Praveen Kumar, V

etd@IISc Electronic Theses and Dissertations at Indian Institute of Science

Y '  SYNOPSIS \ .-i' '/ The thesis entitled "Design and Synthesis of Novel CatalysfsTor the Hydrolysis of Organophosphates in Nanoaggregates: Experimental and Computational Studies" illustrates the effectiveness of vanous cationic mcellar and other nanoaggregates consisting of numerous novel molecular entibes having covalently attached nucleophilic headgroups These systems were employed as putative m m c s  of hydrolase enzymes Thls thesis has been hvided into seven chapters Chapter 1 gives a general introduction about the area of mcellar catalysis Chapter 2 descnbes the effect of host mcellar aggregates such as gemni mcelles on rates of the hydrolysis reactions In chapter 3, the 1-hydroxybenzotnazole based nucleophilic catalysts in cationic mcelles Chapter 4 explams the reactivity of 1-hydroxybenzotnazoles towards hydrolytic reactions by analyzing plausible electronic features of 1-hydroxybenzotnazole by ab znitlo and density functional theory Chapter 5 and 6 deal w~th  the design, synthesis and lunetlcs analysis of 1H-tetrazoles as efficient nucleophilic catalysts in cetyl tnmethyl ammonxum bromde (CTABr) mcellar media In these two chapters the design of efficient catalysts based on the quantum mechanical calculations has been shown Finally, in Chapter 7, the design and synthesis of another class of 1H-tetrazole denvatives have been presented These formed nanorods and nanowires in neutral aqueous meha Such organic ID-nanomatenals exhiblt efficient catalyt~c activity toward hydrolysis of organophosphates and alkanoates Chapter 1. Design and Mimic of Hydrolase Enzymes: an Introduction. Chapter 1 provides an introduction to the catalysis of hydrolybc reactions in vmous suprarnolecular aggregates It gives a comprehensive account of the research work done by several research groups worhng in the area of supramolecular and bioorganic chermstry towards the deslgn and development of enzyme mrmcs Chapter 2. Evidence of Enhanced Reactivity of DAAP nucleophiles toward Dephosphorylation and Deacylation Reactions in Cationic Micellar Media. In chapter 2 the design and synthesis of 4,4'-(d~alkylmno) pyndine (DAAP) based compounds, 1-4 have been presented These nucleophles catalybcally cleave hydrophobic organophosphate and carboxylate esters In vanous host mcellar aggregates at mldly alkalme pH The role of the mcellar reaction medum in such esterolytic reactions has been carefully e x m n e d  in this work Cat~onic 'gemm' surfactants (16-m-16, 2Br') based rmcellar aggregates prov~de more than an order of magnitude better reaction medmm for the above reactions as to rmcelles formed from their conventional single chainlcharge counterpart, CTABr The most rapid hydrolys~s was observed with catalyst 2 for cleavage of p-nitrophenyl d~phen y]phosphate (PNPDPP) and p-nitrophenyl hexanoate (PNPH), which can be attnbuted to its strong association with catlonic host mcelles via hydrophobic and ion-painng interactions The catalytic turnover behavior of DAAP nucleophiles in the presence of excess substrates was also observed in both types of mcellar medla Chapter 3. Ester Cleavage Properties of Synthetic Hydroxybenzotriazoles in Cationic Monovalent and Gemini Surfactant Micelles. In this chapter, the design and synthesis of four new hydroxybenzotnazole denvatives have been presented Two of them, N-tetradecyl-l-hydroxy-1H-benzo[d][1,2,3]tnazole-6-carboxamide (6) and N tetradecyl-1-hydroxy-1H-benzo[d][l,2,3] tnazole-7- carboxamde (7) possess long alkyl cham while the other two, 1-hydroxy-1 H-benzo[d] [1,2,3] tnazole-6-carboxylic acid (8) and 1-hydroxy-1 H-benzo[d] [1,2,3] tnazole- 7-carboxylic acid (9) have carboxylate side chams These compounds along with their parent unsubstituted 1- hydroxybenzotnazole, (HOBt), 5, have been examined for the cleavage of PNPW and PNPDPP in cormcelles w~th  monovalent CTABr and the correspondmg bis-cationic germni surfactants, 16-m-16, 2Bi of identical cham length at 25 OC, pH 8 2 The apparent pK. values of the HOBt denvatives m the comcelles of CTABr or 16-4-16 gemni surfactants have been detemned from the rate vs pH profiles and were found to be comparable Catalpc system 8116- 4-16 shows over 2200 and 1650-fold rate enhancements in the hydrolysis of PNpDPP and PNPH respect~vely for identical reactions carned out at pH 8 2, 25 OC in buffered aqueous medla. The - second-order rate constants for such b~molecular react~ons were detemned employmg pseudophase rmcellar models Experiments m which excess substrate were taken over HOBt denvatlves demonstrated that