Vibrational Circular Dichroism (VCD)

Tutorial Created with Software Release: 2025-2
Topics: Catalysis & Reactivity
Methodology: Molecular Quantum Mechanics
Products Used: Jaguar, Jaguar Spectroscopy, Jaguar, MS Maestro, Maestro

Tutorial files

3.8 MB
This tutorial is written for use with a 3-button mouse with a scroll wheel.
Words found in the Glossary of Terms are shown like this: Workspacethe 3D display area in the center of the main window, where molecular structures are displayed

 

Tip: You can hover over a glossary term to display its definition. You can click on an image to expand it in the page.
Abstract:

 

In this tutorial, we will learn to perform vibrational circular dichroism (VCD) calculations. We will process the obtained spectra and demonstrate how to automatically align these spectra with experimental spectra for comparison and analysis.

 

Tutorial Content

  1. Introduction to Vibrational Circular Dichroism (VCD)

  1. Creating Projects

  1. Preparing the Input Structure

  1. Running the VCD Calculations

  1. Plotting and Superimposing Theoretical and Experimental IR Spectra

  1. Plotting and Superimposing Theoretical and Experimental VCD Spectra

  1. Conclusions and References

  1. Glossary of Terms

1. Introduction to Vibrational Circular Dichroism (VCD)

The primary use of vibrational circular dichroism (VCD) spectroscopy is to establish the absolute configuration of synthesized chiral organic molecules and natural products. Herein, we will describe the technique in application to a compound X with a single chiral center. Compounds with multiple chiral centers can be studied via additional calculations.

If X is an enantio-pure compound with a known chemical formula but an uncertain stereo-configuration, it may either be an R- or S-enantiomer. A determination of the absolute stereo-configuration of X by VCD spectroscopy basically consists of two complementary steps: an experimental measurement and a theoretical calculation. These steps are independent of each other and can be performed in any order. With the help of a specialized spectrometer, an experimental VCD spectrum of X is obtained. The measurement is performed in a solvent in which X is soluble (typically deuterated chloroform or dimethylsulfoxide). In addition, a theoretical VCD spectrum of either the R- or S-enantiomer of X is predicted by a density functional theory (DFT) calculation. It might be important to perform this calculation in a simulated solution phase environment that matches the solvent used in the experimental measurement in order to account for the conformational effects in that environment. It is critical to include all possible conformers, because VCD spectra of different conformations of the same compound may look quite different. A single theoretical spectrum for either the R- or S-enantiomer should be sufficient for the determination of the stereo-configuration of X, since the simulated spectra of R- and S-enantiomers are mirror images of one another.

To assign the absolute configuration, the experimental spectrum is compared with the simulated spectra of the R- and S-enantiomers. If the experimental spectrum clearly matches the theoretical spectrum of the R-form, then X is assigned the R-configuration. If the experimental spectrum is a mirror image, it is the S-form. In rare cases, when the simulated spectrum does not have a sufficient similarity with the theoretical spectra (which usually occurs due to an inadequate accuracy in the theoretical simulation of conformational effects) additional steps need to be taken.

In this tutorial, we will be simulating the theoretical VCD spectra of fenchol, which is a terpenoid with a simple conformational energy landscape. The molecule of fenchol actually contains three stereocenters, but for simplicity, we will be working with only two stereoforms which are enantiomers. Accordingly, we expect the theoretical VCD spectra of these two stereo-configurations to also be mirror images.

An experimental VCD spectrum of unknown stereo-configuration of fenchol (but known to be either fenchol or alt-fenchol) has already been measured in chloroform by BioTools Inc. (Jupiter, Florida), and it is attached to this tutorial.

2. Creating Projects

At the start of the session, change the file path to your chosen Working Directorythe location where files are saved in MS Maestro to make file navigation easier. Each session in MS Maestro begins with a default Scratch Projecta temporary project in which work is not saved. Closing a scratch project removes all current work and begins a new scratch project, which is not saved. A MS Maestro project stores all your data and has a .prj extension. A project may contain numerous entries corresponding to imported structures, as well as the output of modeling-related tasks. Once a project is saved, the project is automatically saved each time a change is made.

