Synthesis of Some Copper(II)-Chelating (Dialkylamino)pyridine Amphiphiles and Evaluation of Their Esterolytic Capacities in Cationic Micellar Media

Article abstract of DOI:10.1021/jo9707996

Three new (dialkylamino)pyridine (DAAP)-based ligand amphiphiles 3-5 have been synthesized. All of the compounds possess a metal ion binding subunit in the form of a 2,6-disubstituted DAAP moiety. In addition, at least one ortho-CH₂OH substitue

Full text of DOI:10.1021/jo9707996

J . Org. Chem. 1998, 63, 27-35
27
Syn th esis of Som e Cop p er (II)-Ch ela tin g (Dia lk yla m in o)p yr id in e
Am p h ip h iles a n d Eva lu a tion of Th eir Ester olytic Ca p a cities in
Ca tion ic Micella r Med ia
Santanu Bhattacharya,* Karnam Snehalatha, and Shaji K. George
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received May 5, 1997X
Three new (dialkylamino)pyridine (DAAP)-based ligand amphiphiles 3-5 have been synthesized.
All of the compounds possess a metal ion binding subunit in the form of a 2,6-disubstituted DAAP
moiety. In addition, at least one ortho-CH OH substituent is present in all the ligands. Complex
2
formation by these ligands with various metal ions were examined under micellar conditions, but
only complexes with Cu(II) ions showed kinetically potent esterolytic capacities under micellar
conditions. Complexes with Cu(II) were prepared in host comicellar cetyltrimethylammonium
bromide (CTABr) media at pH 7.6. Individual complexes were characterized by UV-visible
absorption spectroscopy and electron paramagnetic resonance spectroscopy. These metallomicelles
speed the cleavage of the substrates p-nitrophenyl hexanoate or p-nitrophenyl diphenyl phosphate.
To ascertain the nature of the active esterolytic species, the stoichiometries of the respective Cu(II)
complexes were determined from the kinetic version of J ob’s plot. In all the instances, 2:1 complex
a
ligand/Cu(II) ion are the most kinetically competent species. The apparent pK values of the Cu(II)-
coordinated hydroxyl groups of the ligands 3, 4, and 5, in the comicellar aggregate, are 7.8, 8.0,
and 8.0, respectively, as estimated from the rate constant vs pH profiles of the ester cleavage
reactions. The nucleophilic metallomicellar reagents and the second-order “catalytic” rate constants
toward esterolysis of the substrate p-nitrophenyl hexanoate (at 25 °C, pH 7.6) are 37.5 for 3, 11.4
for 4, and 13.8 for 5. All catalytic systems comprising the coaggregates of 3, 4, or 5 and CTABr
demonstrate turnover behavior in the presence of excess substrate.
In tr od u ction
of such studies, it has been established that metallopro-
teases often use water molecules or internal alcoholic side
chain residues (e.g. serine or threonine) as nucleophiles.
Coordination of the nucleophile or water to the metal ion
enhances their acidity, facilitating deprotonation at
Many enzymes employ metal ions in their active site
for eliciting specific catalytic activities.1 A large number
of metal ion mediated hydrolytic reactions have been
examined to obtain insight into the mechanisms respon-
sible for this kind of catalysis.2 These include designed
ligands for complexation with specific metal ions such
7
physiological pH and speeding reaction with electrophilic
substrates, e.g. amides, esters, or phosphates. In addi-
tion, the electrophilicity of a substrate molecule often gets
potentiated through its coordination with the metal ions
present at enzyme active sites.
3
4
5
6
as Cu(II), Zn(II), Co(II), and La(III). Some are highly
effective in promoting hydrolytic reactions. On the basis
To achieve the ester hydrolysis at physiological pH
*
To whom the correspondence should be addressed. This author
(∼7.5), a whole variety of metal-complex-based hydrolase
is also at the Chemical Biology Unit, J awaharlal Nehru Centre for
Advanced Scientific Research, J akkur, Bangalore 560 064, India.
8,9
analogues have been developed.
Functional am-
X
phiphiles constructed with metal-complexing templates
offer additional advantages because they aggregate in
aqueous media. Such supramolecular ensembles provide
hydrophobic binding sites for the substrates and induce
Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) (a) Kabunde, T.; Strater, N.; Tucker, P.; Witzel, H.; Krebs, B.
