   **1.** Select **SCM** → **Movie** to open a new AMSmovie window.
   **2.** Select **File** → **Open...** to open the file acerxn.results/ams.rkf
 [image]

As can be seen, the full network contains too much information to
display meaningfully in AMSmovie. We will use the shortest_paths
window for any further interpretation.


Interpret an ACE reaction job
=============================

The five shortest paths are also displayed schematically in the
logfile.

   **1.** Go to AMSjobs, select the ACErxn job, and among the created output files double click on **.logfile**
 [image]

   **2.** Scroll down to the bottom of the logfile, to find the schematic depiction of 'The shortest paths from reactant to product'
 [image]

For each of the five paths the names of the intermediates are listed,
separated by arrows. At the end of each line, the total number of
bonds broken and formed is depicted, which will be referred to as the
chemical distance. Inside each arrow, the chemical distance of the
elementary reaction is shown.

The **shortest path** has an overall chemical distance of 3, and
involves intermediate 1_1_2. A quick look at AMSmovie shows that while
this path is the shortest, it is not the lowest energy path.

The **lowest energy path** connects the reactant (R1) and product (P1)
via the two intermediates 1_1_1 and 1_1_5, and has an overall chemical
distance of 5.

The reaction diagram in AMSmovie shows that intermediate 1_1_1
corresponds to state 5, and intermediate 1_1_5 corresponds to state 6.
In the left panel of the AMSmovie window we can scroll to state 5 and
state 6 using the scroll bar at the bottom.

[image][image]

Comparison to our expected reaction mechanism shows that these two
intermediates indeed correspond to our expected intermediates, and we
can conclude that **ACE reaction was able to predict the expected
reaction mechanism**.


Analyze network
===============

The number of shortest paths printed to logfile and exported to
AMSmovie is passed to the job *a priori* in the settings. Since it is
very difficult to visually interpret a network that is too large, the
user may want to extract additional paths from the full network *a
posteriori*. This section describes how to do this.

   **1.** Save the current job in AMSinput under a new name
 [image]

   **2.** Change **Steps:** from **All** to **Analyze Network**
   **3.** Under **Restart directory**, fill in the path to the results directory from the previous job
   **4.** Set **Min number of shortest paths written** to 10 (default is 5), in order to view more paths.
   **6.** Save the job
 [image]

   **7.** Now run the new job and open the result in AMSmovie.

The resulting network as depicted by AMSmovie contains ten paths, and
therefore looks complex.

[image]

All ten paths are also present in the logfile.

[image]

The individual paths have now been stored in the results folder, and
can be opened in AMSmovie.

   **8.** Select **SCM** → **Movie** to open a new AMSmovie window.
   **9.** Select **File** → **Open...** to open the file analyzie.results/path6.rkf

A single path opens in AMSmovie. Compared to path 0, reactions along
path 6 are less likely to occur, as it involves an unnecessary
intermediate, and can in this case be discarded as an option. More
detailed analysis, such as transition state searches, can now focus on
the chemically intuitive pathways.

[image]
