Conformation Searching Applications

Transcription

1 Chemistry Fall 2015 Dr. Jean M. Standard September 23, 2015 Conformation Searching Applications Cycloheptadecane Redux So what would a conformation search on cycloheptadecane using Spartan find? Dr. Standard carried out a conformation search using the Spartan software package and the Monte Carlo torsional searching method. In the search, the MMFF force field was employed and a fold-rotation of 12 was used for all the torsional angles. The search generated random initial structures to minimize and compare, and took about three hours to complete. A total of more than 400 stable conformers were found in the Spartan search. The relative energies of the conformers of cycloheptadecane found in the search ranged from 0-10 kcal/mol. The lowest energy structure obtained is shown in Figure 1a, and the highest energy structure found is shown in Figure 1b. (a) (b) Figure 1. Stable conformations of cycloheptadecane from Spartan search: (a) lowest energy conformer found; (b) highest energy conformer found (9.9 kcal/mol above the lowest energy structure). When compared with the exhaustive search of cycloheptadecane carried out in the literature paper [M. Saunders, K. N. Houk, Y.-D. Wu, W. C. Still, M. Lipton, G. Chang, and W. C. Guida, J. Am. Chem. Soc. 1990, 112, ], the Spartan search found far fewer low-energy conformers. Table 1 presents a summary of the results from the literature study and the Spartan search. Table 1. Numbers of conformations of cycloheptadecane found relative to the global minimum. within 1 kcal/mol within 2 kcal/mol within 3 kcal/mol Literature Spartan

2 2 The two lowest energy conformers from the Spartan search are compared with those from the literature in Figure 2. Spartan Search Literature Search Spartan conformer 1 (E=4.513 kcal/mol) Literature conformer 1 Spartan conformer 2 (E=4.843 kcal/mol) Literature conformer 2 Figure 2. Two lowest conformations of cycloheptadecane from the Spartan search and from the literature search. When comparing the two lowest energy conformers found in the Spartan search with those found in the literature study, it appears that the lowest energy conformation in the literature search was not found in the Spartan search. The lowest energy conformer in the literature study is close to C s symmetry, while the lowest energy conformer in the Spartan search has C 2 symmetry. In fact, the two lowest conformers from the Spartan search both possess C 2 symmetry. These conformers both appear similar to the second lowest conformer found in the literature study. Clearly, the Spartan search needs a little work, since it only obtained a fraction of the low-energy conformers that were found in the literature search. A longer search with a fold-rotation of 18 or higher would likely find more conformers; however, such a search would take several hours of computer time.

3 3 A Somewhat Easier Example: 9-thiacrown-3 Crown ether molecules, such as 18-crown-6, are commonly used to bind cations. In this case, the conformational properties of macrocycles called thiacrown ethers, in which the oxygen atoms are replaced by sulfur atoms, were studied. While crown ethers tend to favor the binding of alkali cations, the thiacrowns favor binding of transition metal cations. A typical thiacrown macrocycle, 9-thiacrown-3, is shown in Figure 3. S S S Figure 3. 9-thiacrown-3. A literature study conducted a conformation search for 9-thiacrown-3 and other thiacrowns [S. E. Hill and D. Feller, J. Phys. Chem. A, 2000, 104, ]. The researchers employed both molecular mechanics and quantum mechanical methods to explore the conformations of a variety of thiacrowns, including 9-thiacrown-3. For 9-thiacrown-3, the literature study found 38 conformers of 9-thiacrown-3 using molecular mechanics. The CVFF force field was employed in the molecular mechanics calculations. However, at higher levels of theory, quantum mechanical calculations located only 6-9 stable conformers of 9-thiacrown-3 within 10 kcal/mol of the global minimum, and a total of 6 within 5 kcal/mol of the global minimum. These results are illustrated in Figure 4. Figure 4. Stable conformations of 9-thiacrown-3 from S. E. Hill and D. Feller, J. Phys. Chem. A, 2000, 104, The first column shows the molecular mechanics results and the other three columns give quantum mechanical results from lowest accuracy, RHF(RHF), to highest accuracy, MP2(MP2).