Science 1995, 268, 1489. (b) Steiz, J . A. Proc. Natl. Acad. Sci. U.S.A.
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1
4
10,11
catalytic effects through appropriate functional groups.
(
2) (a) Chin, J . Acc. Chem. Res. 1991, 24, 145. (b) Fife, T. H. In
Perspectives on Bioinorganic Chemistry; Hay, R. W., Ed.; J AI Press:
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Chem. Rev. 1996, 96, 721. (b) Menger, F. M. Acc. Chem. Res. 1993, 26,
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Menger, F. M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1086. (e) Bunton,
C. A.; Nome, F.; Quina, F. H.; Romsted, L. Acc. Chem. Res. 1991, 24,
357. (f) Breslow, R. Pure Appl. Chem. 1990, 62, 1859. (g) Tabushi, I.
Acc. Chem. Res. 1982, 15, 66. (h) Fendler, J . H.; Fendler, E. J . Catalysis
in Micellar and Macromolecular Systems; Academic Press: New York,
1975.
1
985, 128, 144.
3) (a) Young, M. J .; Chin, J . J . Am. Chem. Soc. 1995, 117, 10577.
b) Wahnon, D.; Hynes, R. C.; Chin, J . J . Chem. Soc., Chem. Commun.
(
(
1
1
994, 1441. (c) Wall, M.; Hynes, R. C.; Chin, J . Angew. Chem. 1993,
05, 1695.
(
Soc. 1995, 117, 8304. (b) Kady, I. O.; Tan, B.; Ho, Z.; Scarborough, T.
J . Chem. Soc., Chem. Commun., 1995, 1137. (c) Kady, I. O. Tetrahedron
Lett. 1995, 36, 4031. (d) Scrimin, P.; Tecilla, P.; Tonellato, U. J . Chem.
Soc., Chem. Commun. 1995, 1163.
4) (a) Kimura, E.; Kodama, Y.; Koike, T.; Shiro, N. J . Am. Chem.
(
5) (a) Hendry, P.; Sargeson, A. M. Prog. Inorg. Chem. 1990, 38, 201.
b) J ones, D. R.; Lindoy, L. F.; Sargeson, A. M. J . Am. Chem. Soc. 1984,
06, 7807.
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(
1
(
S0022-3263(97)00799-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

2
8
J . Org. Chem., Vol. 63, No. 1, 1998
Bhattacharya et al.
Scrimin and co-workers have extensively studied the
esterolytic capacities of various Cu(II)-chelating bidentate
ligand [(2-hydroxymethyl)pyridine] amphiphiles and bo-
laphiles in micellar media.12 The corresponding metal-
lomicelles are powerful catalysts for the cleavages of
substrates, e.g. p-nitrophenyl picolinate or R-amino acid
esters which also have the ability to participate in the
ligation with the catalytic metal-chelating sites. How-
ever, these systems do not cleave esters such as p-
nitrophenyl alkanoates which do not coordinate with the
metal-complex core. Subsequent studies demonstrated
that tridentate ligand amphiphiles such as 1, form Cu(II)-
chelating micelles that are capable of potentiating ester
hydrolysis even when the esters cannot participate in the
complex formation.13 We have designed a variety of
synthetic amphiphilic systems, examined the properties
of their aggregates,14 and developed several catalytic
organized assemblies.15 Efficient catalytic turnover in
the hydrolysis of p-nitrophenyl alkanoates at mildly
alkaline pH was shown by 4-(dialkylamino)pyridine
the results of the kinetic studies under pseudo-first-order
conditions (excess catalysts) and in the presence of excess
substrates, and potential esterolytic pathways are pre-
sented.
