Computational study on hydroxybenzotriazoles as reagents for ester hydrolysis

Article abstract of DOI:10.1021/jo049539w

1-Hydroxybenzotriazole (1) and several of its derivatives (2-5) demonstrate potent esterolytic activity toward activated esters such as p-nitrophenyl diphenyl phosphate (PNPDPP) and p-nitrophenyl hexanoate (PNPH) in cationic micelles at pH 8.2 and 25 °C. The deprotonated anionic forms of such reagents act as reactive species in the hydrolysis of ester. To rationalize the origin of their nucleophilic character, a detailed ab initio/DFT computational study has been performed on 1-5 along with additional hydroxybenzotriazole derivatives (6-13). The geometries of 1-hydroxybenzotriazoles (1-13) and their corresponding bases are discussed in detail. All calculations were carried out using different methods, i.e., restricted Hartree-Fock (RHF) and hybrid ab initio/DFT (B3LYP) using 6-31G* and 6-31+G* basis sets. Free energy of protonation ("fep") of the 1-hydroxybenzotriazoles (1-13), free energy of solvation ΔG_aq, and the corresponding pK_a values have been calculated, Solvation-free energies were calculated using density functional theory and the polarizable continuum model. In addition, to examine the reliability of calculated fep, benzaldehyde oxime (14) and 2-methyl propionaldehyde oxime (15) have been computed as reference systems using different methods and basis sets, the experimental feps of which are known. Our experimental finding shows that the compound 4 is the most effective catalyst for the hydrolytic cleavages of PNPDPP and PNPH, This has been predicted from our calculated fep, pK_a, and natural charge analysis results as well. In general, the introduction of electron-withdrawing substituents on 1-hydroxybenzotriazoles facilitates the lowering of pK_a and fep. As the pK_a values are lowered, a greater percentage of such hydroxybenzotriazoles remain in their deprotonated, anionic forms at pH 8.2. Since the anionic forms are nucleophilic, pK_a lowering should enhance their ester cleaving capacity. However, such substitution also decreases the charge density on the catalytically active oxido atom (O₇). Taking these two factors together, the derivatives are only modestly better nucleophiles in comparison to the parent 1-hydroxybenzotriazole. Interestingly, the introduction of electron-donating groups does not significantly enhance the charge accumulation on the oxido atom (O₇) of 1- hydroxybenzotriazoles.

Full text of DOI:10.1021/jo049539w

Computational Study on Hydroxybenzotriazoles as Reagents for
Ester Hydrolysis
V. Praveen Kumar,† Bishwajit Ganguly,*,‡ and Santanu Bhattacharya*,†
Department of Organic Chemistry, Indian Institute of Science, Bangalore, India 560 012,
and Central Salt and Marine Chemicals Research Institute, Bhavnagar, Gujarat, India 364002
sb@orgchem.iisc.ernet.in
Received March 22, 2004
1-Hydroxybenzotriazole (1) and several of its derivatives (2-5) demonstrate potent esterolytic
activity toward activated esters such as p-nitrophenyl diphenyl phosphate (PNPDPP) and
p-nitrophenyl hexanoate (PNPH) in cationic micelles at pH 8.2 and 25 °C. The deprotonated anionic
forms of such reagents act as reactive species in the hydrolysis of ester. To rationalize the origin
of their nucleophilic character, a detailed ab initio/DFT computational study has been performed
on 1-5 along with additional hydroxybenzotriazole derivatives (6-13). The geometries of 1-hy-
droxybenzotriazoles (1-13) and their corresponding bases are discussed in detail. All calculations
were carried out using different methods, i.e., restricted Hartree-Fock (RHF) and hybrid ab initio/
DFT (B3LYP) using 6-31G* and 6-31+G* basis sets. Free energy of protonation (“fep”) of the
1-hydroxybenzotriazoles (1-13), free energy of solvation ∆Gaq, and the corresponding pKa values
have been calculated. Solvation-free energies were calculated using density functional theory and
the polarizable continuum model. In addition, to examine the reliability of calculated fep,
benzaldehyde oxime (14) and 2-methyl propionaldehyde oxime (15) have been computed as reference
systems using different methods and basis sets, the experimental feps of which are known. Our
experimental finding shows that the compound 4 is the most effective catalyst for the hydrolytic
cleavages of PNPDPP and PNPH. This has been predicted from our calculated fep, pKa, and natural
charge analysis results as well. In general, the introduction of electron-withdrawing substituents
on 1-hydroxybenzotriazoles facilitates the lowering of pKa and fep. As the pKa values are lowered,
a greater percentage of such hydroxybenzotriazoles remain in their deprotonated, anionic forms at
pH 8.2. Since the anionic forms are nucleophilic, pKa lowering should enhance their ester cleaving
capacity. However, such substitution also decreases the charge density on the catalytically active
oxido atom (O7). Taking these two factors together, the derivatives are only modestly better
nucleophiles in comparison to the parent 1-hydroxybenzotriazole. Interestingly, the introduction
of electron-donating groups does not significantly enhance the charge accumulation on the oxido
atom (O7) of 1-hydroxybenzotriazoles.
CHART 1
Introduction
Many persistent chemicals such as paraoxon, par-
athion, and chemical warfare compounds such as VX or
sarin, etc. (Chart 1), are hydrophobic phosphorus(V)
esters or phosphorylating agents.1 Such compounds are
highly toxic to both target and nontargeted organisms.1,2
Paraoxon and parathion, the phosphotriester-based pes-
ticides, are most frequently responsible for the poisoning
of agricultural field workers.2a Remediation of such
contamination therefore continues to be a challenge for
research groups. However, high toxicity of such com-
pounds mandates that most research laboratories employ
simulants instead of the actual compounds. For instance,
* Corresponding authors. Fax: +91-080-23600529.
† Indian Institute of Science.
‡ Central Salt and Marine Chemicals Research Institute.
(1) Sogorb, M. A.; Vilanova, E. Toxicol. Lett. 2002, 128, 215.
(2) (a) Munro, N. B.; Ambrose, K. R.; Watson, A. P. Environ. Health.
Perspect. 1994, 102, 18. (b) Raushel, F. M. Curr. Opin. Microbiol. 2002,
5, 288.
