The goal of a chemical design is to generate molecular structures whose physical properties satisfy a set of constraints. Thus, to design chemicals, Synapse requires:

1. Groups: the pieces of molecular structure from which new chemicals will be designed.
2. Limits: the minimum and maximum number of times each group can occur in a designed structure as well as the minimum and maximum number of groups and rings that designed structures may contain.
3. Constraints: once molecular structures have been created, we can estimate the candidate chemical's physical properties. These properties are then used to evaluate constraints.

Refractive index matching fluids are often used to fill the gaps between the ends of two optical fibers. If the fluid matches the refractive index of the fibers, there will be very little reflective loss as the light travels from one fiber to the next. In addition to constraints on refractive index, it is desired that candidate matching fluids have low freezing points, low vapor pressures and low flash points. It is also important that its refractive index does not change greatly as the temperature changes.

The following examples detail the steps needed to design refractive index matching fluids that have acceptable physical properties.

Synapse combines design groups into the molecular structures of candidate chemicals. Synapse then estimates those physical properties of each candidate chemical needed to evaluate the design's constraints. Thus, every chemical design requires an associated knowledge base which is used as the source of design groups and estimation techniques.

Thus, the first step in a chemical design is develop a knowledge base that contains the all the desired design groups and whose estimation techniques can accuractely predict the properties needed to evaluate design constraints. Often the MKS Core Knowledge Base will be sufficient for a design. However, it is possible that the knowledge base will need to be expanded by adding new groups, new physical property data and new estimation techniques.

At a minimum, you should evaluate your design's constraints on existing chemicals to determine the accuracy of the knowledge base's estimation techniques.

1. Open the MKS Core Knowledge Base document. (Create a copy of the document (see here) to use for these examples.)
2. Change to the Techniques Chapter and navigate to the RI,l,293: Vogel nD Method. (See the Navigation Overview documentation for details on navigating chapters and pages.)
3. Select the Evaluate Technique command from the chapter's Commands menu. The application will use the current technique to estimate the refractive index of every valued chemical in the current knowledge base.

Once the application has evaluated all chemicals having data values, it displays the results in the Technique Evaluation dialog.

1	The Evaluation Records table displays data values, estimated values, errors, absolute errors, percent errors and absolute percent errors for each chemical.
2	The Statistics table displays summary statistics for all "considered" records. Records that have been ignored are not included in the calculation of summary statistics.
3	The Graphs control displays several scatter plots and histograms comparing data values and estimates. Clicking and dragging the left mouse button to enclose data points will select their corresponding records in teh Evaluation Records table.

The Technique Evaluation dialog shows that Vogel's technique generates estimates with an average error of ±0.006 and a maximum absolute error of ±0.0371 for the 124 chemicals analyzed. These errors are quite low. Therefore, Vogel's technique should give good design results without modification.

Once we have verified that we can adequately estimate the physical properties we plan to use in our design, we can develop the design functions that use these estimated physical properties.

1. Select the New command from the File menu. The application will activate the Create a New Document dialog. Select the Chemical Design Document document type and press the dialog's OK button.
2. The application will activate the File Dialog prompting you for the filename of the new document. Enter a name and press the dialog's Save button. The application will create and open the new design document.
3. Enter values for the document's title, subtitle and descriptions. See documentation on the Document Titles Section and Document Information Section for details.
4. Using the tabs at the top of the document, change to the Functions Chapter by clicking the left mouse button on Functions tab. (See the Navigation Overview documentation for details on navigating chapters and pages.)
5. Create a new design function entity by pressing the "+" button in the menubar or executing the "Add New Page" command found on the Edit menu. A new, blank Function page will be added to the current document.
6. Click the left mouse button on the Identifier Pane's edit control. The application will activate the edit dialog. Enter the name "Refractive Index at 20°C" and press the dialog's Save button.
7. Now click the left mouse button on the Function Section's large edit control. The application will activate the Function Code dialog. Enter the following code:
   // Default declarations string prop, candidate; double ri, temp; int err; // Default assignments prop = "Refractive Index, Liquid at 293K"; candidate = Chemical(); temp = 273.15 + 20.0; // Retrieve the candidate's refractive index ri = CProp(candidate, prop, temp, 0, err); if( err != 0 ) return FALSE; // Assign estimate SetResult(ri); // Successful return TRUE;
8. Finally, press the Code dialog's Save button.
9. Refractive index matching liquids should also have a low vapor pressure so they to not evaporate quickly from connections where they are applied. We thus need to add another design function to estimate the vapor pressure at 20°C.