(
DAAP) amphiphiles in different aggregates.15 An ad-
vantage with the DAAP systems (2) is that they are
strongly “nucleophilic”.16 Accordingly, we thought that
the design of alcohol- or amine-pendent lipophilic DAAPs
would be useful for developing metal-complex-based
amphiphiles. Here we introduce three new lipophilic
DAAP ligands, 3-5, which effectively complex different
transition metal ions at ambient pH. We wanted to
explore whether the increased π-electron density on the
N atom of the pyridine ring in DAAP17 relative to
pyridine alone might enhance the capacity of the metal
complexes toward their hydrolytic abilities. We also
compared the reactivities and plausible mechanisms of
the Cu(II) complexes of 2-5 under comicellar conditions
for the cleavages of p-nitrophenyl hexanoate (PNPH) and
p-nitrophenyl diphenyl phosphate (PNPDPP) at pH 7.6,
Resu lts a n d Discu ssion
Syn th esis of th e Am p h ip h ilic Liga n d s. The syn-
thesis of the (dialkylamino)pyridine-based ligand func-
tionalized amphiphiles, as summarized in Scheme 1,
began with the conversion of chelidamic acid into dimeth-
yl 4-chloropyridine-2,6-dicarboxylate, 6, followed by sa-
ponification to the corresponding diacid, 7. Part of 7 was
mixed with aqueous dimethylamine in a screw-top pres-
sure tube at 160 °C for ∼24 h. The solid product was
converted to the corresponding dimethyl ester by treat-
2
5 °C. The routes to the synthesis of the ligands, the
characterization of the catalytically effective complexes,
ment with methanolic SOCl
methylamino)pyridine derivative, 8, in ca. 70% yield. 8
was partially reduced with NaBH to give 9 in 91% yield.
Part of 9 was intimately mixed with n-octadecylamine,
and the resulting mixture was heated at ∼90 °C to a clear
melt and left in that condition for ∼12 h to give crude
amide, 4, which solidified on cooling. Column chromato-
graphic purification over silica gel using 1:1 EtOAc and
petroleum ether (bp 60-80 °C) gave pure 4 in ca. 71%
yield. The remainder of 9 was oxidized with 1 equiv of
2
which afforded the 4-(di-
(
11) (a) Scrimin, P.; Tecilla, P.; Tonellato, U. J . Org. Chem. 1994,
5
9, 4194. (b) Weijnen, J . G. J .; Koudijs, A.; Engbersen, J . F. J . J . Org.
4
Chem. 1992, 57, 7258. (c) Menger, F. M.; Gan, L. H.; J ohnson, E.; Durst,
D. H. J . Am. Chem. Soc. 1987, 109, 2800. (d) Gellman, S. H.; Petter,
R.; Breslow, R. J . Am. Chem. Soc. 1986, 108, 2388.
(12) (a) Scrimin, P.; Tecilla, P.; Tonellato, U.; Vendrame, T. J . Org.
Chem. 1989, 54, 5988. (b) Fornasier, R.; Scrimin, P.; Tonellato, U.;
Zanta, N. J . Chem. Soc., Chem. Commun. 1988, 716. (c) Fornasier, R.;
Milani, D.; Scrimin, P.; Tonellato, U. J . Chem. Soc., Perkin Trans. 2
1
986, 233.
13) Scrimin, P.; Tecilla, P.; Tonellato, U. J . Org. Chem. 1991, 56,
61.
(
1
(
14) (a) Bhattacharya, S.; Snehalatha, K. J . Org. Chem. 1997, 62,
MnO
Condensation of 10 with n-hexadecylamine gave a schiff
base which was carefully reduced with NaBH to furnish
to give the monoaldehyde 10 in ∼88% yield.
2
2
6
1
198. (b) Bhattacharya, S.; De, S. J . Chem. Soc., Chem. Commun. 1995,
51. (c) Bhattacharya, S.; De, S. J . Chem. Soc., Chem. Commun. 1996,
283. (d) Bhattacharya, S.; Haldar, S. Langmuir 1995, 11, 4847. (e)
4
Bhattacharya, S.; Acharya, S. N. G.; Raju, A. R. J . Chem. Soc., Chem.
Commun. 1996, 2101. (f) Bhattacharya, S.; Subramanian, M. J . Chem.
Soc., Perkin Trans. 2 1996, 2027. (g) Subramanian, M.; Mandal, S.
K.; Bhattacharya, S. Langmuir 1997, 13, 153. (h) De, S.; Aswal, V. K.;
Goyal, P. S.; Bhattacharya, S. J . Phys. Chem. 1996, 100, 11664. (i)
De, S.; Aswal, V. K.; Goyal, P. S.; Bhattacharya, S. J . Phys. Chem. B
the secondary amine, 3, in 68% yield. The second part
of 7 was mixed with N-methyl-N-octadecylamine in dry
methanol at ∼120 °C in a screw-top pressure tube to give
the 4-(N-octadecyl-N-methylamino)pyridine derivative,
which was then converted to the corresponding dimethyl
ester, 11, in ca. 49% yield. Reduction of 11 with excess
1
997, 101, 5639.