10.1021/jo049539w CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/13/2004
8634
J. Org. Chem. 2004, 69, 8634-8642

Hydroxybenzotriazoles as Reagents for Ester Hydrolysis
TABLE 1. Kinetic Parameters for Micellar Esterolysis
of PNPH and PNPDPP Mediated by Various HOBt
Systems in CTABr Micellesa
CHART 2. Structures of 1-Hydroxybenzotriazole
and Its Derivatives (1-13) along with the Oximes
(14, 15)
PNPDPP
PNPH
103 kψ,
103 kψ,
b
pKa
entry catalyst [% of ionizaion]
s-1
krel
s-1
krel
c
c
1
2
3
4
5
6
none
-
0.04
3.21
4.52
4.28
5.36
4.75
1.0
80.2
113.0
107.0
134.0
118.8
0.09
5.35
5.76
5.69
6.61
6.02
1.0
59.4
64.0
63.2
73.4
66.9
1
2
3
4
5
7.0 [95.2]
6.5 [98.4]
6.7 [97.5]
6.5 [98.4]
6.7 [97.5]
a Conditions: 0.05 M pH 8.2 (tris-maleate) buffer, 25 ( 0.1 °C,
[substrate] ) 2.5 × 10-5 M, [catalyst] ) 2.5 × 10-4 M, [CTABr] )
1 × 10-2 M, 1 vol-% CH3CN. b Values in [ ] are % of ionization at
c
pH 8.2. krel ) kψ/kCTABr
.
p-nitrophenyl diphenyl phosphate (PNPDPP) is a well-
known standard simulant for studying the hydrolytic
reactions of phosphotriesters.3 Since PNPDPP is not
water-soluble, aqueous micellar solutions are often em-
ployed as reaction media for the cleavage of such sub-
strate esters.3,4 Organic reactants are partitioned into the
surfactant micelles by columbic and hydrophobic interac-
tions, and the observed rate accelerations are largely due
to the enhanced localization of the reactants and also
of the typical physicochemical properties of micellar
environment, which are considerably different from those
of the bulk solvents.4
Chemical means of achieving efficient destruction of
organophosphate esters remains an active area of much
research. The current attention is focused on peroxides,5
iodosoarene carboxylates,6 4-N,N-dialkylaminopyridines,7
and metalloorganics8 employed in cetyltrimethylammo-
nium (CTA+) micelles as media. 1-Hydroxybenzotriazole
(1) is a potent R-effect O-nucleophile.9 The R-nucleophiles
are known to enhance the hydrolytic reaction rates of
toxic organophosphate esters. When solubilized in cat-
ionic micellar solution, 1 and its derivatives, 2-5 prove
to be effective catalysts for the cleavage of reactive
phosphotriester and carboxylate esters. In this report,
the hydrolytic cleavage reactions of PNPDPP and PNPH
in cationic micellar media with 1 and its derivatives 2-5
have been presented. The experimental results (Table 1)
suggest that 4 is the most effective catalyst among 1-5
studied herein.
To understand the origin of the catalytic activity of
1-hydroxybenzotriazoles in 1-5 and to find a more potent
nucleophile from a series of novel hydroxybenzotriazole
compounds for the esterolytic reactions, we have carried
out a detailed ab initio and Becky3LYP density functional
hybrid computational investigation on 1 and a series of
its derivatives bearing different electron-donating and
electron-withdrawing substituents, 2-13 (Chart 2). The
fep, pKa, and charge on the oxido atom (N-O-) of the
conjugate bases responsible for the hydrolytic cleavage
reactions of PNPDPP and PNPH of these hydroxyben-
zotriazoles have been calculated, as they are fundamental
to the understanding of their catalytic properties toward
dephosphorylation or deacylation reactions.
However, the 1-hydroxybenzotriazoles have so far not
received any theoretical attention, although simple cal-
culations have been performed on certain triazoles.
Fabian and Guimon et al. have performed semiempirical
calculations10 to examine and reproduce the tautomeric
phenomena of traizole systems. Anders et al.11 investi-
gated the phenomena of tautomerism for benzotriazole
and triazole systems using ab initio and semiempirical
methods. The calculations performed by Anders et al.
suggested that semiempirical methods are not adequate
to handle these related triazole systems and high level
calculations are required to reproduce the structural and
reactivity trends. Computing benzotriazoles at very high
levels of theory was prohibitively expensive in the 1990s,
and Anders et al. calculated only simple traizole systems
at a higher level (MP2/6-31+G*) to correlate with the
experimental observations. Accordingly, we report here
the structural, conformational aspects of 1-hydroxyben-
(3) (a) Bunton, C. A.; Nelson, S. E.; Quan, C. J. Org. Chem. 1982,
47, 1157. (b) Bunton, C. A.; Hong, Y. S.; Romsted, L. S.; Quan, C. J.
Am. Chem. Soc. 1981, 103, 5788. (c) Simanenko, Y. S.; Karpichev, E.
V.; Prokoke`va, T. M.; Panohenko, B. V.; Bunton, C. A. Langmuir 2001,
17, 581.
(4) (a) Bunton, C. A.; Robinson, L. J. Org. Chem. 1969, 34, 773. (b)
Bunton, C. A.; Nome, F.; Quina. F. H.; Romsted, L. S. Acc. Chem. Res.
1991, 24, 357.
(5) (a) Bhattacharya, S.; Snehalatha, K. J. Org. Chem. 1997, 62,
2198. (b) Toullec, J.; Moukawim, M. Chem. Commun. 1996, 221. (c)
Yang, Y.-C.; Szafraniec, L. L.; Beandry, W. T.; Bunton, C. A. J. Org.
Chem. 1993, 58, 6964.
(6) Rojas, H. M.; Moss, R. A. Chem. Rev. 2002, 102, 2497 and
references cited therein.
(7) (a) Bhattacharya, S.; Kumar, V. P. J. Org. Chem. 2004, 69, 559.
(b) Bhattacharya, S.; Snehalatha, K. Langmuir 1997, 13, 378. (c)
Bhattacharya, S.; Snehalatha, K. Langmuir 1995, 11, 4653.
(8) (a) Bhattacharya, S.; Snehalatha, K.; Kumar, V. P. J. Org. Chem.
2003, 68, 2741. (b) Yan, J.; Breslow, R. Tetrahedron Lett. 2000, 41,
2059. (c) Bhattacharya, S.; Snehalatha, K.; George, S. K. J. Org. Chem.
1998, 63, 27. (d) Mancin, F.; Tecilla, P.; Tonellato, U. Langmuir 2000,
16, 227.
(10) (a) Fabian, W. M.; Naturforsch, Z. F. Phys. Sci. 1990. (b)
Giumon, C.; Khayar, S.; Pfister-Guillouzo, G.; Begtrup, M. Spectrosc.
Lett. 1987, 20, 105.
(11) Anders, E.; Katritzky, A. R.; Malhotra, N.; Stevens, J. J. Org.
Chem. 1992, 57, 3698.
(9) Konig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
J. Org. Chem, Vol. 69, No. 25, 2004 8635

Kumar et al.
TABLE 2. Free Energy of Protonationa Calculated for
14 and 15 Using Different Methods
natural bond orbital (NBO) localization procedures developed
by Weinhold et al.17
To calculate the pKa values of molecules 1-13, we have
considered the thermodynamic cycle shown below.
method
14
15
RHF/6-31G*
377.6
368.1
366.4
353.7
367.5
353.4
389.7
379.0
381.8
366.3
381.4
364.9
RHF/6-31+G*
B3LYP/6-31G*
B3LYP/6-31+G*
MP2/6-31G*
MP2/6-31+G*
a Energies are in kcal/mole. Experimental proton affinity of 14
and 15 are 355.1 and 364.6, respectively.
zotriazole and its different electron-withdrawing/donat-
ing derivatives at ab initio Hartree-Fock and DFT-
B3LYP levels.
