Application of LFER to pKas and Dipole Moments of 1H and 2H Tautomers of Tetrazole: Mimicking Structure-Function Relation as a Chemical Education Perspective

Abstract: Structure-function relation is a 155 years old concept to explain the dependence of biological activity of a drug molecule on its structure put forward by Crum-Brown and Fraser*. Similar line of interest is followed in the present work and it stimulates the understanding of structure-activity relation (SAR) among the graduate students. An attempt is made for the first time from our laboratory to apply the Hammett and Taft equations to a five membered ring system with four nitrogens as heteroatoms viz. tetrazole to identify the aqueous medium 1H and 2H Tautomers. For this purpose experimentally determined aqueous medium pKa values of NH-acidities of a total of fifteen 5-X-1,2,3,4-tetrazoles and DFT/B3LYP method at the 6-31G* level calculated dipole moments of seven 1H and 2H tautomers of 5-X-1,2,3,4-tetrazoles are used to correlate with Hammett σpara and σmeta, and Taft σortho ∗ values. Good correlations are obtained. The promising response of more abundant and more polar 1H tautomer with less susceptibility (ρ* = -1.38 in pKa correlations and ρ* = 0.55 in dipole moments correlation) to Taft equation and less abundant and less polar 2H tautomer with more susceptibility (ρpara = 6.56, ρmeta = 7.79 in pKa correlations, and ρpara = 2.69, ρmeta = 3.26 in dipole moments correlation) to Hammett equation of the tetrazole is well distinguished. Thus it mimics a principle of structure-function study on a chemical property like the ionization of NH proton of tetrazole and on a physical property like dipole moment for the first time. Therefore finding a way is achieved to get the equilibrium identification of 1H and 2H tautomers without using any expensive and time consuming experimental techniques.


Introduction:
Much effort has been made by Wentrup et. al. [1] in the study of tautomeric equilibrium of 5-X-1,2,3,4-Tetrazoles both by theory and experiments specially on 1H and 2H tautomeric equilibrium of both in gas phase and solution phase. There was an excellent review on tetrazoles published by Trifonov and Ostrovskii [2] emphasizing the protolytic equilibriums. In both these studies importance is given mainly on the study of 1H ⇌ 2H tautomeric equilibriums. It is to be noted that UV-Vis, dipole moments and NMR techniques were employed in the entire study of 1H and 2H tautomeric equilibriums [1,2]. In earlier studies [2,3] while applying the LFER to pKa values and the dipole moments, information about the para, meta and ortho positions of the atoms in the five membered heterocyclic ring system are not referred. We have recently published a review where in one can find the visual interpretation and identification of the para, meta and ortho positions of the atoms in the five membered heterocyclic ring system is well explained [ref]. In the present study we have shown for the first time without using expensive and time-consuming methods like 1 H NMR, 13 C NMR and dipole meters, a simple novel protocol is just handy to identify the 1H and 2H tautomers of tetrazole hitherto not reported earlier with the use of Linear Free Energy Relationships (LFER) knowing experimentally determined pKa values [2] and DFT/B3LYP method at the 6-31G* level calculated dipole moments [3]. And mimicking of principle of structure-function study on a chemical and a physical property for the first time is observed.

Methods:
All the linear correlations were done using the KaleidaGraph software, Reading, PA, USA. The chemical structures are drawn using chemdraw.

Results and discussion:
In This is the reason that the pKa values are well correlated in 2H tautomer with both Hammett σpara and σmeta substituent constants. The deviation of NH2 in the correlation with para substituents may be due to the intermolecular hydrogen bonding as shown in scheme 4A.
Non deviation of NH2 group in the correlation with meta substituents could not be explained.
From Taft plots given below in figures 3 and 4, it may be assumed that the ortho-substituent effects originate from 1H-tautomer again with the deviation of NH2 group (blue square, figure 3). The deviation is due to the fact that the 1H tautomer having larger dipole moment than 2H tautomer [2] becomes more favorable for solvation by solvent water as shown in scheme 4B below. In the solvation process of 1H tautomer of 5-aminotetrazole in the formation of hydrogen bonds, both the hetero ring and the amino group are involved (scheme 4B). Also it is noteworthy to see the correlation is improved without the bulky groups like CF3, I and NO2 ( figure 4) is yet an additional evidence to say that position 5 of tetrazole is an orthocarbon to N1-H.    [4] to the pKa data is another strong indication of the ortho effects originate from 1H-tautomer (scheme 1). The study of Taft-Pavelich four parameter equation from our group is frequently observed in several kinetic studies [5][6][7][8]. Table 2 gives the data of gas phase dipole moments, Hammett σpara, σmeta, Taft    Our analysis further gets support from the previously reported tentative ρ-σ analysis [3] in studying the existence of high percentage of 1H tautomers of 5-X-1,2,3,4-tetrazoles in solution compared to 2H tautomers.
Reactivity-Selectivity principle: From the table 2 it can be seen that the dipole moments of 1H-tautomer are higher than that of 2H-tautomer by 2-3 orders of magnitude indicating that the 1H-tautomer is more polar than the 2H-tautomer [3]. From the table 3 it can be seen that the Taft reaction constants (ρ*) of more polar 1H-tautomer are less than the Hammett reaction constants (ρ) of less polar 2H-tautomer by a factor of 5. Therefore, as a principle of structure-function study it can be stated that the more polar is the 1H-tautomer of tetrazole less is its susceptibility to substiuent effects (Taft ρ*) and less polar is the 2H-tautomer more is its susceptibility to substituent effects (Hammett ρ = 7.18 average of the ρpara and ρmeta). Probably mimicking of principle of structure-function study is for the first time on a chemical property like NH deprotonation and on a physical property like dipole moment from our laboratory. There was a report by one of the authors (JV) on the application of similar study like reactivity-selectivity principle on a chemical property of reactivities of unstable carbocation intermediates [9].