# Effect of Heteroatom Insertion at the Side Chain of 5-Alkyl-1H-tetrazoles on Their Properties as Catalysts for Ester Hydrolysis at Neutral pH

Bhattacharya, Santanu and Vemula, Praveen Kumar (2005) Effect of Heteroatom Insertion at the Side Chain of 5-Alkyl-1H-tetrazoles on Their Properties as Catalysts for Ester Hydrolysis at Neutral pH. In: Journal of Organic Chemistry, 70 (24). pp. 9677-9685.

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## Abstract

Herein we introduce tetrazole and its suitably designed derivatives as powerful ester-cleaving reagents. By first performing a detailed ab initio computational study, we found that, in the side chain of 5-alkyl-1H-tetrazoles, introduction of a heteroatom (e.g., N, O, or S at the \alpha position of the tetrazole ring) raises the charge on the tetrazole nucleus significantly. All calculations have been performed using restricted Hartree-Fock (RHF) and hybrid ab initio/DFT (B3LYP) methods employing 6-31G* and 6-31+G* basis sets. To estimate the nucleophilicity of these reagents, the charges on conjugate bases of various tetrazole derivatives have been calculated using natural population (NBO) analysis in gas phase and in water. Free energy of protonation (fep) of the 1Htetrazole derivatives (1-7), free energy of solvation, $\delta G_a_q$, and the corresponding $pK_a$ values have been calculated by self-consistent reaction field (SCRF) methods applying the polarized continuum model (PCM). Since the calculation indicates that incorporation of heteroatom leads to enhanced nucleophilicity in their deprotonated anionic tetrazole forms, a series of 5-substituted 1H-tetrazole derivatives have been synthesized. These compounds indeed catalyze the hydrolysis of p-nitrophenyl diphenyl phosphate (PNPDPP) and p-nitrophenyl hexanoate (PNPH) efficiently in cationic cetyl trimethylammonium bromide (CTABr) micelles at pH 7.0 and $25^\circ C$. The pseudo-first-order rate constants $(k_o_b_s)$ were determined for each catalyst against both substrates. The experimental and theoretical results show that, to achieve better kobs values for the cleavage of PNPDPP and PNPH under micellar conditions, charge on the $N^-$ atom (nucleophile) of conjugate base is important. Replacing the $\alpha CH_2$ in alkyl substituent with S (3), NH (4), or O (5) enhances the accumulation of charge on $N^-$ in conjugate bases of tetrazoles and subsequently increases their intrinsic nucleophilic reactivity toward hydrolytic reactions. Significantly large rate enhancements were observed for the cleavage of PNPDPP and PNPH at pH 7.0 in the presence of catalytic system 5/CTABr over background (only CTABr). Tetrazole 4 (\alpha-isomer) showed 4-5-fold superior reactivity over 6 (\beta-isomer) under identical conditions. Natural charges obtained from NBO analysis (B3LYP/ 6-31+G*) are -0.94 and -0.852 on $N^-$ in the conjugate bases of 4 and 6, respectively. This also predicts that 4 is a better nucleophile than 6. All the newly synthesized tetrazole deriatives in micellar media display true catalytic properties by cleaving several fold excess of substrates.

Item Type: Journal Article The Copyright belongs to American Chemical Society. Division of Chemical Sciences > Organic Chemistry 18 Jan 2006 19 Sep 2010 04:22 http://eprints.iisc.ernet.in/id/eprint/4888