The thermodynamic cycle yields eq 1 in which the aqueous
pKa for the acid N-OH is given by
∆Gaq ) ∆Ggas + ∆Ghyd (N-O-) + ∆Ghyd (H+) -
∆Ghyd (N-OH) (1)
Computational Methods
All the ab initio Hartree-Fock and Becky3LYP density
functional hybrid method12 calculations reported in this work
were performed using the Gaussian 98 suite program.13 The
stable conformers of 1-hydroxybenzotriazole derivatives (2-
13) have been located and optimized at the level of restricted
Hartree-Fock (RHF) and DFT (B3LYP) using the 6-31+G*
basis set.14 All structures were completely optimized without
any symmetry constraints. For all systems studied, vibrational
frequency calculations were carried out to confirm that they
converged to true minima.
For the sake of simplicity, we define the deprotonation
enthalpy of the neutral protonated forms of hydroxybenzo-
triazoles as free energy of protonation (fep) of the negatively
charged species. Fep values were obtained by following Dew-
ar’s definition.15 Essentially, we consider the cases as in the
instances when we deal with isodesmic processes (e.g., ROH
+ MeO- f RO- + MeOH) and internal comparisons of the
energy differences.16
To probe the relative validity of the basis sets and to
evaluate the influence of electron correlation and diffuse
functions, we calculated the free energy of protonation (N-
OH f N-O-) of two molecules, for instance, benzaldehyde
oxime (14) and 2-methyl propionaldehyde oxime (15) (Chart
2) as references, whose experimental proton affinities are
known. The results (Table 2) show that the electron correlation
and diffuse functions are important to closely match with the
experimental data. Results obtained employing B3LYP/6-
31+G* and MP2/6-31+G* methods provide the best match
with the experimental results, and accordingly we have chosen
B3LYP/6-31+G* for further calculations. In addition this
method requires less CPU time than the MP2 method. Natural
charges calculated on the oxido (O7) atom of N-O- in the
conjugate bases of 1-13 were calculated on the basis of the
At a given temperature T, the pKa is then given by
pKa ) ∆Gaq/2.303 RT
(2)
The gas phase fep is calculated at the same level of theory
used for the calculation of solvation free energy. The free
energy of solvation in water has been calculated using SCRF
(self-consistent reaction field) methods using the polarized
continuum model (PCM).18-22 A dielectric constant (∈) of 78.39
(water) was used in the solvation calculations, at the B3LYP/
6-31+G* level. The solvation-free energy of the proton taken
from the experimental ∆Ghyd (H+) is equal to -254 kcal/mol.23
Results and Discussion
Synthesis of 1-Hydroxybenzotrizoles (2-5). De-
rivatives of 1-hydroxybenzotriazole, 2 and 3, have been
synthesized following the procedure outlined in Scheme
S1 (Supporting Information). First, 4-chloro-3-nitroben-
zoic acid was converted to the corresponding acid chloride
by refluxing in SOCl2. Removal of excess SOCl2 afforded
4-chloro-3-nitrobenzoyl chloride, which on reaction with
n-tetradecylamine in the presence of Et3N in dry THF
gave the corresponding amide derivative, 7 (82%), as a
yellow solid. This was then treated with ∼10-fold excess
of hydrazine hydrate, and the mixture was refluxed in
dry EtOH for 20 h to give 2 as a light yellow solid (60%).
Compound 3, the regioisomer of 2, was synthesized start-
(17) (a) Reed, A. E.; Weinhold, F. J. Chem. Phys. 1983, 78, 4066.
(b) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985,
83, 735.
(12) Becke, A. D. J. Chem. Phys. 1993, 98, 1372.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J. A. Gaussian 98, revision A.11.3; Gaussian, Inc.: Pittsburgh,
PA, 1998.
(18) (a) Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027. (b)
Structure and Reactivity in Aqueous Solutions; Cramer, C. J., Truhlar,
D. G., Eds.; ACS Symposium Series 568; American Chemical Society:
Washington, DC, 1994. (c) Rivali, J. L.; Rinaldi, D. In Computational
Chemistry, Review of Current Trends; Leszczynski, J., Ed.; World
Scientific Publishing: Singapore, 1996. (d) Orozco, M.; Alhambra, C.;
Barril, X.; Lopez, J. M.; Busquets, M. A.; Lugue, F. J. J. Mol. Model.
1996. (e) Cramer, C. J.; Truhlar, D. G. In Solvent Effects and Chemical
Reactivity; Tapia, O., Bertran, J., Eds,; Kluwer Academic Publishers:
Dordrecht, 1996.
(19) (a) Miertus, S.; Scrocco, E.; Tomasi, J. J. Chem. Phys. 1981,
55, 117. (b) Pascual-Ahuir, J. L.; Silla, E.; Tomasi, J.; Bonaccorsi, R.
J. Comput. Chem. 1987, 8, 778.
(20) (a) Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239. (b) Cossi,
M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996, 255,
347. (c) Wiberg, K. B.; Rablen, P. R.; Rush, D. J.; Keith, T. A. J. Am.
Chem. Soc. 1995, 117, 4261. (d) Tomasi, J.; Persico, M. Chem. Rev.
1994, 94, 2027.
(14) Hehre, W. J.; Radom, L.; Schleyer, P. v. R. Ab Initio Molecular
Orbital Theory; John Wiley & Sons: New York, 1986. For description
of basis sets and refs, see pp 63-91.
(15) Dewar, M. J. S.; Dieter, K. M. J. Am. Chem. Soc. 1986, 108,
8075.
(21) Pera¨kyla¨, M. J. Chem. Soc., Perkin Trans. 2 1997, 2185.
(22) Pera¨kyla¨, M. J. Org. Chem. 1996, 61, 7420.
(23) Reiss, H.; Heller, A. J. Phys. Chem. 1985, 89, 4207.
(16) Ponomaraev, D. A.; Takhistov, V. V. J. Chem. Educ. 1997, 74,
201.
8636 J. Org. Chem., Vol. 69, No. 25, 2004

Hydroxybenzotriazoles as Reagents for Ester Hydrolysis
Kinetic Studies in Micelles. Kinetics were per-
formed under pseudo-first-order conditions, monitoring
the appearance of p-nitrophenoxide at 400 nm, 0.05 M
tris-maleate buffer, pH 8.2, at 25 ( 0.1 °C, using
[substrate] ) 2.5 × 10-5 M and [catalyst] ) 2.5 × 10-4
M at different CTABr concentrations. The buffer solu-
tions also contained 1.0 vol % CH3CN. Pseudo-first-order
rate constants, kψ, were spectrophotometrically deter-
mined for both substrate (PNPH and PNPDPP) cleavages
at each combination of [CTABr]/[catalyst] by following
the release of p-nitrophenoxide ion at 400 nm. The
reproducibility of kψ was generally (2% with all the
catalytic formulations. Determination of full rate con-
stant vs [CTABr] profiles for the cleavage reactions of
PNPH and PNPDPP in micellar aggregates allowed
assessment of the ester cleavage abilities of 1 to 5. The
plot of kψ vs [CTABr] gave maxima for all the catalysts
at [CTABr] ) 10 mM (data not shown).
