Computational and Experimental Study of Isomerization in N,N-dimethylacetamide (DMA) and its Derivatives

Jonathan Smith

Gustavus Adolphus College

            In this investigation, we explore the kinetics of the hindered rotation about the C—N bond in N,N-dimethylacetamide (DMA). If DMA were a completely rigid molecule, it is expected that the amino methyl protons will exhibit two resonances integrating for three each in the proton NMR, corresponding to CH₃ groups that are "cis" and "trans" to the carbonyl group. If, on the other hand, there was free rotation about the C—N bond, then one would observe only one resonance as all six protons would have the same "average" chemical environment. In fact, DMA is an intermediate case, with two, slightly broadened resonances existing at room temperature. With increased temperature these resonances broaden and coalesce into a single transition. Our goal is to determine the activation barrier for the rotation about the C—N bond by measuring the rate of the isomerization as a function of temperature.

            We will first study this system from a computational perspective trying to understand the relative energies of the different conformers and the electronic structure of these compounds and how this electronic structure influences the energetics of conformational isomerization. Concurrently we will examine the temperature dependent NMR spectrum to get a sense as to the relative population of these conformers and the barrier to isomerization.  The computational and experimental results will be combined to develop a detailed understanding of this class of molecules and their 3D conformation.  This study has increased relevance because the amide linkage in these systems is functionally identical to the peptide bond which connects amino acid residues to form large and biologically important proteins.

In preparation we will read a paper to determine previous experimental and computational approaches to this question.

 

 

Steps

• The experimentation and computation will span two weeks during which groups of ~three will carry out extensive molecular modeling and will spend about 2 hours recording temperature dependent NMR spectra.
• Each group will record the temperature dependent proton NMR spectrum of either N,N-dimethylacetamide (DMA), formamide, methylformamide, or other derivative.
• We will do calculations using WebMO as a graphical Web-based front-end to Gaussian 03 to explore and understand the underlying electronic structure, relative energies of conformations, and other relevant comparisons using a variety of different model chemistries.  Outline specific properties that you will examine but use the calculations to explore and understand the subtle differences between a series of compounds.  Use the article by Wiberg and Breneman for ideas as to useful questions to explore.  We will explore several aspects of 3-5 different derivatives including relative energies of conformers, the barrier to isomerization through relaxed potential energy scans, NBO (natural bond order) analysis yielding bond orders and atomic charges, and examination of molecular orbitals.  Use the tools and the ideas developed to also examine a dipeptide and its conformational flexibility.  Diglycine or dialanine might be reasonable starting points.  The aim is to put together a fairly complete picture of the dynamics of isomerization in a range of these compounds and write out several paragraphs with tables providing an overview of the specific molecules and the trends you observe.  Be creative in selecting some interesting derivatives to examine, they are free since they are just in silico! (See: Gustavus Computational Resources). 
• Prior to your investigation sketch these structures and an approximate proton NMR spectrum.  In preparation for your investigation read the paper (concentrating on the abstract and the first couple of sections):

Resonance Interactions in Acyclic Systems. 3. Formamide Internal Rotation Revisited. Charge and Energy Redistribution along the C-N Bond Rotational Pathway

Kenneth B. Wiberg and Curt M. Breneman
Journal of the American Chemical Society, 114, 831-840 (1992).{copy available outside my office}

Questions:

1. What do they find from their computations to be the barrier to isomerization?

2. Why is it useful to look at the changes in C-N and C-O bond length upon isomerization?

Experimental Investigation

• We will record the temperature dependent NMR spectrum for one of the compounds. (See Gustavus NMR tips)
• Ethylene Glycol will be used for temperature calibration.
• Use Mestrec to analyze your spectrum.
• For analysis of the data see following Journal of Chemical Education Paper

NMR Determination of the Rotational Barrier in N,N-dimethyl Acetamide

Francis P. Gasparro and Nancy H. Kolodny
Journal Of Chemical Education, 54, 258-261 (1977).{copy available outside my office}

• We will want to determine the activation energy for the isomerization process and compare this with the below computed value
• Use the Mathcad document: NMR_Bloch.mcd to analyze the temperature dependent spectra and determine the most appropriate value of t at each temperature.  Construct a plot to determine the activation energy for isomerization. 

            Arrhenius Equation

• Using regression E_a can be determined from the slope and A (the Arrhenius pre-exponential factor, the rate in absence of a barrier) can be determined.  An example Mathcad document for the example of N,N-dimethylformamide is at: Mathcad: Kinetics of Isomerization in N,N-dimethylformamide, Matcad file: NMR_Temp_data.mcd

Computational Investigation

This investigation is self directed but below are some details you may want to examine.  You need to explore the barrier to isomerization to compare this to your experiment. There are two parts, the quantum chemical calculations handled by WebMO as a front-end to Gaussian 03 and molecular dynamics calculations in which the motions of the system and its exploration of the energy surface (energy vs. geometry) can be examined over time using a classical “ball and spring” type molecular model.  These molecular dynamics calculations will be carried out using the Gustavus WebAmber interface to the Amber suite of programs.

1.     Quantum Chemical Calculations

Draw N,N-dimethylacetamide, formamide, and methyl-formamide in WebMO

Optimize and examine these structures within two different model chemistries (ie. AM1 or HF and 6-31G(d) or others).

Compare the structures and record some pertinent geometrical data.

Examine the energy associated with the barrier to isomerization using the potential energy function in WebMO with Gaussian 03.