   Repeat the previous steps to create another design function. Name this function "Vapor Pressure at 20°C [kPa]" and enter the following code.

   // Default declarations string prop, candidate; double pvp, temp; int err; // Initialize values prop = "Vapor Pressure, Liquid - f(T)"; candidate = Chemical(); temp = 273.15 + 20.0; // Retrieve vapor pressure value pvp = CProp(candidate, prop, temp, 0, err); if( err != 0 ) return FALSE; // Convert from Pa to kPa pvp = pvp / 1000.0; // Assign value SetResult(pvp); // Successful return TRUE;

Before performing a chemical design, it is important to ensure the constraints and design functions have been entered correctly. Synapse provides a testing mechanism in which you can run a design function on an existing chemical entity.

1. Activate the copy of the knowledge base document we created in the first example.
2. Change to the Chemicals Chapter and navigate to Diethylene glycol dimethyl ether. (See the Navigation Overview documentation for details on navigating chapters and pages.)
3. Select the Compute Estimates command from the Commands menu. The application will activate the Property Estimation Dialog.
4. Press the dialog's Start button. The application will begin estimating all properties of the current chemical.
5. Once all estimations have been performed, press the dialog's Save button to store the estimated values into the current document.
6. Scroll to the Optical Properties Section and make a note of the estimated liquid refractive index, i.e., nD,l,293.

   1	The estimation liquid refractive index is 1.39251.

7. Now navigate to the "Refractive Index at 20°C" design function in the Functions Chapter of our newly created chemical design document.
8. Select the Test Chemical Function command from the Commands menu.
   The application will activate the Test Chemical Function Dialog.
9. Select Diethylene glycol dimethyl ether as the chemical candidate press the dialog's Calculate button. Synapse will execute the design function using the selected chemical candidate and display the results in the dialog. In this example, the design function successfully calculated a refractive index of 1.39251, the same value estimated in the knowledge base.

1. Activate the chemical design document we created in a previous example.
2. Using the tabs at the top of the document, change to the Combinatorial Designs Chapter by clicking the left mouse button on the Combinatorials tab.
3. Create a new Combinatorial design by pressing the "+" button in the menubar or executing the "Add New Page" command found on the Edit menu. A new, blank page will be added to the current document.
4. Click the left mouse button in the Identifier Pane, the large white box at the top of the page. The application will activate the pane's datum edit dialog.
5. Enter a name for the new design. Optionally enter a reference and comment.
6. Finally, press the dialog's Save button. The application will save the new design's identifier into the current document and display the new name you just entered.

A combinatorial chemical design will assemble groups in all possible combinations to generate candidate molecular structures, use estimation techniques to obtain physical properties for each candidate chemical and then use these physical property values to evaluate each design constraint. The groups and estimation techniques used in this process are retrieved from the design's associated knowledge base.

1. Ensure the copy of the knowledge base document we created in the first example is open.
2. Navigate to the new combinatorial chemical design we created in the previous example.
3. Click the left mouse button on the Source Knowledge Base Section's edit control. The application will activate the Knowledge Base selection dialog.
4. Select the knowledge base we have been using in these examples and press the dialog's OK button. The application will store this selection into the current document.

Synapse generates candidate chemicals by assembling a given set of groups in all possible combinations. The limits on the total number of groups to use and the total number of rings that may occur in these generated molecular structures are specified in the Design Parameters Section.

For this example we will use the following design parameters:

Parameter	Minimum	Maximum
# Groups	6	10
# Rings	0	0

1. Activate the chemical design document we created in a previous example.
2. Using the tabs at the top of the document, change to the Combinatorials Chapter by clicking the left mouse button on Combinatorials tab.
3. In the Design Parameters Section click the left mouse button on the Min # Groups field's edit control. The application activates the Enter Minimum Groups dialog.
4. Enter a value of 6 and, optionally, a comment. Then press the dialog's OK button.
5. Enter the remaining design parameters.

   1	Candidate chemicals are limited to having between 6 and 10 groups.
   2	Candidate chemicals are limited to having between 0 and 0 ring, i.e., candidate chemicals cannot contain rings.