the catalysts "turned over", hydrolysls of the acylated or phosphorylated HOBt mtermed~ates was rap~d In e~ther host rmcelles Chapter 4. Computational Study on Hydroxybenzotriazoles as Reagents for Ester Hydrolysis. In this chapter, a detaded computational study on several denvatlves of 1-hydroxybenzotnazole was presented As shown m chapter 3, 1-hydroxybenzotnazole (5) and several of ~ t s  denvatlves (6-9) demonstrate esterolyt~c act~v~ty toward activated esters such as PNPDPP and PNPH in cat~on~c rmcelles at pH 8 2 and 25 "C The deprotonated anlonic forms of such reagents act as reactive species in the hydrolysls of ester To rat~onalize the ongin of their nucleophilicity, an ab ~nztlolDFT computational study was performed on 5-9 along with addt~onal hydroxybenzotnazole denvatives (10-17) The geometnes of 1-hydroxybenzotnazoles (5-17) and then correspondmg bases are discussed m detad All calculations were carned out uslng different methods, vlz restncted Hartree-Fock (RHF) and hybnd ab znltzolDFT (B3LYP) usmg 6-31G* and 6-31+G* baas sets Free energy of protonation ('fep') of the 1-hydroxybenzotnazoles (5-17), free energy of solvation AGaq, and the corresponchng pKa7s have been calculated Solvation free energes were calculated using dens~ty funcbonal theory and the polanzable continuum model In addibon, to exarmne the reliability of calculated proton affinity, benzaldehyde oxlme (18) and 2-methyl proplonaldehyde oxlme (19) (the expenmental proton affinities of whlch are known) have been computed as reference systems using hfferent methods and basis sets SvnofJsisThe experimental results indicate that the catalyst 8 is the most effective catalyst for thehydrolytic cleavages of PNPDPP and PNPH. The calculated 'fep', pKa and natural chargeanalysis results also predict same outcome. In general, the introduction of electron-withdrawingsubstituents on I-hydroxybenzotriazoles facilitates the lowering of pKa and 'fep'. As the pKavalues are lowered, greater percentage of such hydroxybenzotriazoles remains in theirdeprotonated, anionic forms at pH 8.2. Since the anionic forms are nucleophilic, pKa loweringshould enhance their ester cleaving capacity. However, such substitution also decreases thecharge density on the catalytically active oxido atom (07). Taken these two factors together, itmakes the derivatives only modestly better nucleophile in comparison to the parent 1-hydroxybenzotriazole. Interestingly, calculations indicated that the introduction of electron-donating groups d~es not significantly enhance the charge accumulation <?nthe oxido atom (07)of I-hydroxybenzotriazoles.Chapter 5. Aromatic IH- Tetrazole Derivatives in Cationic Micelles as Potent Reagents forEsterolysis at Neutral pH. Computational and Experimental Studies.In this chapter the design,N-N N=N N=NHN - N HN /;NOOHN /;N'f(5H "-':: r'r'1Tet I ~ ~ ~20 21N-N -N6~:'N 06~ ~:'Nr'1 r'r'~ ~ ~ I23 24N=NI ,c60HN /; NI "-':: "-':: "-'::~ ~ .02225synthesis and kinetics of several5-substituted tetrazolederivatives, 20-25 have beendescribed. performingBy adetailed ab initio computationalstudy, it has been found that in 5-substituted IH-tetrazole systems,introduction of an aromatic groupat the 5-position of the tetrazolering reduces the charge on the tetrazole nucleus significantly. However, insertion of a methylenegroup between the tetrazole moiety and the aromatic ring raises the charge on the tetrazolenucleus considerably. All calculations have been performed using restricted Hartree-Fock (RHF)and hybrid ab initiolDFT (B3LYP) using 6-31G* and 6-31+G* basis sets. To estimate thenucleophilicity of these reagents the charges on the conjugate bases of each tetrazole derivativeswere calculated using natural population (NBO) analysis both in gas-phase and in water.Attachment of aromatic residues with tetrazoles also enhances the hydrophobicity of the resultingIVSvnops~s systems and this in turn nses their parWionmg into mcellar pseudophase Notably, tetrazoles (20- 25) also Induced catalytic hydrolysis of hydrophobic organophosphate and carboxylate esters In catlonic mcelles at neutral pH when excess substrates were employed To acquire better kOb, values for the cleavages of PNPDPP and PNPH under rmcellar conditions, the hydrophoblclty and charge on the N- atom (nucleophile) of conjugate bases of tetrazoles are important Ngher hydrophoblclty and large charge accumulation on N- atom synergistically act together to make 25 as a very potent catalyst in this senes of compounds Impressive rate enhancements were observed wlth 25lCTABr over background rates (CTABr alone) for the cleavages of PNPDPP and PNPH at pH 7 0 Chapter 