Computational Study for the Aromatic Nucleophilic Substitution Reaction on with Amines

Our previous research showed that aliphatic amines were put in order of high reactivity as “ethylamine > ammonia > t-butylamine > diethylamine” on the aromatic nucleophilic substitution of 1-dimetylamino-2,4-bis(trifluoroacetyl)-naphthalene 1 in acetonitrile. The DFT calculation study (B3LYP/6-31G* with solvation model) for the reactions of 1 with above four amines rationally explained the difference of each amines reactivity based on the energies of their Meisenheimer complexes 3 which are assumed to formed as the reaction intermediates in the course of the reaction giving the corresponding N-N exchange products 2. Intramolecular hydrogen bond between amino proton in 1-amino group and carbonyl oxygen in 2-trifluoroacetyl group stabilizes Meisenheimer complexes 3 effectively, and accelerates the substitution reaction from 1 to 2. Our calculation results also predicted that the above order of amines is also true if less polar toluene is used as a solvent instead of acetonitrile even though more enhanced conditions are required.


Introduction
In our previous research, we found that dimethylamino group on naphthalene system activated by two trifluoroacetyl groups is easily substituted with various nucleophiles, even though such substituent is commonly understood to have a International Journal of Organic Chemistry poor leaving-group ability [1] [2] [3]. This unique aromatic nucleophilic substitution has provided diverse synthetic methods having capability to access a lot of kinds of fluorine-containing heterocycles [4]- [14]. These are the class of fluorine-containing heterocycles of which potential biological activities might be focused on as unique active ingredients in the various life science fields [15] [16] [17] [18]. On the above investigations was attained a newfound knowledge in which the N-N exchange reaction rate of aliphatic amines resulted in order of decreasing as "ethylamine > ammonia > t-butylamine > diethylamine" by making observations for the reaction of 1-dimetylamino-2,4-bis(trifluoroacetyl)naphthalene 1 in acetonitrile (Scheme 1) [19]. This reactivity order is hard to be understood by traditional electronic theories of organic chemistry.
Therefore, these situations prompted us to demonstrate the DFT calculation (RB3LYP/6-31G*) study on the reaction of 1 with the above four kinds of amines to have led to an interesting outcome rationalizing the reaction rate order of the four amines. Moreover, we discuss an elucidation of the solvent effect on the present substitution by making use of C-PCM model calculation.

Calculations for 1-Dimethylamino-2,4-bis(trifluoroacetyl)naph-thalene
First, we calculated the optimized structure of 1-dimetylamino-2,4-bis(trifluoroacetyl)naphthalene 1 which is the key substrate of the present nucleophilic substitution. In Figure 1 is depicted an estimated most stable structure of 1 in acetonitrile together with its energy. It also shows LUMO of 1 and its frontier electron densities (

Analyses for Reaction Processes
Energy diagrams of the present substitution course from 1-dimetylamino-2,4bis(trifluoroacetyl)naphthalene 1 to the corresponding N-N exchanged products 2a-d are depicted in Figure 4. The rate determining step of this substitution would be the first addition step (Step 1) giving the corresponding adducts 3a-d in which one of the aromatic benzene-ring systems is destroyed. It is hard to estimate directly the transition state structures and their energies in the rate determining step since the present available computational methods cannot enable us to access an exact transition state structure of ionic reaction in polar solvents.
However, it is possible to approximate activation energies of the rate determining step using energy changes (ΔE 1 ) from substrate 1 to Meisenheimer complexes 3a-d which have the structures relatively close to each transition states. The one is using solvation model and the other one is not using it. Acetonitrile (aprotic polar solvent) and toluene (aprotic less polar solvent) was adopted as   Table 2 respectively. The largest ΔE 1 value is given in the case of the reaction of 1 with ammonia based on the simple DFT calculation without the use of solvation model. Additionally, ΔE 1 of the reaction of 1 with amines decreases according to the order of "ammonia > diethylamine > t-butylamine > ethylamine" ( Table 2). The results predicts that amines are put in order of high reaction rate as "ethylamine > t-butylamine > diethylamine > ammonia" on the N-N exchange reaction of 1 though this assumption is not compatible with the experimental results (ethylamine > ammonia > t-butylamine > diethylamine). We also calculated overall energy changes (ΔE 2 ) from 1 to 2a-d to as "ethylamine < ammonia < t-butylamine < diethylamine", which suggests the acceleration of the N-N exchange reaction on 1 in the order of "ethylamine > ammonia > t-butylamine > diethylamine". This order is completely consistent with our experimental evidence examined previously. It allows us to explain that stabilization by intramolecular hydrogen bond in Meisenheimer complexes 3a-c would be one of the reasons why ΔE 1 on the reaction affording 3a-c are smaller than the case of 3d.
We also calculated ΔE 1 about the reaction in toluene. As shown in Table 2, ΔE 1 in toluene are larger than ones in acetonitrile in all cases. It follows that the substitution reaction of 1 with amines in less-polar toluene is predicted to require more enhanced conditions than the one in polar acetonitrile.
The ΔE 1 values in toluene predict that the order of amines on the substitution rate in toluene is the same as the one in acetonitrile. Differences of ΔE 1 values between the reactions in toluene and the corresponding ones in acetonitrile are summarized in Table 3. In the case of the reaction with ammonia, ΔE 1 is obviously more decreased than the cases using the other three amines in acetonitrile solvent instead of toluene. Meisenheimer complex 3b has one more amino  proton in addition to the other one which is used for intramolecular hydrogen bond ( Figure 2). It is explained rationally that stabilization by such hydrogen bond of this free amino proton in 3b surrounded by acetonitrile would contribute to additional decrement of ΔE 1 on the reaction of 1 with ammonia compared to the cases using the other three amines.

Conclusion
The unexpected order of the reaction rate (ethylamine > ammonia > t-butylamine > diethylamine) on the aromatic nucleophilic substitution of 1-dimetylamino-2,4-bis(trifluoroacetyl)naphthalene 1 with nucleophiles (ammonia and three kinds of aliphatic amine) giving the corresponding N-N exchanged products 2 is rationalized by the energy changes for forming the corresponding Meisenheimer complexes 3, i.e. the rate determining step of the present substitution reaction. These energy changes are closely correlated with the relative stabilities of 3 under the reaction conditions. Intramolecular hydrogen bond between amino proton in 1-amino group and carbonyl oxygen in 2-trifluoroacetyl group stabilizes Meisenheimer complexes 3 effectively, and accelerates the substitution reaction from 1 to 2, consequently. Our calculation results also predict that the above order of amines is also true if less polar toluene is used as a solvent instead of acetonitrile even though more enhanced conditions are required.

Computational Methods
All calculations employed in this paper were accomplished by making use of the computer programs packages PC SPARTAN 16 [20]. For geometrical optimizations, it was performed with the 6-31G* basis set at B3LYP [21] level. For a solvation calculation, C-PCM model [22] was used. The starting geometries employed for all optimizations were resulted from molecular mechanics using SYBYL [23] force field and subsequent semi-empirical PM3 [24] optimizations.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.