Synapse generates candidate chemicals by assembling design groups into new molecular structures. The Design Groups Section is used to specify these design groups as well as the limits on their occrrence in new molecular structures.

For example, the previous image shows that five groups can be used to generate new molecular structures. It also shows that every new molecular structure must have between 0 and 2 -OH groups.

1. Click the left mouse button on the Design Groups Section's table control. The application activates the Design Groups Limits Dialog.
2. Click the left mouse button on the first row of the Design Groups Limits Dialog's table control and then press the dialog's Edit button. The application activates the Design Group Limits Dialog.
3. Enter the name of a design group, the minimum number of times the group must occur in a candidate structure, the maximum number of times the group may occur in a candidate structure and, optionally, values for the reference and comments. Finally, press the dialog's OK button.
4. Continue adding all the design groups and limits shown in the image below. Once all the groups and limits have been entered, press the dialog's Save button. The values are stored in the current document.

Synapse bonds design groups togehter in all possible combinations to form candidate molecular structures. Some combinations of design groups may not be desired due to chemical stability or reactivity. For example, the design groups presented in the previous example can be bonded for form acetals and peroxides, e.g.,

-O-CH-O-

-O-O-

For the design of refractive index matching fluids, such unstable chemicals are not desired.

The Sustructure Limits Section enables you to enter limits on the occurrence of non-design groups. Typically, the groups you enter into this section are larger groups which require or disallow particular combinations of design groups.

1. Click the left mouse button on the Substructure Limits Section's table control. The application activates the Substructures Limits dialog.
2. Click the left mouse button on the table control's first row and then press the dialog's Edit button. The application activates the Substructure Limits dialog.
3. Enter "-O-CH2-O-", the name of the group to restrict, 0, the minimum number of times the group may occur in a candidate structure, 0, the maximum number of times the group may occur in a candidate structure and, optionally, values for the reference and comments. Finally, press the dialog's OK button.
4. Repeat the previous steps to add a restriction on the occurrence of the "-O-O-" group. Then press the dialog's Save button. The values are stored in the current document.

Each chemical design contains one or more constraints which viable candidates must satisfy. Design constraints can be imposed on a single physical property, such as density or viscosity, or on a complex function of physical properties such as a heat transfer coefficient calculated by a Nusselt number correlation.

Each constraint contains a function name, a minimum value, a goal value and a maximum value. Some example constraints are shown in the following table.

Function	Minimum	Goal	Maximum
Freezing Point [°C]	-40	-10	0
Liquid Density at 20°C [kg/m3]	850	1000	1150
Heat Transfer Coefficient at 20°C [W/m2 K]	1000	1200	2000

We will use two constraints for our example refractive index matchnig fluid design:

• Refractive Index: the refractive index of viable candidates must be close to 1.458, the refractive index of the fused silica used in fiber optic cable.
• Vapor Pressure: the vapor pressure of viable candidates must be less than 0.40 kPa to reduce evaporation.

Additional constraints on density and viscosity could also be imposed but these two contraints will be enough for demonstration purposes.

1. Navigate to the new combinatorial chemical design we created in a previous example.
2. Scroll the datapane and click the left mouse button on the Constraints Section's large table control. The application activates the Edit Constraints dialog.
3. Click the left mouse button on the dialog table's first row. Then press the dialog's Edit button. The application activates the Edit Constraint dialog.
4. Enter "Refractive Index at 20°C", the name of the function we created in a previous example into the Constraint Function edit control. You can also press the dialog's List button for a list of all functions present in the current document. Enter a minimum value of 1.438, a goal value of 1.458 and a maximum value of 1.478. Optionally, enter values into the Reference and Comment controls. Finally, press the dialog's OK button.
5. Repeat the previous steps to enter a second constraint on the vapor pressure as shown in the following image.
6. Finally, press the Constraints Dialog to save the entered constraints into the current document.

1. Navigate to the new combinatorial mixture design we created in a previous example.
2. Select the Design Candidates command from the Commands menu. Synapse activates the Combinatorial Chemical Design dialog.
3. Press the dialog's Start button. Synapse will:
   • Generate candidate chemicals by combining all groups in all possible ways.
   • Estimate the refractive index and vapor pressure of each candidate chemical.
   • Check if these estimated properties satisfy the entered constraints.

   The Design dialog shows that Synapse generated 26,248 candidates, 329 of which satified our design constraints.