15) (a) Bhattacharya, S.; Snehalatha, K. Langmuir 1995, 11, 4653.
b) Bhattacharya, S.; Snehalatha, K. J . Chem. Soc., Perkin Trans. 2
(
(
NaBH
4
gave the 2,6-dihydroxymethyl derivative, 5, in
1
3
996, 2021. (c) Bhattacharya, S.; Snehalatha, K. Langmuir 1997, 13,
78.
7
2% yield. The final products, 3-5, and the appropriate
1
(
16) (a) Hofle, G.; Steiglich, W.; Vorbrungen, H. Angew. Chem., Int.
Ed. Engl. 1978, 17, 569. (b) Scriven, E. F. V. Chem. Soc. Rev. 1983,
2, 129. (c) Knolker, H.-J .; Braxmeir, T.; Schlectingen, G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2497.
17) Ohno et al. have shown that by variation of the substituent on
intermediates showed expected IR, H NMR (200 MHz),
mass spectra, and elemental analysis data, cf. Experi-
mental Section.
1
(
Liga n d P r op er ties a n d Com p lex F or m a tion . The
lipophilic ligands 3-5 are not soluble in water, and their
corresponding metal complexes are also only sparingly
soluble in water at pH ∼7.0. However, they form stable
pyridine ring, it is indeed possible to control the electron density at
N-1 of the resulting pyridine system, See, for example: Sugano, Y.;
Kittaka, A.; Otsuka, M.; Ohno, M.; Sugiara, Y.; Umezawa, H. Tetra-
hedron Lett. 1986, 27, 3635.

Cu(II)-Chelating (Dialkylamino)pyridine Amphiphiles
J . Org. Chem., Vol. 63, No. 1, 1998 29
Sch em e 1a
a
Reagents and conditions: (a) (i) PCl5, CCl4, 120 °C, (ii) dry MeOH, reflux 54%; (b) 1 M NaOH, 80 °C; aqueous HCl; (c) Me2NH, 120
°
C; aqueous H2SO4, 43%; (d) SOCl2, MeOH, -10 °C; then reflux, 83%; (e) NaBH4 (1 equiv), CH2Cl2-MeOH, 0 °C (30 min), rt (5 h), 91%;
(f) melt n-C18H37NH2, 90 °C, 71%; (g) MnO2, CH2Cl2, rt, 88%; (h) (i) n-C16H33NH2, dry THF, rt, (ii) NaBH4, MeOH, rt, 68%; (i) (i)
n-C18H37NHMe, MeOH, 120 °C, (ii) SOCl2, MeOH, reflux, 49%; (j) NaBH4, MeOH, rt, 72%.
aqueous solutions when employed as comicelles in the
presence of excess host, surfactant CTABr. The am-
phiphile bearing an amide linkage, i.e. 4, requires at least
a 20-fold molar excess of CTABr for dissolution in water.
Amphiphiles 3 and 5, however, dissolve at lower CTABr/
hydrolysis reactions, and all further studies are therefore
confined to the Cu(II) complexes.
UV-Ab sor p t ion St u d ies of Cu (II) Com p lexes in
Micelles. The formation of different Cu(II) complexes
under the comicellar conditions was demonstrated by the
appearance of an absorbance with a λmax in the range
650-750 nm for ligand:Cu(II) ratios of 2:1 for ligands
3-5. Ligand 3 in the presence of Cu(II) ion yielded a
complex with λmax at ∼718 nm in a comicellar CTABr
solution. Under comparable conditions, 4:Cu(II) and
5:Cu(II) complexes gave absorption maxima at ∼670 and
∼739 nm, respectively. Thus the UV-visible absorption
spectra of the Cu(II) complexes of 3-5 in micelles are
consistent with the formation of four coordinated species,
with weak axial interactions as shown by the presence
[amphiphile] ratios. The Cu(II) complexes of ligands 3-5
were generated in situ under comicellar conditions of
CTABr in HEPES buffer, pH 7.6, by adding the appropri-
2
ate amount of stock solution of CuCl in water (see
below). Similarly the Co(II), Ni(II), and Zn(II) complexes
of ligands 3-5 were prepared in situ in buffered comi-
cellar media.
