Synthesis and Acidity of 5-(m-Terphenyl-2′-yl)-1H-tetrazoles: Evidence for an Enhanced Polar−π Effect Compared to Carboxylic Acids

Abstract

The polar−π effect on tetrazoles, medicinal chemistry isosteres of carboxylate, is tested by a Hammett pK a (microtitration) analysis over a series of 5-(m-terphenyl-2′-yl)-1H-tetrazoles. A comparison with m-terphenyl-2′-yl-carboxylic acids supports the isostere analogy also in response to environmental changes. Computational (B97D/def2TZVPPD) extension of the series plus a scan of solvents (vacuum to water) demonstrates the trend with the dielectric constant. The effect is energetically small but may make statistically significant contributions to the tetrazole pharmacological profile.

Through-Space Stabilization of an Imidazolium Cation by Aromatic Rings

“…Plotting the p K a values of para-substituted imidazoles 1–5 against the Hammett σ values revealed a good linear correlation with ρ = 0.65 and R 2 = 0.95. The p K a values of the conjugated acid of the imidazoles 1–6 are in the range 4.6–5.8, which are comparable to another heterocycle tetrazole that showed a comparable ρ value of 0.86 . It is apparent that the p K a values of the imidazoles are affected by the presence of substituents at distant position of flanking aromatic rings; electron-donating groups (e.g., OMe, Me) make imidazoles more basic, whereas electron-withdrawing groups (e.g., F, CF 3 ) make imidazoles less basic.…”

“…The pK a values of the conjugated acid of the imidazoles 1−6 are in the range 4.6−5.8, which are comparable to another heterocycle tetrazole that showed a comparable ρ value of 0.86. 34 It is apparent that the pK a values of the imidazoles are affected by the presence of substituents at distant position of flanking aromatic rings; electron-donating groups (e.g., OMe, Me) make imidazoles more basic, whereas electron-withdrawing groups (e.g., F, CF 3 ) make imidazoles less basic. Despite the fact that the meta-substituted F has a significantly different σ value than the para-substituted F (0.34 vs 0.06, respectively), their pK a values are very similar (5.07 and 5.17 for m-F and p-F, respectively).…”

“…Noncovalent interactions involving aromatic rings are of great importance in both molecular and biological recognition. , The imidazole side chain of histidine is a conjugative aromatic ring, which participates in π–π stacking interactions with aromatic side chains of other aromatic amino acids in proteins. , A computational study demonstrated that the imidazolium cation stacks over the aromatic residues of phenylalanine, tyrosine, and tryptophan . 2,6-Diaryl aromatic compounds have been used as particularly suitable model systems for studies of intramolecular polar−π interactions with several functional groups, such as carboxyl, hydroxyl, thiol, silyl, boronic acid, tetrazole, sulfonamide, and various anions and cations. − The electronic properties of two flanking rings can be fine-tuned by substituents at the para position. Inspired by these precedents, we here hypothesize that the basicity of imidazole can be fined-tuned by substituents at the flanking aromatic rings, enabling us to investigate the underlying molecular mechanism for noncovalent interactions between the neutral imidazole ring/positively charged imidazolium cation and the adjacent aromatic rings (Figure ).…”

Probing Noncovalent Interactions in [3,3]Metaparacyclophanes

“…In addition to examinations of π–π stacking interactions, fluorinated aromatic molecules have found applications as probes for physical-organic studies of cation−π interactions in protein science. ,,− In this regard, our work demonstrates that the fluorination strategy can be effectively applied to studies of the underlying noncovalent interactions in cyclophanes. More generally, we highlight that, along with molecular balances − and 2,6-diarylaromatic systems, − cyclophanes are powerful model systems for probing noncovalent interactions involving aromatic rings, an area of current chemical and biological interest.…”

Probing Polar‐π Interactions Between Tetrazoles and Aromatic Rings**

“…Siegel et al . recently reported that the acidity of tetrazoles correlates well with Hammett sigma values, indicating the presence of polar‐π interactions between tetrazole and neighboring rings in 2,6‐diaryl aromatic systems [8d] . However, a critical structural support and in‐depth theoretical analysis of its physical nature have not been analyzed yet.…”