Carry out a “relaxed” potential energy scan to get at the barrier to isomerization.  You can create a calculation that will scan the desired dihedral angle (the angle formed by four atoms with the first three defining a plan and the fourth forming an angle with the rest) to get energy versus angle, the potential energy.  Use a coordinate scan type of calculation in WebMO with the computational model chemistry you are using (ie. AM1/3-21G or HF/6-31G(d) ) and check preview input.  Add the following line to the bottom of the text file when you preview input:

 

3 4 5 6 20.0 S 40 10.0

Leave a blank line and then enter the above with the 3 4 5 6 representing the numbers of the atoms in the dihedral you are examining (you can get the atom numbering in the job window by clicking on the lowest icon on the left of the view window), the 20.0 representing the starting angle, the S indicates a scan, the 40 is the number of steps, and the 10.0 is the number of degrees increment in each step.  This same strategy can be used to examine bond lengths and bond angles by specifying only 2 or 3 parameters, respectively.  WebMO will provide a link to a plot in the output file after the calculation completes.  You can also save the x,y data from this plot to use in Excel or SigmaPlot through the menu above the plot.

Examine the molecular orbitals (use appropriate calculation type in WebMO) and the charges on the atoms to gain insight into changes upon isomerization, the nature of the 90 degree (approximately the transition state structure).  To get a 90 degree structure, take an optimized structure and use it as the basis of a new job, open the editor, select the 4 atoms making up the dihedral and then go to the adjust menu and set the dihedral to 90 degrees.  The calculation should either be a energy calculation (not optimization) or for advanced users the “z-matrix” can be edited to fix this angle by changing the code in the WebMO z-matrix window from an O to a F (for fixed) next to the proper combination of for atoms (dihedral).

Discuss in detail any conclusions that can be drawn from these calculations and compare them to the higher level calculations and results presented in the above paper.

Come up with a three or more paragraph discussion of the combined results with an attempt to maximize insights gained from experiment, computation, and the literature results.

See further computational approaches for maximum insight development…: Computational Investigation of Dimethylacetamide derivatives

2.     Molecular Dynamics Calculations

To initiate these calculations you will need an initial structure.  The simplest in this case is to view the job results from one of the optimized structures in WebMO.  There is a button on the view job screen to export a structure.  Export the structure as a “.mol” structure.  The text file will come up on the screen or you can open the file in an external viewer.  If Chime is correctly installed this will open a Web page with the structure.  Right click and save the structure to your local computer.  Now you can load your structure into WebAmber.  Go to http://bert.chem.gac.edu and click on computational tools and then the Amber label.  Change the user to pchem or another user as instructed.  At this point we will use GB solvation which is an approximate continuum solvation model as opposed to the other options which explicitly add water or methanol solvent but which increase computational time.  Change the file format to “.mol”, browse for the file and upload.  Upon successful upload you can click a link to view you uploaded file in Chime to check for successful upload.

To initiate a calculation click the appropriate link.  There are two basic types of calculations, energy minimization (geometry optimization) and dynamics.  Generally we start with a minimization and take the results of this calculation (use job #) to initiate a dynamics run.  Dynamics runs may be used to initiate subsequent dynamics runs as well.  This type of calculation is initiated from the front WebAmber page using the job #.  Once you have a minimized geometry load the results and initiate a molecular dynamics run. 

Molecular dynamics takes the static optimized structures from the first calculations which are calculated at 0 K and can carefully add energy to these systems to probe their behavior at room temperature or other temperatures over time.  So a reasonable initial dynamics calculation might be going from 0 K to 300 K in 10 picoseconds.  The results of this calculation can be examined on the results page and with the associated links for each job.  How long did the calculation take (CPU)?  How long would a 100 psec calculation take?  How long would a calculation for a molecular system twice as big take (you might need to try this to find out, use the number of atoms to identify a trend in your compounds)?  Examine the graphs.  What do they tell you about the system and the types of energy it contains as it “warms” up?  Run another dynamics run based on the results of this job (use job # to restart).  This time keep the temperature fixed at 300 K for 100 psec.  Examine the details of this calculation as above. 

This time we will download the calculation and the “snapshots” of the molecular movement (trajectory) into the VMD (visual molecular dynamics) program available on the Windows machines.  In WebAmber you will need to save the “.top” (topology, parm7) file by right clicking on the link under the job.  To save the file without the “.txt” ending appended click on other files in the save dialog.  You will also need the trajectory “.crd” (coordinate) file.  In VMD you must first load the “.top” file and select “parm7” as the format.  Once this is loaded, the coordinates must be loaded into the topology.  Keeping the dialog open, now load the “.crd” file selecting the “crd” format (or crdbox if using an explicit solvent).  Now the molecular should have loaded.  The main window has “play” buttons to get the molecule to go through the snapshots in a molecular movie.  Look at the flexibility the molecule is showing at the temperature, what can you say about the effect of temperature on the system?  Does the system isomerizes?  Does the system vibrate?  How fast are the different motions (vibrations)?  Use the mouse to select a dihedral (see mouse, label, dihedrals menu).  Select four atoms which describe the dihedral angle under investigation.  Examine the displayed angle.  Now look at how this angle varies over time in the dynamics run.  This is available from the Graphics, Labels, dihedrals menu.  Select the graph ply and show preview.  The maximum and minimum is labeled.  What can you say about the range of angles explored by the molecule?  How do these relate to the quantum chemical calculations?  Save the data and load it into Excel or SigmaPlot to generate a plot.  Carry out dynamics at a higher temperature and overlay the plots.  What conclusions can you draw?  Try another system following the same protocol. 

Combine the insights from the experimental and two computational studies to write a detailed discussion.

Back to Kinetics and Thermodynamics Page

 

Created by Jonathan M. Smith

Updated September 22, 2005

Gustavus Adolphus College