The lack of adequate solubility and the complex nature
of comicellar aggregation prevented determination of
M
binding constants, K , of various ligands with Cu(II) and
2
0,21
other metal ions. Approximate magnitudes of the as-
sociation constants were estimated from the values
reported18 for 2-(aminomethyl)pyridine, 2-[[N,N-(dihy-
droxyethyl)amino]methyl]pyridine and 2,6-bis(amino-
methyl)pyridine. Considering possible effects of micel-
lization, in particular coaggregation with a cationic
of the single d-d band in each UV-vis spectra
and
their EPR data (see below). Ligand 2 did not give a d-d
band above 350 nm, indicating that substituents at the
2,6-positions of the pyridine moiety are essential for
complex formation. The results are summarized in Table
1.
nonligating surfactant,1
2a
K
> 10 for Cu(II) is a reason-
9
P ossible Geom etr ies of th e Com p lexes. One of the
most useful applications of the EPR is in distinguishing
different geometries of a series of metal complexes for
which the crystal structures are not available. The
approximate geometry of the complex in solution is
M
able measure of the association constant. The binding
constants for Zn(II), Co(II), and Ni(II) metal-ligand
association are probably 2-3 orders of magnitude lower.19
Only the Cu(II) complexes of ligands 3-5 speed ester
(
18) Damu, K. V.; Shaikjee, S. M.; Michael, J . P.; Howard, A. S.;
Hancock, R. D. Inorg. Chem. 1986, 25, 3879.
19) Bunton, C. A.; Scrimin, P.; Tecilla, P. J . Chem. Soc., Perkin
Trans. 2 1996, 3, 419.
(20) Casell, L.; Carugo, O.; Gullotti, M.; Doldi, S.; Frassoni, M. Inorg.
Chem. 1996, 35, 1101.
(21) Hathaway, J. B. Comprehensive Coordination Chemistry; Wilkin-
son, G., Ed.; Pergamon: New York, 1987; Vol. 5, p 533.
(

3
0
J . Org. Chem., Vol. 63, No. 1, 1998
Bhattacharya et al.
Ta ble 1. UV-Visible Wa velen gth Ma xim a for Cu (II) Com p lexes of Liga n d s 2-5 in CTABr Com icella r Con d ition sa
λmax, nm (ꢀ, M- cm-1
1
)
emtry
catalystb
ligand
Cu(II) complexc
1
2
3
4
2
3
4
5
284 (3700), 262 (4050), 245 (4350)
282 (6050), 247 (6650), 234 (6250)
308 (5800), 262 (2400)
304 (3500), 265 (3800), 240 (4200)
713 (100), 296 (5300), 270 (4900)
671 (100), broad 326 (750)
310 (6200), 256 (6600), 240 (6850)
740 (100), 295 (4900), 239 (4650)
a
Complexes were formed in situ by solubilizing individual ligands in CTABr micellar solutions at pH 7.6, 0.05 M HEPES buffer, 0.1
M KCl, at 25 ( 0.1 °C, [ligand] ) 2.5 × 10 M. For the entries, 1-4, [Cu(II)] ) 1.25 × 10 M. b Ratio of ligand:Cu(II) is 2:1 for all the
-
4
-4
c
entries. The d-d bands in each absorption spectrum are underlined.
F igu r e 1. X-band EPR spectrum of Cu(II) complex of 3 diluted
with Zn(II) complex (1:10) at 298 K. Spectrometer settings:
microwave frequency, 9.05 GHz; microwave power, 2 mw;
modulation frequency, 100 kHz; modulation amplitude, 4 G.
assigned by experimentally determining the anisotropic
g values for different coordination compounds of Cu(II).21
To extract information about the possible geometries of
the Cu(II) complexes, EPR spectra were recorded for
solutions of ligands 3-5 in water or in MeOH with Cu(II)
and in micellar CTABr solutions at ambient temperature.
All samples showed isotropic signals presumably because
rapid tumbling led to average anisotropic g and A values.
Frozen samples (-196 °C) of the complexes in CTABr
F igu r e 2. Computer-generated models of the Cu(II) complex
of 3 showing (A) distorted octahedral geometry of Cu(II)
complex of 3 (active site); (B) distorted square-pyramidal
solutions also failed to show any significant anisotropy.
