Conformational Analysis of Cyclohexanone Ring Systems by DFT and Other Computational Methods

Francisco E. Jimenez, Randy M. Miller, David B. Ball

California State University, Chico - Department of Chemistry & Biochemistry

Introduction
Chair conformation interconversion of cyclohexane has been well characterized in previous experiments, and accepted values are available in most chemistry textbooks. Coversely, available literature data suggests that cyclohexanone systems, while representing a possible logical step for the study of flexible ring systems, have seemingly been studied to a much lesser degree. These systems present an interesting perturbation problem through the stereoelectronic effects resulting from addition of an electron-rich oxygen to the system. In this study, we described as fully as possible the energy landscapes of several cyclohexane and cyclohexanone systems of increasing complexity from a purely computational standpoint, using semi-empirical methods, denisty funstional theory, and 2nd- and 4th-order MllerPlesset perturbation theory.

which the cyclohexanone was methylated, and finally brominated. Transition state searches were carried out by first performing conformer generation using ConFab. Each resulting stable conformation was minimized in Gaussian and ranked according to energy.

As would be expected, the potential energy surface for increasingly complex systems showed more features. Of interest however, was the fact that addition of oxygen to the system resulted in a dramatic decrease in the chair-chair isomerization energy barrier. (Fig.3) Furthermore, the potential energy surface was dramatically changed with the addition of oxygen. In cyclohexane, steep slopes in the potential energy surface were evident, and structures consistently converged as expected. Conversely, in cyclohexanone, the PES was extremely shallow, making clacluational convergence more difficult.

Conclusions
The dramatic decrease observed in the calculated chair-chair interconversion energies of cyclohexanone as opposed to those of cyclohexane raised questions of a stereoelectronic nature. It is likely that delocaliztion from the oxygen's lone-pair electrons * to vacant anitbonding orbital of the adjacent ring carbon plays an important role in the stereoelectronic behavior of this system. The change in isomerization energy and behavior observed in cyclohexanone could be attributed to the presence of oxygen's nonbonding atomic orbitals, as the result of both steric and electronic influence. Several studies have beeen done using NBO analysis to verify this. Calculations done substituting oxygen with sulfur gave similar results with a slightly less shallow PES. Future work to be done includes analysis of the system through NBO calculations and ab inito block-localized wavefunction calculations (BLW).

Fig. 1a - Cyclohexane isomerization energy landscape. (Gaussian '09, B3LYP/6-311+g(2d,p))

Fig. 1a - Cyclohexanone isomerization energy landscape. (Gaussian '09, B3LYP/6-311+g(2d,p))

Objectives
Our primary objective in this study was to establish a comparison between established experimental chair-chair interconversion energy barriers, and energy barriers calculated computationally. This entailed elucidating as much of the energy landscape of several model structures as time and computational resources permitted. It was hoped further insight could be gained into the potential energy surfaces and resulting behaviors of cyclohexanone systems. Furthermore, we wanted to explore possible perturbations in the potential energy landscapes as the flexible ring systems became increasingly complicated through the addition of functional groups. The resulting minima were then used in QST calculations to find the connecting transition state structure. Transition state structures were verified using vibrational frequencies to show a saddle point had been found.

Results
Fig. 3 - Overlay of calculated potential energy surfaced obtained using QST3 saddle point calculations in G09 (B3LYP/6-311+g(2d,p)), showing relative isomerization energies of different calculated systems.

Fig. 4a-HOMO

Fig. 4b-LUMO

Fig. 4c-HOMO Electron Density

HOMO, LUMO and HOMO electron desity isosurfaces for cyclohexanone. (B3LYP-6-311+g(2d,p)

Methods
All computational work was performed via Gaussian 03 and Gaussian 09, through the browser-based interface WebMo. All final calculations were performed using Becke, three-parameter, Lee-Yang-Parr (B3LYP) hybrid functional theory, and a diffuse, split valence Pople basis set, 6-311+g(2d,p). Conformer generation was carried out using ConFab open-source conformational software. A typical approach to our computational modeling involved the use of scaffolds, in order to help reduce computational cost. Cyclohexane was modeled in a chair conformation, and optimized via a geometry algorithm. To the optimized energy minimum was then added a carbonyl group, after

Fig. 2 - Calculated potential energy surface for 2-bromo-3,3,5,5-tetramethylcyclohexanone at B3LYP/6-311+g(2d,p) level of theory/basis set.

Calculations indicate that in cyclohexanone, the twist conformation is the most readily accessible high-energy transition state step, and that the boat conformation is a geometric minimum. Additionally, the energetically favorable boat conformation places the oxygen on the side of the "boat" form. (Fig.1) Modeling of a siimilar boat structure with the oxygen in the up position yielded energies between 4.5-5 kcal/mol higher. This seems to suggest the ring "flexes around" the oxygen. Also of interest was the result that adding alkyl functional groups to a cyclohexanone group not only added more features, but also seemed to enhace the features of the PES, giving steeper slopes and more well-defined minima and saddle-points without changing the relative energies of the various structures greatly.

References
1. Gaussian 09, Revision B.01, Gaussian, Inc., Wallingford CT (2009) by M. J. Frisch, G. W. Trucks, H. B. Schlegel, et al. 2. WebMO Pro. WebMO, LLC, Holland, MI, USA. Available from http://www.webmo.net. by J. R. Schmidt, W. F. Polik 3. N. O'Boyle, T. Vandermeersch, C. Flynn, A. Maguire, G. H. Confab - Journal of Cheminformatics, Vol. 3, No. 1. (2011), 8 4. Yirong Mo. (2010). Computational evidence that hyperconjugative interactions are not responsible for the anomeric effect. Nature Chemistry.