The values of kψ for the cleavages of PNPDPP and
PNPH by each catalyst at 10 mM [CTABr] are shown in
Table 1. When the molar ratio of catalyst to CTABr was
fixed at 1:40, we observed the best kψ values for each
catalyst, 1-5. The last column of Table 1 provides a
comparison of the cleavage abilities of the all catalysts
under pseudo-first-order conditions. The ratio kψ/kCTABr
reveals the catalytic capacities of these hydroxybenzo-
triazoles compared to background cleavage rates at
identical pH and temperature in CTABr micelles alone.
Data in Table 1 reveal that compounds 1-5 are reason-
ably effective reagents for the cleavage of both PNPDPP
and PNPH and afford almost 2 orders of magnitude rate
acceleration over CTABr alone.
Comicellar 4/CTABr displayed the highest esterolytic
activity among all the catalytic systems toward both
PNPDPP and PNPH. Thus, 4/CTABr cleaved PNPDPP
134 times faster than the same reaction in CTABr
micelles alone. 5/CTABr comicelles were the next most
effective ester cleavage agent (Table 1). Incorporation of
n-tetradecyl chain potentiates the kinetic efficiency in 2
or 3 over 1. However, such enhancement in reactivity for
the hydrolysis of both PNPDPP and PNPH by 2 or 3 over
1 was not enormous. To rationalize the origin of nucleo-
philicity in this type of reagent and to enable us to design
more potent hydroxybenzotriazoles, we decided to per-
form detailed ab initio/DFT calculations on a large set of
compounds bearing either electron-withdrawing or elec-
tron-donating substituents.
We also performed saturation kinetics experiments in
CTABr comicelles at pH 8.2 and 25 °C for 1-5 with
solutions containing increasing amounts of catalyst and
CTABr with molar ratios relative to the catalyst of 30,
40, and 50, using PNPDPP as the substrate. Analysis of
the curves by fitting the kobs vs [catalyst] data using the
Michaelis-Menten equation8a allows the estimation of
the klim, that is, the rate constants expected for the
substrate being fully incorporated into the micellar
aggregates, Kb, is the apparent binding constant and
second-order rate constants, k2.
FIGURE 1. Observed rate constant kψ vs pH profiles for the
comicellar cleavages of PNPDPP (2.5 × 10-5 M) by 2 (2.5 ×
10-4 M) (9) and 4 (2.5 × 10-4 M) (b) in CTABr (1 × 10-2 M)
micelles at pH 8.2.
ing from 3-chloro-2-nitrobenzoic acid employing a similar
procedure as adopted for 2 (Scheme S1, Supporting
Information). The corresponding 1-hydroxybenzotriazole
carboxylic acids 4 and 5 were also synthesized to examine
their efficacy as esterolytic agents in cationic micellar
media. These were obtained upon treatment of 4-chloro-
3-nitrobenzoic acid or 3-chloro-2-nitrobenzoic acid with
a ∼10-fold excess of hydrazine hydrate under refluxing
conditions in dry EtOH for 15 h. Acidification of the
respective reaction mixture gave 4 and 5 as white solids
in 76 and ∼55% yields, respectively. The final products
1
and intermediates were characterized by IR, H NMR,
mass, and elemental analysis (Supporting Information).
pKa Determination. It is known that the anion of
hydroxybenzotriazole (N-O-) acts as a reactive species
in the hydrolysis of esters.9 Therefore, the reactive species
of 1-5 are the corresponding anionic forms N-O- in the
hydrolysis of PNPH or PNPDPP. Consequently, the pKa
for the conversion of the N-OH to the N-O- form in each
of 1-5 represents an important datum in all these cases.
A pH-rate constant profile for the esterolytic cleavage
of 2.5 × 10-5 M PNPDPP by 2.5 × 10-4 M reagent in
host CTABr (cetyltrimethylammonium bromide) micelles
(1 × 10-2 M) gave the apparent pKa values for each
reagent in 0.05 M tris-maleate buffer adjusted to ap-
propriate pH.
Typically, the pseudo-first-order rate constants for
PNPH or PNPDPP cleavages at 25 °C were determined
at different pH values between 6.2 and 8.5 by following
the release of the p-nitrophenoxide ion at 400 nm
spectrophotometrically. In Figure 1, we present repre-
sentative pH-rate constant profiles for the cleavage of
2.5 × 10-5 M PNPDPP by 2.5 × 10-4 M of 2 and 4 in
micellar CTABr (1 × 10-2 M) and 0.05 M tris-maleate
buffer at 25 °C. The plots of log kψ vs pH (Figure 1) gave
discontinuities at pH 6.5 and 6.5, which were taken as
systemic pKa for 2 and 4, respectively, under CTABr
micellar conditions. A pKa value of 7.4 for 1 in pure water
has been reported.24 Solubilization of 1 in micellar CTABr
lowered the pKa value to ∼7.0. The pKa values similarly
determined for compounds 3-5 in CTABr micellar ag-
gregates were 6.5 for 2, 6.7 for 3, 6.5 for 4, and 6.7 for 5.
Data in Table S1 also reveal that 4 has higher klim, Kb,
and k2 values, which again suggests that indeed catalyst
4 has better catalytic activity among other catalysts in
(24) Boyle, F. T.; Jones, R. A. Y. J. Chem. Soc., Perkin Trans. 2 1973,
160.
J. Org. Chem, Vol. 69, No. 25, 2004 8637

Kumar et al.
SCHEME 1. Three Different Orientations
this series of molecules even in the fully bound form, i.e.,
where catalyst and substrates should be fully transferred
to micellar aggregates. Hence, we assume that the higher
catalytic activity of 4 is due to the higher nucleophilicity
of the N-O- of 4, which arises from the higher natural
charge on the oxido atom.
of the N-OH Bond Considered for
1-Hydroxybenzotriazoles 1-13 Calculations
To examine the true catalytic activities of different
HOBt derivatives, kinetic experiments were performed
in the presence of excess substrate in CTABr micellar
media. At pH 8.2 (0.05 M tris-maleate buffer, 25 °C, [4]
) 2.5 µM, [CTABr] ) 1 mM and 25-fold excess PNPH
with respect to catalyst concentration), we observed a
quantitative monoexponential release of p-nitrophenoxide
ion (not shown). The catalytic effectiveness of 4 was still
intact even after complete hydrolysis of 25-fold PNPH.
This was also true for the cleavage of excess PNPDPP.