Structures can be built in MS Maestro or can be imported using File > Import Structures (or drag-and-dropped), and are added to the Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion and Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data. The Entry Lista simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion is located to the left of the Workspacethe 3D display area in the center of the main window, where molecular structures are displayed. The Project Tabledisplays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data can be accessed by Ctrl+T (Cmd+T) or Window > Project Table if you would like to see an expanded view of your project data.

OR

  1. Double-click the Maestro or Materials Science icon

Note: This Jaguar workflow can be performed in Maestro or Materials Science Maestro. Use whichever interface you are comfortable with or typically use for your projects.

Figure 2-1. Change Working Directory option.

  1. Go to File > Change Working Directory
  2. Find your directory, and click Choose
  3. Pre-generated experimental files are included to be used in the analysis stage. Download the zip file here: schrodinger.com/sites/default/files/s3/release/current/Tutorials/zip/vcd.zip
  4. After downloading the zip file, unzip the contents in your Working Directory for ease of access throughout the tutorial

Figure 2-2. Save Project panel.

  1. Go to File > Save Project As
  2. Change the File name to VCD_fenchol_tutorial, click Save
    • The project is now named VCD_fenchol_tutorial.prj

3. Preparing the Input Structure

There are several ways to create 3-dimensional structures of fenchol or alt-fenchol in the workspace, but perhaps the easiest way is through the 2D Sketcher panel. We will proceed to draw fenchol.

Figure 3-1. The structure of fenchol in the 2D Sketcher

If you would like to draw the structure yourself, proceed to follow the steps in this section. If you would rather import the starting structure, go to File > Import Structures, navigate to where you downloaded the tutorial files and import fenchol.mae. Then skip to Section 4.

  1. Go to Edit > 2D Sketcher
    • The 2D Sketcher panel opens
  2. Draw the structure of fenchol, as shown in the Figure on the left

 

The 2D sketcher functions like many standard 2D molecular drawing tools. For a complete overview of using the sketcher panel, see the 2D Sketcher Panel documentation or watch the Building Small Molecules video in the Getting Going with Materials Science Maestro Video Series.

Note: Ensure that the stereocenters are correctly defined (go to View > Stereo to see R/S labels in the sketcher)

Figure 3-2. Saving and naming the entry.

  1. Click Save as New
  2. For Input Entry Title write Fenchol
  3. Click OK
    • A new entry is added to the entry list entitled Fenchol
  4. Close the 2D Sketcher panel

Figure 3-3. Fenchol in the workspace after sketching.

The fenchol enantiomer is now in the entry list. If you would like, change the representation to ball-and-stick by clicking on the Style menu and choosing Apply ball-and-stick representation

4. Running the VCD Calculations

We will now proceed to use the Jaguar Spectroscopy panel (panel help documentation here) to compute the VCD spectrum. In practice, to determine the stereochemistry of the unknown, we only need to compute the spectrum for one enantiomer. Thus, we will do so for just fenchol here. Note that you could follow the same workflow for alt-fenchol and you will arrive at the same stereochemical assignment.

Figure 4-1. Accessing the Jaguar Spectroscopy panel.

  1. Select Fenchol from the entry list
    • Recall that selecting means to highlight the entry in the entry list
  2. Go to Tasks > Browse All > Jaguar > Spectroscopy Workflows

Figure 4-2. The Jaguar Spectroscopy panel.

  1. Ensure that for Use structures from, Project Table (1 selected entry) is chosen
  2. Ensure that for Calculate spectra, VCD and IR is chosen

The panel can launch a variety of spectroscopy calculations. For this exercise, we will only need VCD and IR.

The panel allows the user to set different parameters, mainly associated with the particulars of the built-in conformational search. In this tutorial, we will maintain the default settings, which are typically sufficient, even for molecules with complicated conformational energy landscapes.

Figure 4-3. Selecting the Solvent.

