Some reactions seem to obvious to fail, so what happens when they do? Quantum calculations yield invaluable insight to the nature of a reaction mechanism. Presented at the Virtual Conference on Computational Chemistry VCCC 2014 Credit due to Guillermo Caballero on whose BSc thesis this presentation is based.

1. Reluctance towards Aromatization of Vinamidine
Analogues into Substituted Pyridines.
A Theoretical Evaluation of the Reaction Mechanisms that Never were
VCCC – MRU 2014
Dr. Joaquín Barroso-Flores
jbarroso@unam.mx
Centro Conjunto de Investigación en Química Sustentable UAEM–UNAM Carretera Toluca –
Atlacomulco km 14.5, Unidad San Cayetano, Toluca, Estado de México, Mexico

2. Introduction
Computational analysis of reaction mechanisms poses a
powerful tool for achieving intimate knowledge about a chemical
transformation at an electronic level.
Herein, we rationalize the absence of an expected reaction in
terms of the electronic structure of every step involved;
concluding thus that, at least under the tested conditions, this
reaction cannot take place at any cost.
Scheme 1. Unobserved tautomerism in picoline.
Aromaticity is considered a
major driving force in a
tautomerization reaction as
well as some other classical
organic transformations

3. Introduction
We have studed both in the lab and computationally the
reaction of glutarimide with the Vilsmeier-Haack reagent
(DMF/oxalyl chloride) that yields the non-aromatic,
substituted isopicoline analogue, 1.
Scheme 2. Reaction of glutarimide with the Vilsmeier-Haack reagent. Substituted
pyridine 2 is not observed to be formed in the reaction.

4. Computational Details
• All calculations were performed using the Gaussian09 suite of programs.
• Geometry optimizations were performed under the Density Functional Theory (DFT)
using the hybrid B3LYP, PBEPBE and B97D functionals and the 6-31+G(d,p) basis
set.
• Frequency analysis was performed at the same level of theory to which the
optimization was calculated.
• Single point (SP) energies were calculated at the M05-2X/6-31+G(d,p) level of theory,
an approach that has been demonstrated to yield good results for the study of
reaction mechanisms.
• Intrinsic Reaction Coordinate (IRC) calculation was performed for each transition state
found at the level of theory to which the transition state was found.
• Ab initio calculations at the HF/cc-PVQZ were performed taking the B3LYP/6-
31+G(d,p) geometries to calculate frontier orbitals and population analyses under the
Natural Bond Orbitals (NBO) formalism with the use of the NBO3.1 program as
supplied within Gaussian09.

5. Results and Discussion
Figure 1. X-ray molecular structures of synthesized compound 1 (left) and 3 (right). 50 %
thermal elipsoids.

6. Results and Discussion
QST2 and QST3 methods were used to find a plausible transition state
that would link species 1 and 2. Two mechanistic pathways were
suggested based on the transition states found (scheme 3). Transition
states TS1A, TS1B and TS2B were located and intermediate 5
computationally found. (IRC calculations were carried out to further
confirm the plausibility of every TS found.) The energy profile is presented
in figure 2.
Scheme 3. Mechanistic paths A and B for the
aromatization process of compound 1. Path A follows a
1,3-hydrogen displacement, whereas path B a two-step
mechanism.

7. Figure 2. Relative energy profile for path A and B. Numbers correspond to the B3LYP (red)
functional used for the geometry optimisation; PBEPBE functional (green) and to the B97D
functional (blue). After optimisation with each functional, SP energies were calculated at the M05-
2X/6-31+G(d,p) level of theory

8. Results and Discussion
From the energy profile we observe that
• The aromatic tautomer 2 is more stable, as expected, than isopicoline 1
for about 20 kcal/mol.
• For both A and B mechanistic paths barrier heights are unreachable,
about c.a. 40 kcal/mol. Such values correspond to a pyrolysis, meaning
that even if the energy is provided, the compound would burn down.
• Despite the isolated compound is thermodynamically unstable respect to
the aromatic species, the large barrier heights avoid the tautomerization.
• Energy differences between the hybrid functionals used are within
chemical accuracy (1 kcal/mol), thus, the remaining calculations were
only performed at the B3LYP/6-31+G(d,p) level of theory followed by SP
energy calculation at the M05-2X/6-31+G(d,p) level.