The hydroxybenzotriazoles are rapidly acylated or
phosphorylated by PNPH or PNPDPP at pH 8.2 in
micellar conditions. The resulting products do not, how-
ever, retain the acyl or phosphoryl groups. In fact, the
acylated or phosphorylated hydroxybenzotriazoles rapidly
deacylate in a second and even faster step, regenerating
the parent hydroxybenzotriazoles. Therefore, the hy-
droxybenzotriazole reagents are not stoichiometric acyl
transfer agents; they are true catalysts. The observed
reactions are therefore purely hydrolytic reactions and
not mere reactions between triazoles and phosphate
esters.
at B3LYP/6-31+G* levels and their conjugate bases are
shown in Figure 2. In general, the U-type conformation
(Scheme 1) was predicted to be the most stable conforma-
tion for 1-hydroxybenzotriazole, 1, and its substituted
derivatives 4, 6, 8, 9, 12, and 13 by 0.3-0.6 kcal/mol in
comparison to their corresponding R-type conformations.
In these cases, L-type conformations have been found to
be least stable. Interestingly, all three initial conforma-
tions for 2, 3, and 10 converged with the U type-
conformations (Figure 2). In the case of 5, 5L and 5U
converged to the same conformation with intramolecular
hydrogen bonding. These conformations have been found
to be more stable than their corresponding 5R conforma-
tion by 8.1 kcal/mol. A similar trend has been predicted
for 7. Conformations 7L and 7U have been found to be
more stable than 7R by 5.8 kcal/mol. 11L is predicted to
be a more stable conformation than the corresponding
11R and 11U conformations by 0.6 kcal/mol due to the
favorable intramolecular hydrogen bonding. The pre-
ferred “U-type” orientation achieved by HOBt and their
derivatives over L- and R-type structures is due to the
lone-pair repulsions between the adjacent nitrogen and
oxygen atoms. The -OH group orients perpendicular to
the ring plane to minimize lone pair-lone pair repul-
sions, which otherwise would be larger in the other two
forms.
The computed benzotriazole rings for 1-13 are pre-
dicted to be almost planar (torsional angle N1-N2-N3-
C1) (Figure 2). Such planarity was also observed for
triazole rings at the MP2/6-31+G* level.11 The Hartree-
Fock RHF/6-31+G* calculated bond lengths for 1-13 are
generally shorter than the B3LYP/6-31+G* calculated
bond lengths (Tables S2a and S2b, Supporting Informa-
tion). However, the calculated internal bond angles and
torsional angles are comparable at both levels of theory
(Table S3a, S3b, and S4, Supporting Information). The
influence of electron correlation on the structural pa-
rameters were also observed by Anders et al. while
calculating the triazole ring systems.11 The calculated
bond lengths obtained for the triazole rings of benzo-
triazoles 1-13 at B3LYP/6-31+G* are found to be in good
agreement with MP2/6-31+G*-calculated bond lengths
for triazole rings reported by Anders et al. The only
discrepancy observed was in the bond lengths of N2-N3.
The bond lengths based on B3LYP/6-31+G* calculations
are relatively shorter than the bond lengths obtained
from MP2/6-31+G* calculations. It is interesting to note
that the isolated (-NdN-) double bonds of the diazene
is 1.26 Å, and B3LYP/6-31+G* as well as MP2/6-31+G*
predict longer -NdN- bonds (1.30 and 1.34 Å, respec-
tively) for benzotriazole and triazole rings than isolated
diazene. A Cambridge-based crystallographic structural
data search indicates that the N2-N3 bonds in triazole
Theoretical Calculations
Accounting for solvent effects computationally is a
challenging task. Rate constants are sensitive to small
free energy changes. Also, there are uncertainties in
heats of formation from even high-level calculations,
which apply to isolated molecules and do not of them-
selves provide evidence on structural effects on entropy.
However, these concerns should not preclude computa-
tional studies in this direction. Especially with the
development of statistical Monte Carlo and quantum
mechanical methods, it is possible to gauge the role of
solvents with reasonable accuracy.25 Although continuum
models may not be the best in analyzing reactions such
as dephosphorylation, there is an advantage in using a
continuum description in that it speeds up computation
considerably with reasonable accuracy. Accordingly, we
have herein attempted to understand the experimental
results using quantum mechanical methods.
Ab Initio/DFT Results of 1-Hydroxybenzotriaz-
oles (1-13). 1-Hydroxybenzotriazole and its derivatives
1-13 have been optimized at RHF/6-31+G* and B3LYP/
6-31+G* levels of theory. To examine the most stable
form of 1-13, three different orientations for the N-OH
bond have been considered for each molecule and opti-
mized without any symmetry constraints (Scheme 1). For
simplification of calculations and to economize CPU
usage, long n-tetradecyl chains in 2 and 3 have been
replaced with methyl group. RHF/6-31+G* and B3LYP/
6-31+G* levels, in general, arrived at similar stable
conformations for 1-hydroxybenzotriazole and its deriva-
tives 1-13. Most stable conformations predicted for 1-13
(25) (a) Gilson, M. K.; Honig, B. H. Proteins 1988, 4, 7. (b) Jorgensen,
W. L. Acc. Chem. Res. 1989, 22, 184. (c) Cramer, C. J.; Truhlar, D. G.
Chem. Rev. 1999, 99, 2161.
8638 J. Org. Chem., Vol. 69, No. 25, 2004

Hydroxybenzotriazoles as Reagents for Ester Hydrolysis
FIGURE 2. Most stable conformations for 1-13 and their conjugated bases at the B3LYP/6-31+G* level of theory. Hydrogen
bonding distances are in Å.
moieties are 1.29-1.31 Å.26 Therefore, the elongation of
N2-N3 bond appears to be slightly longer at the MP2
level. The most significant changes are found for the
N-O- bonds in the conjugate bases 1-13, which are
much shorter than the normal N-OH bonds (Tables S2a
and S2b). Such shortening can arise from the influence
of an anomeric effect, which originates due to the
interaction of an oxygen (O-7 ) with a σ* bond orbital of
the N1-C2 ring bonds. The high-level ab initio calcula-
tions performed for the anomeric charged species have
shown similar shortening in anomeric bonds.27 The N2-
N3 bonds are found to be elongated in conjugate bases
1-13 in comparison to their corresponding acids at both
RHF/6-31+G* and B3LYP/6-31+G* levels of theory
(Tables S2a and S2b). Such elongation of N2-N3 bonds
in the conjugate base forms of 1-13 in comparison to N2-
N3 bonds in the corresponding acids could be the result
of electrostatic repulsions between N1,N3 centers. Natural
charge analyses at B3LYP/6-31+G* levels suggest that
the N1,N3 centers carry more negative charge in the
conjugate bases than their corresponding acids.
The RHF/6-31+G* and B3LYP/6-31+G* calculated
results show that the -C(O)NHCH3 attached to 1-hy-
droxybenzotriazole ring at 4-position 2 deviates from
planarity in the case of both the acid and its conjugate
base due to the steric interaction between the amide
N-H and the neighboring benzene hydrogen. Disrupted
conjugation has been observed for the conjugate base 10
in which the N,N-dimethyl group deviates significantly
from the ring planarity. However, its corresponding acid
shows that the N,N-dimethyl group lie in the plane of
the ring (Figure 2). Other substituents attached at
4-positions of the 1-hydroxybenzotriazole rings prefer to
lie in the plane of the ring for extended conjugation.