The panel operates a workflow which combines conformation search performed by MacroModel and DFT calculations performed by Jaguar.

As the Keywords entry box suggests, in this calculator, Jaguar will be using the B3LYP-D3 functional in conjunction with the LACVP** basis set.

  1. From the Solvent dropdown menu, choose Chloroform
    • This is to match the experimental measurement which was performed in chloroform

Note: The geometry of the molecule will be optimized in solution phase using an implicit solvent PCM model. Single point energy calculations will be performed with the PBF model acting on the optimized structures produced by PCM. The reason the workflow is using split PCM/PBF solution phase calculations is that PCM drives less computational expensive and usually better-behaved geometry optimizations, whereas PBF provides more accurate final energetics.

Figure 4-4. Naming and running the job.

  1. Change the Job name to jaguar-spectroscopy_fenchol
  2. Adjust the job settings () as needed
    • This job requires a CPU host and, for reference, should complete in about 25 minutes with 6 CPUs
  3. If you would like to run the job yourself, click Run. Otherwise go to File > Import Structures, navigate to where you downloaded the tutorial files and Open Section_04 > jaguar-spectroscopy_fenchol > jaguar-spectroscopy_fenchol > jaguar-spectroscopy_fenchol_cd-out.mae

 

Note: MacroModel will return all the MM conformers matching the conditions specified in the panel (see the Figure on the left) and pass them to Jaguar. Jaguar will apply DFT calculations to these conformers and will return the optimized conformers in the incorporated results.

Figure 4-5. The output after incorporation.

  1. Close the Jaguar Spectroscopy panel

When the calculations finish or when the structures are successfully imported, the conformations found for fenchol will be incorporated into the workspace and the entry list will update accordingly.

Three conformations for the enantiomer were found in the course of the VCD calculation. They differ by orientation of the OH-group. Feel free to include and visualize the various outputs.

5. Plotting and Superimposing Theoretical and Experimental IR Spectra

When the VCD calculations finish, we can compare the predicted spectra with the experimental one. The analysis and comparison of the spectra is done in the Spectrum Plot panel.

Figure 5-1. The VCD Plot Spectra panel.

  1. Go to Tasks > Browse All > Jaguar Mechanics > Plot Spectra

The Spectrum Plot handles various types of spectra predicted by Jaguar. First, it is advisable to compare and align IR spectra which come with both experimental measurements as well as theoretical predictions of VCD spectra.

  1. For Type, ensure that VCD-IR/Raman is selected in the upper-left dropdown
  2. To import the experimental IR spectrum, change the Plot dropdown to Other Experimental Spectrum and click Browse

Figure 5-2. The experimental IR spectrum after importing.

  1. Navigate to the provided tutorial files and open the Section_05 > Experimental-IR.prn file

Figure 5-3. The overlaid theoretical and experimental IR spectrum after importing.

For the computed spectrum, we are going to plot the conformationally-averaged spectra which the workflow automatically creates.

  1. To import the theoretical IR spectrum for fenchol, change the Plot dropdown to Other Theoretical Spectrum and click Browse
  2. Navigate to the provided tutorial files and open the Section_05 > jaguar-spectroscopy_fenchol > jaguar-spectroscopy_fenchol_Fenchol > jaguar-spectroscopy_fenchol_Fenchol_avg_vib.spm file

Figure 5-4. The Align to Experimental tool.

  1. Click on the Align to Experimental button at the top of the panel
  2. Click Options and set the bounds to Low: 800 and High: 1600
    • This is a good representative region
    • Click back into the Align to Experimental panel to save the options
  3. Click Align & Plot

Figure 5-5. Stacked experimental and predicted IR spectra.

  1. Change the Multiple spectra dropdown to Stacked
    • Three spectra can be viewed in the plotter

The theoretically predicted spectrum (red) is aligned to match the experimental spectrum (black) in the best possible way, resulting in the aligned spectrum (blue). The label for the blue spectrum, which is automatically added to the plot, includes the Pearson coefficient, which is 0.94 in this case.