The Cu(II) complexes of individual ligands 3 or 5 were
prepared as described above in methanol and diluted
with Zn(II) ions such that the ratio of Cu(II)/Zn(II) was
geometry of the Cu(II) complex of 3. Note that in either case
the long n-C H chain is not shown for clarity.
1
6
33
1
:10. Evaporation of the solvent gave residues which
showed anisotropic EPR spectra at ambient temperature.
The X-band EPR spectrum of Zn(II)-doped L Cu (L )
, 298 K) is shown in Figure 1. The spectrum (g ) 2.26
and g ) 2.06 with A ) 150 G) resembles the EPR
alternative geometries of the active site of 3 as drawn
using this program are shown in Figure 2. In a distorted
square-pyramidal geometry (Figure 2B), the central
2
3
⊥
Cu(II) ion utilizes one of the CH
the 4-(dimethylamino)pyridine (DAAP) units in addition
to the pyridine N and the C16 residues at DAAPs
without requiring the participation of the other CH OH
2
OH group from two of
|
|
spectrum of a typical monomeric tetragonal Cu(II) com-
plex. Although no well-resolved hyperfine coupling to
first coordination sphere donor atoms is detected (Figure
H
33NCH
2
2
group or any outside water molecules in coordination
with the Cu(II) ion. In contrast, in a distorted rhombic
octahedral geometry (Figure 2A), the Cu(II) ion utilizes
1
), some structural information was obtained from the
EPR parameters. The g values of 3 Cu indicate either a
distorted square-pyramidal or an elongated rhombic
octahedral geometry.22 The Cu(II) complexes of ligand
2
one of the CH
in addition to the pyridine N and the C16
residues at DAAPs without requiring the coordination
of the other CH OH group. However, one outside water
2
OH group from one of the two DAAP units
H
33NCH
2
4
or 5 when diluted (1:10) with Zn(II) ions showed similar
anisotropic EPR spectra (figures not shown), but were
not well-resolved and their anisotropic g values from 5
could not be obtained with adequate precision.
On the basis of these findings (EPR) and the kinetic
studies (see below), computer-generated structures for
the Cu(II) complexes of 3 were drawn using Insight II
program version 2.2.0 (Biosym. Technology). Probable
2
molecule is required in this situation to satisfy the
coordination sites surrounding the Cu(II) ion for an
octahedral geometry. On the basis of the data obtained
a
experimentally on the apparent value of pK and due to
the lack of the presence of two ionization residues, it
appears that the distorted square-pyramidal geometry
may be likely to be kinetically more relevant. To
ascertain the nature of the active esterolytic species, the
stoichiometries of the respective Cu(II) complexes were
(
22) (a) Brown, S. J .; Stephen, D. W.; Mascharak, P. K. J . Am. Chem.
Soc. 1988, 110, 1996. (b) Hathaway, J . B. Struct. Bonding 1987, 57,
5.
5

Cu(II)-Chelating (Dialkylamino)pyridine Amphiphiles
J . Org. Chem., Vol. 63, No. 1, 1998 31
F igu r e 3. Kinetic J ob’s plot for the cleavage of p-nitrophenyl
F igu r e 4. pH rate constant profile for the hydrolysis of
-
5
-5
-4
hexanoate (2.5 × 10 M) by 3 (O), 4 (0), and 5 (4). Reaction
p-nitrophenyl hexanoate (2.5 × 10 M) by 3 (2.5 × 10 M) in
-4
2
conditions: 0.05 M HEPES buffer (pH 7.6), 25 ( 0.1 °C, [ligand
the presence of 1.25 × 10 M CuCl
. Reaction conditions: 25
( 0.1 °C and [CTABr] ) 5 × 10 M.
II
-4
-2
-3
+
Cu ] ) 5 × 10 M, [CTABr] ) 1 × 10 M.
further determined from the kinetic version of J ob’s plot
see below). Notably in all the instances, 2:1 complex
by the addition of an aliquot of 5 µL of stock solution of
PNPH in CH CN. The pseudo-first-order rate constants
(
3
ligand/Cu(II) ion were found to be the most kinetically
competent species.
for PNPH cleavage at 25 °C by each catalytic system were
determined spectrophotometrically by following the re-
lease of the p-nitrophenoxide ion at 400 nm at different
pH values between 5 and 9.0. We also determined the
pH-rate constant profiles for PNPH hydrolysis induced
by Cu(II) complexes of comicellar 4 and 5 at the concen-
Kin etic Stu d ies. Kinetic studies were performed
either under the pseudo-first-order conditions or in the
presence of excess substrates, monitoring the appearance
of p-nitrophenoxide ion at 400 nm at 25 °C in 0.05 M
HEPES buffer (pH 7.6). The stoichiometries of the active
Cu(II) complexes were determined to establish the mecha-
nistic aspects of the process.