However, the orientation of the substitutents at the
3-position of 1-hydroxybenzotriazole rings in acids and
their conjugate bases depend on the hydrogen bonding
and repulsive electrostatic interactions with the neigh-
boring N-OH group (Figure 2).
(26) (a) Allen, F. H.; Kennard, O. Chem. Des. Automat. News 1993,
8, 3137 (CSD version 5.24, Nov 2002). (b) Kavounis, C. A.; Bozopoulos,
A. P.; Cheers, C. J.; Renzepers, P. J.; Theocharis, A. B. Acta Crystallogr.
Sect. C 1988, 1063.
(27) Ganguly, B.; Fuchs, B. J. Org. Chem. 1997, 62, 8892.
J. Org. Chem, Vol. 69, No. 25, 2004 8639

Kumar et al.
to the repulsive electrostatic interactions between N-O-
and the neighboring carboxyl group, which will contribute
to enhance the fep for 5 (Figure 2). Feps calculated for
hydroxybenzotriazoles bearing electron-donating groups
(N,N-dimethyl and methoxy groups) 10-13 are either
comparable to the parent 1-hydroxybenzotriazole 1 or
slightly higher than the latter (Table 3). Results of the
fep calculations suggest that the deprotonation (N-OH
f N-O-) is more facilitated in the case of compounds
with electron-withdrawing groups.
The experimentally determined pKa values for 2-5 in
miceller media show that the electron-withdrawing sub-
stituents on 1-hydroxybenzotriazoles have lower pKa
values than that of the parent 1-hydroxybenzotriazole,
1. These data are in general in agreement with our
calculated free energy of protonation (Table 3). However,
calculating the pKa for these 1-hydroxybenzotriazole
systems would allow a better comparison with our
experimentally observed results. Since the experimental
results are not available for other 1-hydroxybenzotriazole
derivatives 6-13, it will be interesting to predict the pKa
for these systems, as it is an important factor for
predicting the catalytic activities toward dephosphory-
lation or deacylation reactions in cationic micellar media.
The trends projected from calculations will be useful for
understanding the catalytic activity of theoretically
examined systems 6-13; in particular, the electron-
donating-substituted 1-hydroxybenzotriazoles 10-13.
Calculated pKa. The prediction of absolute pKa from
first principle theory remains extraordinarily difficult,
in part because of the difficulty in computing accurate
gas-phase deprotonation free energies and also because
of the large magnitude of solvent effects for charged
species.28 Typical accuracies in the computed quantities
are rarely better than 2-5 kcal/mol, which results in
absolute errors of possibly a few log units in pKa, a dis-
appointing result given the accuracy possible from ex-
perimental measurements (when such measurements can
be made). Fortunately, trends in pKa values for similar
compounds suggest more accurate predictions,28b,e-g,29
although rationalizing differences in some simple series,
e.g., the methylated amines, continue to be challeng-
ing.28,30 Efforts have been put forward to predict the abso-
lute pKa for systems of particular interest by developing
new parameters and by fitting the computational results
with experimental ones using linear regression analysis.31
TABLE 3. Calculated Free Energy of Protonation and
pKa Values for 1-13 at B3LYP/6-31+G* Levels
free energy of
b
protonationa
pKa
1
2
323.1
316.3
307.9
314.5
327.4
307.5
319.8
319.9
320.7
327.3
324.1
325.2
326.6
5.81
5.47
3.64
5.32
6.42
4.70
5.26
5.40
5.18
6.48
5.86
6.61
5.19
3
4
5
6
7
8
9
10
11
12
13
a Energies are in kcal/mole. b Calculated in water by using
dielectric constant (∈) of the solvent 78.39.
Free Energy of Protonation. Free energy of proto-
nation (fep) calculated for 1-hydroxybenzotriazole and its
derivatives 1-13 (monoanionic forms) at the B3LYP/6-
31+G* level is shown in Table 3. We have calculated the
fep at the RHF/6-31+G* level also. Hartree-Fock-
calculated feps are found to be relatively higher than the
ones calculated using B3LYP (data not shown). However,
the trends predicted with electron-withdrawing and
electron-donating substituents of 1-hydroxybenzotriaz-
oles are quite similar in both the cases. (The possibility
of free energy of dideprotonation (i.e., via deprotonation
of the carboxylic acid group to form dianion) was also
examined for 4 and 5, and the values were 711.2 and
730.0 kcal/mol for 4 and 5, respectively. However, for
direct comparison with 1 and other related systems 2-13,
we have only discussed monoanionic deprotonation in the
text. The relative feps for dianionic forms for 4 and 5
follow a trend similar to that obtained for monoanionic
forms).
In general, electron-withdrawing substituents show
lower fep in comparison to parent 1-hydroxybenzotriaz-
ole, 1, with an exception of 5, which shows a relatively
higher fep. Calculations at B3LYP/6-31+G* and RHF/6-
31+G* levels show that the substituents attached at
different positions in 1-hydroxybenzotriazoles have an
influence on the fep. The predicted fep for 3 has been
found to be ∼10 kcal/mol lower than the fep calculated
for its regioisomer, 2. Such a lowering in fep for 3 may
be understood by examining the geometries of the acid
and its conjugate base (Figure 2). The most stable form
of 3 calculated at both levels of theory shows that the
N-OH hydrogen is not involved in the intramolecular
hydrogen bonding and hence is free for deprotonation.
The O-H oxygen in this geometry, being an acceptor,
facilitates the deprotonation of the -OH proton. Further,
upon deprotonation, the conjugate base 3 should be
stabilized due to the strong hydrogen bonding (N-
H...-O7), and hence the fep of 3 would be expected to be
lower than that of the regioisomer, 2.
(28) (a) Chen, Y.; Noodleman, L.; Case, D. A.; Bashford, D. J. Phys.
Chem. 1994, 98, 11059. (b) Richardson, W. H.; Peng, C.; Bashford, D.;
Noodleman, L.; Case, D. A. Int. J. Quantum Chem. 1997, 61, 207. (c)
Floria`n, J.; Warshel, A. J. Phys. Chem. B 1997, 101, 5583. (d)
Schu¨u¨rmann, G. Quantum Struct. Act. Relat. 1996, 15, 121. (e)
Schu¨u¨rmann, G. J. Chem. Phys. 1998, 109, 9523. (f) Colominas, C.;
Orozco, M.; Lugue, F. J.; Borrell, J. I.; Texido, J. J. Org. Chem. 1998,
63, 4947. (g) Schu¨u¨rmann, G. J. Phys. Chem. A 1998, 102, 6706. (h)
Cramer, C. J.; Truhlar, D. G. Chem. Rev. 1999, 99, 2161.
(29) Topol, I. A.; Tawa, G. J.; Burt, S. K.; Rashin, A. A. J. Phys.
Chem. A 1997, 101, 10075.