4 4 The molecular mechanics results seem to be inconsistent when compared with the quantum mechanical results. This suggests perhaps that the force field employed was not particularly well suited for describing the thiacrowns. Testing this notion by carrying out the conformation search with a different force field would possibly provide an answer regarding the CVFF force field used in the literature study. Dr. Standard therefore carried out a conformation search on 19-thiacrown-3 using Spartan and the MMFF force field. A Monte Carlo search was performed with a fold-rotation set to 12 for each dihedral angle. The conformation search located 10 stable conformers of 9-thiacrown-3 within 7 kcal/mol of the global minimum, and the search located 7 stable conformers within 5 kcal/mol of the global minimum. The structure of the lowest energy conformer found is shown in Figure 4, and a summary of all the conformers found in the Spartan search is listed in Table 2. Figure 4. Lowest energy structure of 9-thiacrown-3 found in a Monte Carlo conformational search with the MMFF force field, carried out using the Spartan software package. Table 2. Conformations of 9-thiacrown-3 from Monte Carlo search using Spartan. Conformer Relative E (kcal/mol) Conformer Relative E (kcal/mol) The results from the Spartan suggest that the MMFF force field is superior for representing thiacrown macrocycles when compared to the CVFF force field employed in the literature study. The MMFF results include 10 conformers within 7 kcal/mol. The highest level literature calculation, MP2(MP2), found 6 conformers within 5 kcal/mol of the global minimum. The next highest level of theory, MP2(RHF) located 9 conformers within 8 kcal/mol of the global minimum. The CVFF force field, on the other hand, located close to 20 conformers within 7 kcal/mol, many of which were not stable at other levels of theory. The geometries of the stable structures found in the MMFF search may be compared with those found in the literature study at the quantum mechanical MP2(HF)/aVDZ level. The comparisons are shown in Figure 5. Reasonably good correlation is found between the MMFF structures and literature, except that the energy ordering is scrambled. For example, the global minimum in the literature search is found as conformer #2 in the MMFF search (and conformer #2 in the literature search is the global minimum of the MMFF search). Also, the ion-binding conformer is located as conformer #6 in the literature; this corresponds to conformer #4 in the MMFF search. Conformers #4 and 5 from the literature correspond to conformers #6 and 3 in the MMFF search.

5 5 Figure 5a. Stable conformations of 9-thiacrown-3 from S. E. Hill and D. Feller, J. Phys. Chem. A, 2000, 104, Figure 5b. Stable conformations of 9-thiacrown-3 from MMFF conformer search.

6 6 The one conformer that did not match up particularly well with the literature study is #3 from the MMFF study; this conformer is similar to, but not quite the same as, #5 in the literature study. Further investigation reveals that conformer #7 in the MMFF study is much closer to conformer #5 in the literature study; thus, MMFF conformer #3 most likely appears at higher energy in the literature study. An energy diagram summarizing the correlation between the MMFF and literature conformer search for 9- thiacrown-3 is shown in Figure 6. Figure 6. Relative energies of conformers of 9-thiacrown-3 from the MMFF search and from the highest level MP2 quantum mechanical study from the literature. All the various levels of theory applied to 9-thiacrown-3 indicate that the cation-binding conformation does not correspond to the global minimum in the gas phase. The cation-binding conformer is #6 in the literature study at the highest level of theory, whereas it corresponds to conformer #4 in the MMFF study. A side view of the conformer, illustrating the orientation of sulfur atoms for cation binding, is shown in Figure 7. Figure 7. Side view of cation-binding conformation of 9-thiacrown-3 from MMFF study. The ion-binding conformation ranges from about 4 to 7 kcal/mol higher in energy than the global minimum in the gas phase, depending on the level of theory. It has the largest dipole moment of any of the conformers, 4.5 Debye, and thus would be expected to be stabilized in polar solution.