4. Finally, press the dialog's Save button to store the design results into the current document.

The Design Dialog will often very good insight into how the design inputs might be modified to produce improved results. For example, the Vapor Pressure histogram, shown in the Sequential Constraint Statistics section, shows that candidates were rejected because their vapor pressure was too low. Since, low vapor pressure chemicals are desired in this design, this result indictes that we should modify our vapor pressure constraint by lowering the range of acceptable values.

Further examining the design's results, we will also find candiates that contain the substructure:

Note that this substructure violates our desire to avoid acetals (and hemiacetals, ketals, and hemiketals). However, our current substructure limits do not restrict the occurrence of this group. We should thus replace the limit on the -O-CH2-O- group with a limit on a more general group.

In the previous example, Synapse designed 329 candidate chemicals that had refractive indices near 1.458 and vapor pressures below 0.40 kPa. This example shows how it is often useful to transfer candidates to a knowledge base for further analysis.

1. Open the MKS TGER Template Knowledge Base document. The template knowledge base contains techniques, elements, groups and references but no chemicals and no mixtures. We will use the template knowledge base as the starting point for creating our compilation of design candidates. (Note: the MKS TGER Template Knowledge Base can be downloaded from the MKS Documents section of our website's Library page.)
2. Choose the 'Save a Copy' command from the File menu. Synapse displays the Save As dialog.
3. Choose a location and enter a name for the knowledge base copy, e.g., “RI Matching Fluids Candidates”.
4. Finally press the dialog’s Save button. The application will display the Save Copy Progress dialog showing the progress of the save operation. The dialog will indicate when the document has been copied and give you the option of opening the copied document.
5. Press the dialog's Open button.
6. Update the document's titles and descriptions. (See documentation on the Document Titles Section and the Document Information Section for editing details.)

1. Activate the chemical Design document we created and navigate to the combinatorial chemical design we ran previously.
2. Select the Transfer Candidates command from the Commands menu. Synapse activates the Transfer Chemical Candidates dialog.
3. In the Destination Knowledge Base control, select the name of the newly copied template knowledge base. (IMPORTANT: make sure the original MKS TGER Template Knowledge Base is not selected.) Then press the dialog's Select All button. All candidates will be selected for transfer. Finally, press the dialog's Transfer button. Synapse will create a new chemical entity in the knowledge base for each chemical candidate.
4. Once the transfer is complete, press the Transfer Candidates Dialog's Done button.
5. Activate the knowledge base, change to the Chemicals chapter and navigate to any one of the newly transferred candidates.
6. Select the Estimate Multiple Chemicals command from the Commands menu.
7. Synapse activates the Estimated Multiple Chemicals dialog. Select "Refractive Index, Liquid at 293K" from the Estimated Property control and press the dialog's All button.
8. Press the dialog's Start button. Synapse will estimate the liquid refractive index at 293K for every chemical in the current knowledge base.
9. Finally, press the dialog's Save button. The application stores the estimated properties into the current document.

Each newly designed candidate contained in the new knowledge base can now be examined further. Refractive index can be estimated at other temperatures. Vapor press curves can be generated. Other properties such as viscosity and density can also be estimated.

The main concept is that using Synapse, you generated a new knowledge base containing refractive index matching fluid candidates, many of which could be novel chemical products.

1. Click the right mouse button on the liquid refractive index field's estimate control and select the Compile Values command from the displayed commands menu.
2. Synapse activates the Compile Property Values dialog. Select the "Estimates Only" option from the Status control and press the dialog's Compile button.

   1	Select the Estimates Only option from the Status control.

3. Synapse will compile all the refractive index values estimated in the previous example and display them in the Compiled Property Values dialog.

It is very interesting to note that the Maximum value shown in the dialog's Value Statistics section is below our goal value of 1.458, i.e., the refractive index of fused silica. This might indicate that we should perform another design with larger molecules or additional design groups.

Topic	Description
Estimating Chemical Properties	a short video demonstrating how to estimate the physical properties of pure chemical using either Synapse or Cranium.
Estimating Mixture Properties	a short video demonstrating how to estimate the physical properties of mixtures using either Synapse or Cranium.
Getting Started using Cranium	provides a quick tour of Cranium's capabilities including physical property estimation and a discussion of structure editing.
Getting Started using Synapse	provides a quick tour of Synapse's capabilities including examples of chemical product design.