6. Computational and Kinetic Studies on 5-substituted IN-Tetrazoles as Potent Reagents for Ester Hydrolysis at Neutral pH. By perfomng a detailed ab znztlo computat~onal study, it has been noticed that in 5-substituted 1H-tetrazole systems, mtroduction of a heteroatom e g N, 0 or S at the a-position of the tetrazole nng raises the charge on the tetrazole nucleus significantly All calculations have been performed using restncted Hartree-Fock (RHF) and hybnd ab inrtzolDFT (B3LYP) methods employing 6-3 lG* and 6-3 1+G* basis sets To estimate the nucleophiliclty of these reagents, the charges on conjugate bases of vatlous tetrazole denvatwes have been calculated using natural population (NBO) analysis in gas-phase and in water Free energy of protonation (fep) of the lH-tetrazole denvatives (Tet and 26-30), free energy of solvation, AG,,, and the corresponding pK,'s have been calculated Since the calculaQon indicates that incorporation of heteroatom leads to enhanced nucleophllicity In their deprotonated anIonic tetrazole forms, a senes of 5-substituted 1H-tetrazole denvatwes have been synthesized These compounds indeed hydrolyze PNPDPP and PNPH (m cationic CTABr mcelles at pH 7 0 and 25 0 C) with high efficiency The pseudo-first-order rate constants (ko) were detemned for each catalyst for both substrates. The expenmental and theoretical results showed that to achieve better kv values for the cleavage of PNPDPP and PNPH under mcellar cond~tions, charge on the N- atom (nucleophile) of conjugate base is important Replacing the a-CH2 in hydrocarbon cham Synopszs with S (27), NH (28) or 0 (29), enhances the accumulation of charge on N- in conjugate bases of these tetrazoles and subsequently increases inherent nucleophillc reactiv~ty of above reagents in hydrolyhc reachons Significantly large rate enhancements were observed for the cleavage of PNPDPP and PNPH at pH 7 0 in the presence of catalytic system 29lCTABr over background (only CTABr) Tetrazole, 28 (a-~somer) showed 400-500% supenor reactivity over 30 (p-isomer) under identical conditions Natural charges obtained from NBO analysis (B3LYPl6-31+G*) are - 0 94 and -0 852 on N- In the conjugate bases of 29 and 30 respectively This also predicts that 29 is a better nucleophle than 30 All the newly synthesized tetrazole denvatives in mcellar media d~splayed true catalytic properties by cleaving several fold excess of substrates Chapter 7. Synthesis and Esterolytic Properties of aqueous suspensions of Novel ID- Organic Nanomaterials. Chapter 7 deals with the preparatxon of novel organic nanoaggregates and thelr utility as efficxent hydrolase m m c s  One-dimensional organic nanomatenals such as nanorods and nanowires were prepared by slmple reprecipitation method DMSO solutions of 5(9- anthracenemethylarmno) 1H-tetrazole (31) and 5(1-pyrenemethylarmno) 1H-tetrazole (32) upon injection into water produce such nanoscale aggregates, whlch have been charactenzed by transrmssion electron rmcroscopy, d y n m c  light scattering as well as absorption and emssion spectroscopy Nanorods (31) of length in the range of couple of rmcrometers and dtameters rangmg 200 to 300 nanometers were observed Nanowires of 32 lengths m the range of couple of mcrometers and dmneters of several tens of nanometers were observed. Thus, the aggregates had high aspect ratios These nanomatenals were investigated for l e i r  abil~ty to catalyze the hydrolysis of hydrophobic organophosphate and carboxylate esters at pH 7.0 They exhlbit classical Michaehs-Menten lunet~cs The parameters such as %ba, KM, Vmu and k, were detemned for the two types of nanoaggregates for both types Synopsls of substrates (PNPDPP and PNPH) At higher temperatures (25-80 "C) also these nanoaggregates were still Intact and able to catalyze the hydrolytic reactions TEM, absorption and ermssion studies reveal that 33 or 34 have formed no aggregates in water They also do not catalyze the cleavage of either PNPDPP or PNPH This clearly suggests that an appropnate hpophile- hydrophile balance is essential for the formation of nanoaggregates and their consequent abilities to mediate catalytic esterolysis reactions at ambient pH 

Design And Synthesis Of Novel Catalysts For The Hydrolysis Of Organophosphates In Nanoaggregates : Experimental And Computational Studies

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Design And Synthesis Of Novel Catalysts For The Hydrolysis Of Organophosphates In Nanoaggregates : Experimental And Computational Studies

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etd@IISc Electronic Theses and Dissertations at Indian Institute of Science