Stoich iom etr ies of th e Kin etica lly Active Com -
p lexes. Information pertaining to the esterolytically
optimal stoichiometry of the metal ion/ligand complex
was obtained from the kinetic version of a J ob plot
analysis.23 Briefly, the pseudo-first-order rate constants,
trations of PNPH, ligand, CTABr, and CuCl
above. Plots of log k vs pH gave discontinuities at pH
ca. 8.0 for comicellar 4 and 5, which were taken as
2
mentioned
ψ
)
systemic pK
a
values for the ionization of hydroxyl (CH
2
OH
-
f CH
2
O ) bound to Cu(II) ion in micelles (see below).
We ascribe these inflections with the systemic pK
values of the pendent CH OH functions on ligands 3-5
a
2
as a consequence of coordination to the Cu(II) ion in
micellar conditions. The small differences in the experi-
mentally obtained pK values are in accord with the
a
structural differences in the other substituents in these
DAAP ligands. Therefore, such pH dependencies of the
esterolytic reactions could originate from participation
ψ
k , for the hydrolysis of PNPH or PNPDPP were mea-
sured in solutions containing a given ligand, L, and the
metal ion, Cu(II), where the ratios of [L]/[Cu(II)] were
changed while keeping the total concentration of the two
species constant. The results obtained with catalysts
3
-5 under comicellar conditions are shown in Figure 3.
of Cu(II)-activated CH
2
OH group in the rate-determining
Cleavage rates of PNPH and PNPDPP with 3-5 under
comicellar conditions all go through maxima at [L] ) ca.
24
step. A pK
a
value of 7.7 has been reported for a Cu(II)-
13
coordinated hydroxyl by Scrimin in holometallomicellar
aggregates. We believe that the electron-donating char-
2
[Cu(II)]. These stoichiometries are consistent with the
information obtained from the EPR spectra and also with
the computer-generated structures for these complexes.
To make kinetic comparisons under identical conditions,
the concentration of the host surfactant CTABr was kept
constant for all the kinetic runs. Further increases in
acter Me
nucleus raises the pK
.3 unit in 4 and 5, respectively. Similar pK
2
N group at the 4-position of the pyridine
values in 3 by ca. 0.1 unit and by
values were
a
0
a
obtained by Tagaki and others in the studies of Cu(II)
complexes of 2-(hydroxymethyl)imidazole functionalized
[L] probably give complexes of other stoichiometries
25
surfactant aggregates.
which compete with the kinetically most efficient L
stoichiometries and reduce the observed rates.
2
Cu
Hyd r olysis in th e Absen ce of Meta l Ion s. The
reactions of lipophilic ligands 2-5 in CTABr comicellar
conditions with PNPH and PNPDPP in HEPES buffer,
pH ) 7.6, show small rate accelerations when compared
to PNPH or PNPDPP cleavage reactions conducted in
CTABr only (background). The observed modest but
definitive rate acceleration is probably caused by the
a
p K Deter m in a tion s. Hydrolysis rates of PNPH in
complexes 3-5 in cationic (CTABr) micelles are pH-
dependent. A pH-rate constant profile for the cleavage
-
5
-4
-2
of 2.5 × 10 M PNPH by 2.5 × 10 M 3 in 1 × 10
CTABr in the presence of 1.25 × 10 M CuCl in 0.05 M
buffer (µ ) 0.1 M KCl) gave an apparent pK
of ∼7.8
Figure 4). Cu(II) complexes of 3-5 were generated in
situ by the addition of appropriate amount of stock
solution of aqueous CuCl to the CTABr comicellar
solution of the respective ligand. Reactions were initiated
M
-
4
2
a
(
(
24) (a) Tagaki, W.; Ogino, K.; Machiya, K. Bull. Chem. Soc. J pn.