(30) (a) Cramer, C. J.; Truhlar, D. G. J. Am. Chem. Soc. 1991, 113,
8552. (b) Terryn, B.; Rivail, J.-L.; Rinaldi, D. J. J. Chem. Res., Synop.
1981, 141. (c) Kawata, M.; Ten-no, S.; Hirata, F. Chem. Phys. 1996,
203, 53. (d) Miklavc, A. J. Chem. Inf. Comput. Sci. 1998, 38, 269. (e)
Safi, B.; Choho, K.; DeProft, F.; Geerlings, P. Chem. Phys. Lett. 1999,
300, 85.
The calculated fep for 5 has been found to be the
highest among the series of hydroxybenzotriazoles bear-
ing electron-withdrawing groups, i.e., 2-9. The calculated
geometry suggests that the N-OH hydrogen in 5 is
intramolecularly hydrogen bonded with the carboxyl
oxygen, less available for deprotonation, and the corre-
sponding conjugate base formed will be less stable due
(31) (a) Lim, C.; Bashford, D.; Karplus, M. J. Phys. Chem. 1991,
95, 5160. (b) Jorgensen, W. L. Acc. Chem. Res. 1989, 22, 184. (c) Jang,
Y. H.; Sowers, L. C.; Cagin, T.; Goddard, W. A., III. J. Phys. Chem. A
2001, 105, 274. (d) Pera¨kyla¨, M. J. Am. Chem. Soc. 1998, 120, 12895.
(e) Major, D. T.; Laxer, A.; Fischer, B. J. Org. Chem. 2002, 67, 790.
8640 J. Org. Chem., Vol. 69, No. 25, 2004

Hydroxybenzotriazoles as Reagents for Ester Hydrolysis
TABLE 4. Calculated Natural Charges on O7 for
In this study, we compare the trends of pKa calculated
for 1-hydroxybenzotriazoles 1-13 using the thermody-
namic cycle mentioned in the computational methodology
section. We wanted to compare computed pKa values of
1-5 with our experimental pKa results for these com-
pounds in micellar solutions. We also sought to examine
the pKa for those systems (6-13), which could not be
studied experimentally. This is because several of these
are difficult to synthesize and, when feasible, may be
prepared only in very poor yields.32 Therefore, we directed
our efforts in the direction of comparing trends observed
from calculations even if it was not possible to examine
the absolute pKa for 6-13. Polarizable continuum model
(PCM) as a solvation model has been used to calculate
the free energy of hydration. Most theoretical approaches
differ concerning solvation treatment in calculating pKa.
Several solvation models exist, each having its strengths
and weaknesses. Some of the discrete solvation methods
used in pKa calculations include free energy perturbation
simulations in explicit water33 and the Langevin dipole
method.34 On the other hand, the commonly used con-
tinuum models are based on the Born model,35 the
Poisson-Boltzmann (PB) equation,31a,c and various imple-
mentations of the polarizable continuum model (PCM).36,28f
The advantage of continuum models over discrete meth-
ods is that the solvent reaction field may be incorporated
into the quantum mechanical Hamiltonian, and thus an
accurate description of the solvated solute may be
achieved.
Conjugate Base (1-13) at B3LYP/6-31+G* Level
Conjugate base
B3LYP/6-31+G*
1-O-
2-O-
3-O-
4-O-
5-O-
6-O-
7-O-
8-O-
9-O-
10-O-
11-O-
12-O-
13-O-
-0.647
-0.629
-0.644
-0.609a (-0.675)b
-0.615a (-0.626)b
-0.585
-0.592
-0.647
-0.623
-0.652
-0.643
-0.652
-0.626
a Charge on the Oxido atom of carboxylic acid form. b Charge
on Oxido atom of di-deprotonated (carboxylated) form.
electron-donating groups, 10-12, it appears that the pKa
values are generally higher than for the parent system,
1, although the calculated pKa shows a lower value for
compound 13 (Table 3). The calculated and observed pKa
data suggest that the 1-hydroxybenzotriazoles bearing
electron-withdrawing substituents can facilitate the for-
mation of ionized N-O- species. This in turn can help
the acceleration of the hydrolysis rates of PNPDPP and
PNPH in comparison to 1. However, the nucleophilicity
of the conjugate bases is another important factor, which
contributes significantly to determining the catalytic
strengths of these compounds.
The computed pKa values for 1-13 at the B3LYP/6-
31+G* level are shown in Table 3. Examining the pKa
values for 1-5, it appears that the calculated values are
in general shifted ∼1 unit lower than the experimentally
observed values (Table 1). The 1-hydroxybenzotriazoles
2-9 with electron-withdrawing substituents show lower
pKa values than the parent 1-hydroxybenzotriazole, in
agreement with the available experimental observations.
The apparent discrepancy in the calculated pKa shifts for
3 and 5 may be due to the fact that, in aqueous solution,
intervening water molecules will attenuate the intramo-
lecular hydrogen bonding in the gas-phase structures.
Thus, the conformations predicted in the gas phase may
not be the same in the solution, and hence the calculated
pKa values differ significantly from the experimentally
determined values. The conformational effects on pKa
have been observed in several other cases.37 Further, it
should be noted that the experimental pKa values were
obtained in water (miceller) media, and hence the com-
pared experimental and calculated pKa values are not
derived under similar reaction conditions. Comparing the
calculated pKa for the hydroxybenzotriazoles bearing
Natural Charges Calculated for Oxido Atoms
(O7). Since N-O- is the nucleophile in the hydrolytic
reactions of PNPDPP and PNPH, the charge on the oxido
atom (O7) will give an idea of nucleophilicity of these
conjugate bases (for the numbering of the atoms see
Chart 2). To ascertain the relative charges on the oxido
atom (O7) for 1-13, natural population analysis was
performed. Relative natural charges calculated at the
B3LYP/6-31+G* level for the conjugate bases of 1-13
on the oxido atoms are shown (Table 4). Natural charges
obtained from the NBO calculations show that the oxido
atom (O7) carries comparable or slightly less charge for
electron-withdrawing-substituted 1-hydroxybenzotriaz-
oles 2-9 than the parent molecule 1 (-0.647). Therefore,
the relative nucleophilicity should not be significantly
different from 1 in these cases. However, the available
experimental kinetic data for 1-5 indicate that molecule
4 has considerably better catalytic activity than that of
other molecules studied (Table 1). Since 4 and 5 pos-
sessed a -CO2H group, one might expect that the
carboxylic O-H residue must also get deprotonated at
pH 8.2 in cationic micellar solution and can influence the
overall distribution of electrons within the molecule. The
dideprotonated form of 4 and 5 will also help to associate
with cationic micellar interfaces more tightly, making
them effective catalysts. Therefore, we considered the
dideprotonated form of 4 and 5 for the calculations and
compared the computed N-O- oxygen charges. The
relative oxido charge calculated at B3LYP/6-31+G* for
the dideprotonated form of 4 (-0.675) was found to be
larger than that for the monodeprotonated form (-0.609)
and apparently higher in the series. However, such
enhancement in the charge of the oxido atom for didepro-
tonated form 5 (-0.626) was not observed (Table 4). The
(32) Indeed, we attempted to synthesize the alkoxy derivatives of
1-hydroxybenzotriazole in our laboratory. However, the yields of these
compounds were extremely poor (<1-2%) and the literature procedures
were not found to be reproducible in our hands.