9. Figure 3. Energy profile for mechanistic pathways A and B for compound 3. In
both cases barrier heights remain unreachable

10. Figure 4. Superposed energy profiles for compounds 1 and 3. Numbers in black
correspond to compound 1, numbers in red to compound 3 and numbers in blue to the
energy difference between the corresponding species

11. Results and Discussion
As these energy profiles do not fully explain the reluctance of
these systems to become aromatic, ab initio electronic
calculations were performed at the HF/cc-PVQZ level of theory.
From these new calculations, an electron corridor is observed to
be formed from the nitrogen atom in the dimethylamino moiety to
the carbonyl group. This corridor is formed with the occupied
molecular orbitals, being all in-phase, as well as with the vitual
unoccupied orbitals, being all out-of-phase along the corridor.
These observations are summarized in figure 5 in the next slide.

12. Results and Discussion
5a 5b 5c
Figure 5. Delocalisation energies (2nd order perturbation theory analysis of the
natural hybrid orbitals) between bonding or lone pairs to antibonding orbitals are
shown (kcal/mol) (5a). Electron corridor formed with occupied (5b) and virtual (5c)
frontier and close to frontier orbitals in compound 1. Electrostatic potential mapped
onto the electron isodensity surface at the HF/cc-pVQZ level of theory (5d).
Similar trends are observed for compound 3
From this data, compound 1 resembles a vinamidine push-pull
effect controled system.
5d

13. Results and Discussion
In order to test the influence of the extended push-pull effect as
the reluctancy force, the analogues shown below were
evaluated using the same computational methodologies as for
compounds 1 and 3. In those molecules, the dimethylamino
moiety was varied from electron-donating groups (7) to electron-accepting
(9) and electron-withdrawing (10) ones.
Scheme 4. Analogues of compound 1 sharing different electron-donating or
electron-withdrawing groups

14. Figure 5. Energy profile for the theoretical aromatisation mechanisms
of analogue 7, sharing an electron-donor methoxy moiety.

15. Results and Discussion
Figure 6. Energy profile for
the theoretical aromatisation
mechanism of analogue 8,
with no moiety present.
Figure 7. Energy profile for the
theoretical aromatisation mechanism
of analogue 9, sharing a borane
electron-accepting group.

16. Figure 8. Energy profile for the theoretical aromatisation mechanisms
of analogue 10, which has an electron-withdrawing nitro group.

17. Results and Discussion
Some notable facts arise from the use of an NO2 group (figure 8)
• The presence of a strong electron-withdrawing group, lowers the
energy of path B, which is a two-step mechanism.
• Barrier heights are lowered enough (c.a. 22 and 30 kcal/mol) to be
reached.
• The intermediate nitrone formed has an energy of -23.04 kcal/mol
respect to that of the starting material, meaning that such an
intermediate might be isolated.
• According to barrier heights for a mechanistic pathway B-type, the
aforementioned aromatization process is possible, at least
theoretically.

18. Figure 9. Comparison between analogues with electron-donating and electron-withdrawing
groups. Numbers in red correspond to the relative energy to the aromatic tautomer in kcal/mol.
Figures in the second row are the electron corridors formed with occupied frontier orbitals. Third
row are the electron corridors formed with virtual unoccupied frontier orbitals. Last row shows
the electrostatic potentials mapped onto the density isosurface.

19. Conclusions
 Based on the energy profiles it is concluded that (at least for
compounds 1 and 3) the aromatic and non-aromatic tautomers
can be obtained following different synthetic routes.
Interconversion between them is never to be observed.
 The high delocalization along the p electron corridor stabilizes
that system up to the point that aromatization is avoided.
 The stronger an electron-withdrawing moiety is attached to the p
system, the easiest the aromatization process becames.
 The stonger the electron-donation of a group attached to the
corridor, the most difficult the aromatization process is.

20. Acknowledgements
Funding and computing
• PAPIIT – UNAM for funding under contract IB200313
• DGTIC – UNAM for access to the supercomputer MIZTLI
Students and collaborators
• Dr. Moises Romero
• Guillermo Caballero
• Dr. Diego Martínez (crystallographer)
Thank you for your attention!