Hindered Rotation of Acetamide:

Free Rotation of Acetamide Enolate:

Acetamide, CH₃CONH₂, like all amides, has a significantly higher C-N bond rotation barrier than a normal sigma bond. This hindered rotation of the C-N bond can lead to differences in the NMR signals of the atoms atached to nitrogen. The two protons attached to N in acetamide (blue and green) are inequivalent at low temperatures but become averaged by C-N rotation at higher temperatures. Typical bond rotation barriers for amides in solution are experimentally determined by NMR to be between 17 and 22 kcal/mol. However, the acetamide enolate, [CH₂CONH₂]^-, has a much lower barrier. According to recent NMR experiments, the enolate has free rotation at all accessible temperatures. Based on this knowledge, the maximum barrier possible for acetamide enolate is 10 kcal/mol and is probably considerably less than that.

The study of amide C-N rotation barriers is not just an esoteric exercise--amide C-N bonds make up protein backbones. The prefered amide conformations play an important role in enzyme structure and the barrier to rotation has an effect on the rigidity of that structure. The rigidity of an enzyme's structure can affect its selectivity in binding substrates.

In this experiment we seek to use quantum chemical methods to understand the nature of the hindered C-N bond rotation in acetamide and contrast it with the barrier of its enolate.

Procedures:

AM1 Geometries: Do all exploratory work to find the global minimum energy geometry and the lowest energy transition state before using higher levels of theory. Only the best geometries (i.e., the global minimum and the lowest energy transition state) will be re-optimized at the higher level of theory.

AM1 Minima

First, use the AM1 method to find the global minimum geometry of acetamide and its enolate.

• Consider all of the possible conformations that could be present.
• Verify that your structure is a true minimum by making sure that all of the frequencies are real ("positive").
• Verify that it is a global minimum by comparing energies with your neighbors to find the lowest energy conformation (or calculate all possibilities yourself to be sure).

AM1 Transition States

The transition states will also be computed, first, at AM1 level of theory. The transition state for C-N bond rotation is C_s symmetry. Evaluate the structure of your two minima and find the C_s symmetric transition structure that would average the two protons on N. Since any rotation about C-N breaks the symmetry plane the optimized geometry should correspond to the proper TS for C-N rotation. As long as the C_s symmetry is imposed on your starting geometry, Gaussian will not break that symmetry plane.

• Prepare the geometry:
  • Start from your AM1-optimized global minimum geometry;
  • rotate the C-N bond using a dihedral angle (OCNH);
  • Symmetrize the molecule.
• Submit the job:
  • If the C_s symmetry is recognized you can submit the calculation as an optimization.
  • If you're having trouble getting Gaussian to recognize your symmetry then you can take the more general method for finding a TS:
    • Change the job type to "Transition Search"
    • Type "opt=noeigentest" in the extra keyword section
    • Submit the job.
    • This can easily go astray. If it doesn't work then we need to pull out the big guns: Edit as before but change to "opt=(ts,noeigentest,calcall)". This calculation may take a very long time.
• Verify that the transition state is correct:
  • inspect it and see if the geometry makes sense
  • compare your energy with your neighbor--the lowest energy TS is the one you want
  • calculate a frequency from the optimized geometry
  • make sure that ONE and only one of your frequencies is imaginary ("negative").

HF/6-31+G(d) Geometries

Semi-emipirical calculations are not adequate to fully characterize these processes and, therefore, we will re-optimize the important geometries at a higher level of theory. Semi-empirical calculations partially (or wholly) neglect overlap of non-adjacent atomic orbitals (e.g., the N and O orbitals in acetamide). This overlap is important in this system. Using Hartree-Fock theory will give better answers. Since we want to investigate anions, we will need to use diffuse functions ("+") to get the best answers, HF/6-31+G(d). Since the optimal geometry using this method will differ significantly from that obtained using AM1, we will re-optimize the important molecules using this higher level of theory. The AM1 calculations were good enough to give us the global minimum and the lowest enegy transition state for each molecule but we'll only use these semi-empirical calculations as a stepping stone for the final calculations (below). Starting at the AM1-optimized geometries saves time because it is closer to the HF geometry than any guess we could make and therefore will take fewer optimization steps to find the new geometry.

• Start with the AM1-optimized geometries (by opening the appropriate log file) for each of the four important conformations.
  1. acetamide global minimum
  2. the lowest energy acetamide TS
  3. enolate global minimum
  4. the lowest energy enolate TS
• Impose symmetry (if it exists), in order to cut down on the calculation time.
• Since HF/6-31+G(d) frequencies will take too long we will assume the ZPVE and Cv do not change appreciably from AM1 as long as the geometry is qualitatively similar.
• Note the new energy, optimized geometric parameters (see below), and atomic charges for each.
• Save a jpeg for the two molecules and their transition states for C-N rotation (four jpegs, total).

Results:

Complete these 3 data tables with your HF/6-31+G(d)-optimized parameters. Also include pictures for all final geometries. Note that:

• pyramidalization of N = sum of all angles around N
  360 is flat, (109.5 x 3 =) 328.5 is pyramidal.
• pyramidalization only applies to trivalent atoms so pyr-C is only appropriate for the enolate.
• charges on heavy atoms (w/ H atoms summed into heavy atoms) can be found at the end of your log file

Analysis:

Consider the following issues:

• In comparison to the experimental values for acetamide, is HF/6-31+G(d) better than AM1?
• What roles do resonance and hybridization play in the geometries and energies of each species?
  • Draw the most important resonance contributors for acetamide and the enolate.
• Does the pyramidalization on N change for acetamide while rotation occurs? Why?
  • Consider this: can the same resonance structures shown above contribute to the stability of the rotation transition state?
• Why do amides have somewhat hindered C-N bond rotation?
• What computational data supports your rationale?
  • Examples of computational data include: charges, bond-lengths, pyramidalization angles, molecular orbitals, etc.
• The experimental rotation barrier comes from solution NMR experiments. These computational results represesent the gas-phase experiment. Would you expect the presence of solvent to increase or decrease the gas phase rotation barrier? (Hint: Charged molecules are stabilized more than neutral molecules by the presence of solvent.) [If you'd like to check your assumptions you can, but are not required to, run a single point energy calculation on acetamide and the acetamide TS.]
• Why does the enolate behave differently than acetamide?
  • First explain this in qualitative terms
  • Then show that your calculational data back up your explanation (comparative change in charges, bond-lengths, pyramidalization angles, molecular orbitals, etc.).