(33) (a) Jorgensen, W. L.; Briggs, J. M.; Gao, J. J. Am. Chem. Soc.
1987, 109, 6857. (b) Jorgensen, W. L.; Briggs, J. M. J. Am. Chem. Soc.
1989, 111, 4190. (c) Gao, J.; Pavelites, J. J. J. Am. Chem. Soc. 1992,
114, 1912.
(34) Warshel, A. Biochemistry 1981, 20, 3167.
(35) (a) Yang, B.; Wright, J.; Eldefrawi, M. E.; Sovitj, P.; Mackerell,
A. D., Jr. J. Am. Chem. Soc. 1994, 116, 8722.
(36) (a) Kallies, B.; Mitzner, R. J. Phys. Chem. B 1997, 101, 8722.
(b) Shapley, W. A.; Bacskay, G.; Mann, G.; Cossi, M.; Barone, V.;
Tomasi, J. J. Phys. Chem. A 1998, 102, 6706. (c) Pera¨kyla¨, M. Phys.
Chem. Chem. Phys. 1999, 1, 5643.
(37) Bashford, D.; Karplus, M. Biochemistry 1990, 29, 10219.
J. Org. Chem, Vol. 69, No. 25, 2004 8641

Kumar et al.
experimental kinetic data support this result that 5 has
lower catalytic activity than its regioisomeric form 4.
The natural charges calculated for the hydroxybenzo-
triazoles with electron-donating groups 10-13 do not
show any significant enhancement of charges on the oxido
atom (O7) in comparison to the parent system 1 (Table
4). The B3LYP/6-31+G* level-calculated natural charges
on oxido atom in conjugate bases of 1, 10, 11, 12, and 13
are -0.647, -0.652, -0.643, -0.652, and -0.626, respec-
tively. Therefore, the predicted rates of hydrolytic cleav-
age reactions of PNPDPP and PNPH seem to be compa-
rable or slightly higher with the electron-donating groups.
By examining the electronic structure, pKa values, fep,
and the nucleophilicity of reactive N-O- oxido atoms,
the ab initio/DFT results provide a rationale for under-
standing the catalytic potential of 1-hydroxybenzotriazole
derivatives as nucleophiles in the hydrolytic cleavage
reactions of PNPDPP and PNPH. The available experi-
mental results show that compound 4 has greater cata-
lytic activity in the series studied herein. The calculated
results predict lower fep and pKa values for 4 than for
the parent system 1, in agreement with our experimental
observations. The natural charge calculated for the oxido
atom (O7) in the dideprotonated form of 4 supports the
above kinetic experimental data and explains why it is
more nucleophilic than other derivatives examined in this
study. Furthermore, the calculated results predict that
the incorporation of electron-donating substituents on to
1-hydroxybenzotriazole (10-13) would not enhance the
catalytic activity significantly. Since the present methods
of synthesis of compounds such as 10 or 12 are inefficient
in view of their very low yield, the calculated results may
be used to predict their catalytic effectiveness. However,
as the predicted nucleophilicity values of N-O- are not
enhanced appreciably, the present investigation strongly
suggests that undertaking alternative or elaborative
synthetic routes to compounds such as 10-13 may not
be practical.
cleavages of PNPDPP and PNPH, a detailed computa-
tional study has been performed at ab initio and hybrid-
DFT levels of theory. Most stable conformations of 1-13
and their conjugate bases have been predicted. The
calculated geometries on the basis of B3LYP/6-31+G*
were found to be in good agreement with the earlier
calculations by Anders et al.11 and the available crystal
structure results.11 The fep and pKa values calculated for
hydroxybenzotriazoles bearing electron-withdrawing
groups were generally found to be lower than for the
parent 1-hydroxybenzotriazole, 1. However, the corre-
sponding compounds with electron-donating groups show
higher fep and pKa. The experimentally measured pKa
values for 2-5 show that the electron-withdrawing
groups lower the pKa in comparison to 1. This is in
agreement with our calculated results. The natural
charge calculated at the B3LYP/6-31+G* level for the
oxido atom of N-O- for 2-5 shows that the monoanionic
forms carry comparable or slightly less charge than the
N-O- of 1. However, the natural charge calculated for
the dideprotonated form of 4 on N-O- is higher in the
series and supports the experimental observation that 4
is a better catalyst for the hydrolytic cleavages of PNP-
DPP and PNPH. Fep and pKa values were predicted to
be higher, in general, for the hydroxybenzotriazoles
having electron-donating substituents in comparison to
the parent system 1. This suggests that the deprotonation
will be less facile in these cases. Comparing the natural
charge calculated on the oxido atom (O7) for electron-
donating 10-13, it appears that they are comparable to
the charge calculated for the oxido atom of N-O- in 1.
This in turn predicts that the incorporation of electron-
donating substituents into 1-hydroxybenzotriazole may
provide similar or slightly better catalytic strength in
them in comparison to 1. Herein we have made available
a substantial amount of data, viz., energies, geometrical
parameters, and properties such as fep, pKa, charges on
the nucleophilic species. The full discussion of such a
large body of information is too space demanding. How-
ever, we believe that these will be useful for many
research groups.
The theoretical work presented herein is important,
and it is possible to isolate the factors that affect
deprotonation and reactivity in water. Whether these
conclusions are directly applicable to reactions in cationic
micelles is, however, another question. It is possible that
the rate differences in Table 1, for example, could be due
to transfer effects and not inherent reactivities. While
the hydrophobic substrate esters should be completely
in the micelles, this is probably not so for all the
hydroxybenzotriazoles. The relatively small effect on
introduction of the tetradecyl group suggests that here
transfer effects are not large, but nor are the rate effects
in Table 1. Therefore, the experimental conclusions may
be qualitative.
Acknowledgment. This work was supported by the
Department of Science and Technology (Swarnajayanti
Fellowship grant to S.B.). V.P.K. thanks CSIR for a
Senior Research Fellowship. We thank Supercomputer
Education and Research Centre (SERC) for providing
the computational facilities.
Supporting Information Available: Synthetic scheme
of 2-5 and characterization of compounds, geometry param-
eters (bond lengths, bond angles, and torsion angles) of 1-13
and their conjugate bases, total energies of 1-13 and their
conjugate bases, Cartesian coordinates of fullly optimized
geometries of 1-13 and their conjugate bases, and kinetic and
thermodynamic parameters for the cleavage of PNPDPP by
1-5 with CTABr micelles. This material is available free of
charge via the Internet at http://pubs.acs.org.
Conclusion
To examine the catalytic acitivity of a series of 1-hy-
droxybenzotriazoles, 1-13, bearing electron-withdrawing
and electron-donating substituents for the hydrolytic
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8642 J. Org. Chem., Vol. 69, No. 25, 2004