A coefficient of 1.0 signifies a perfect match, a coefficient of -1.0 signifies a perfect anti-match, and that of 0.0 indicates no match at all. A coefficient of 0.94 suggests a very good match.

Note: The alignment algorithm identifies the theoretically predicted peaks automatically. In doing so, it tends to ignore the fine structure of the peaks, and that is why the aligned (blue) spectrum may look somewhat smoother than the original (red) spectrum. Please note that the algorithm to align the spectra does not provide a uniform frequency shift, so exercise caution.

6. Plotting and Superimposing Theoretical and Experimental VCD Spectra

Now that we are satisfied with the agreement between the experimental and theoretical IR spectra, we can proceed to perform the analogous analysis on the VCD spectra.

Figure 6-1. The experimental VCD spectrum after importing.

  1. Reset the Spectrum Plot panel (do so using the blue arrow icon at the bottom of the panel)
  2. For Type, change to VCD-IR-Raman in the upper-left dropdown
  3. To import the experimental VCD spectrum, change the Plot dropdown to Other Experimental Spectrum and click Browse
  4. Navigate to the provided tutorial files and open the Section_06 > Experimental-VCD.prn file

Figure 6-2. Stacked experimental and predicted VCD spectra.

For the computed spectrum, we are going to plot the conformationally-averaged spectra, which the workflow automatically creates.

  1. To import the theoretical VCD spectrum for fenchol, change the Plot dropdown to Other Theoretical Spectrum and click Browse
  2. Navigate to and open the Section_05 > jaguar-spectroscopy_fenchol > jaguar-spectroscopy_fenchol_Fenchol > jaguar-spectroscopy_fenchol_avg_vcd.spm file
  3. Repeat the Align to Experimental steps (Steps 9-11 in the previous section) and change the Multiple Spectra to Stacked
    • An automatically aligned spectrum will appear with the same color-scheme as in the IR case

The aligned spectrum (blue) matches the experimental spectrum (black) quite well. The Pearson coefficient is 0.95. Note that the Pearson coefficient of the aligned IR and VCD spectra may be close but do not have to be the same; it is only coincidence in this case that they are so close. Another useful thing to note is that if we had aligned the experimental VCD spectrum with the theoretical spectrum of alt-fenchol, the Pearson coefficient would have been negative of the alignment for fenchol (-0.95 in this case).

 

As was already noted above, a coefficient of 1.0 signifies a perfect match. Thus, in our case, the Pearson coefficient for the alignment of the theoretical spectrum of fenchol and the experimental spectrum provided by BioTools, Inc. of 0.94 clearly indicates that the enantiomer used in the VCD measurement experiment was fenchol rather than alt-fenchol.

7. Conclusion and References

In this tutorial, we demonstrated how to compute theoretical VCD spectra and how to compare them to an experimental VCD spectrum. In this exercise, we computed the spectra of an enantiomer of fenchol, and by comparing the computed spectra with the experimental one, we have established that the absolute stereo-configuration used in the experimental measurement correspond to fenchol and not alt-fenchol.

For further learning:

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For some related practice, proceed to explore other relevant tutorials:

For further reading:
  • Visit the panel help documentation here.

8. Glossary of Terms

Entry List - a simplified view of the Project Table that allows you to perform basic operations such as selection and inclusion

Included - the entry is represented in the Workspace, the circle in the In column is blue

Project Table - displays the contents of a project and is also an interface for performing operations on selected entries, viewing properties, and organizing structures and data

Recent actions - This is a list of your recent actions, which you can use to reopen a panel, displayed below the Browse row. (Right-click to delete.)

Scratch Project - a temporary project in which work is not saved. Closing a scratch project removes all current work and begins a new scratch project

Selected - (1) the atoms are chosen in the Workspace. These atoms are referred to as "the selection" or "the atom selection". Workspace operations are performed on the selected atoms. (2) The entry is chosen in the Entry List (and Project Table) and the row for the entry is highlighted. Project operations are performed on all selected entries

Working Directory - the location where files are saved

Workspace - the 3D display area in the center of the main window, where molecular structures are displayed