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-Floresjbarroso@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

Introduction

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

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.

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.

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.

Results and Discussion

Figure 1. X-ray molecular structures of synthesized compound 1 (left) and 3 (right). 50 %

thermal elipsoids.

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.

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

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.

Figure 3. Energy profile for mechanistic pathways A and B for compound 3. In

both cases barrier heights remain unreachable

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

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.

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

Results and Discussion

From this data, compound 1 resembles a vinamidine push-pull

effect controled system.

5a 5b 5c5d

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

Figure 5. Energy profile for the theoretical aromatisation mechanisms

of analogue 7, sharing an electron-donor methoxy moiety.

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.

Figure 8. Energy profile for the theoretical aromatisation mechanisms

of analogue 10, which has an electron-withdrawing nitro group.

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.

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.

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.

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!