991, 64, 74. (b) Ogino, K.; Kashihara, N.; Ueda, T.; Isaka, T.; Yoshida,
T.; Tagaki, W. Bull. Chem. Soc. J pn. 1992, 65, 373.
25) (a) Fujita, T.; Ogino, K.; Tagaki, W. Chem. Lett. 1988, 981. (b)
1
2
(
Wodsworth, W. S., J r. J . Org. Chem. 1981, 46, 4080. (c) Petitfaux, C.
Ann. Chim. 1973, 14 (8), 33. (d) Fornasier, R.; Scrimin, P.; Tacilla, P.;
Tonellato, U. J . Am. Chem. Soc. 1989, 111, 2214.
(23) J ob, P. Ann. Chim. (Rome) 1928, 113, 9.

3
2
J . Org. Chem., Vol. 63, No. 1, 1998
Bhattacharya et al.
Ta ble 2. P seu d o-F ir st-Or d er Ra te Con sta n ts for th e
without any ligand) under similar conditions. The second
most reactive compound 5 has a rate acceleration of ∼24
for PNPH and ∼10 for PNPDPP. The least reactive is
the Cu(II) complex of 4 which has ∼20-fold rate accelera-
tion for PNPH and is only 2 times more reactive toward
PNPDPP when compared to background.
Clea va ges of p-Nitr op h en yl Hexa n oa te a n d
p-Nitr op h en yl Dip h en yl P h osp h a te by Liga n d s 2-5 in
th e Absen ce of Meta l Ion in 0.01 M CTABr a
PNPH
catalyst
PNPDPP
3
3
entry
10 kψ
kψ/kCTABr
10 kψ
kψ/kCTABr
1
2
3
4
5
none
0.04
5.11
0.31
0.16
0.64
1
127.8
7.8
4.0
16.0
0.05
0.13
0.31
0.07
0.15
1
We have also included in Table 3 the calculated second-
obs
2
3
4
5
2.6
6.2
1.4
3.0
order “catalytic” rate constants (kcat ) k
/[catalyst].
ψ
These have been corrected for the 100% ionization of the
Cu(II)-coordinated OH group responsible for the nucleo-
philic activities. It might be noted that the comparisons
of rate constants and dissociation constants are compli-
cated by the dependence on concentrations of reactants,
surfactant, and sometimes pH. Therefore, insofar as with
the use of one CTABr concentration, comparisons may
also depend on the choice of concentrations. Nevertheless
at this given situation, a qualitative comparison of kcat
may be useful. On this basis the analysis of the kcat
values for the PNPH cleavages clearly indicates that
a
Conditions: 0.05 M HEPES buffer; µ ) 0.1 M KCl; pH ) 7.6,
5 ( 0.1 °C; [cat.] ) 5 × 10 M.
-
4
2
nucleophilic (dimethylamino)pyridine moiety in 3-5. The
relevant kinetic parameters with pertinent experimental
conditions are summarized in Table 2. Comicelles of
2
/CTABr comicelles represent the best catalytic formula-
tion for the cleavage of PNPH under these conditions.
This result indicates that in the absence of metal ions,
the presence of ortho substituents on the DAAP moiety
mitigates the esterolytic potential of these catalysts
presumably due to steric effects. However, it is not
apparent why 3/CTABr comicelles showed greater cata-
lytic activity than their counterparts for PNPDPP hy-
drolysis.
Hyd r olysis in th e P r esen ce of Meta l Ion s. The
coordination complexes of the lipophilic ligands 3-5 with
various transition metal ions such as Zn(II), Co(II), Ni(II),
and Cu(II) were tested for their abilities to cleave
alkanoate (PNPH) and phosphate (PNPDPP) esters. The
complexes of ligands 3-5 with Zn(II) and Ni(II) showed
insignificant rate accelerations. However, the complexes
of Cu(II) and Co(II) show substantial activity. Cu(II)
complexes of 3-5 are the most reactive, ∼2 times more
reactive than Co(II) complexes (results not shown).
3
2
Cu catalysts are the most effective systems for such
reactions. The next best catalyst is 5 Cu. Perhaps the
electron-withdrawing character of the amide linkage in
mitigates its catalytic activity. Similar trends are also
observed for the cleavage of PNPDPP.
Involvement of the CH
OH unit in DAPP for Cu2
2
4
+
2
coordination in 3-5 should be anticipated because of the
following reasons: (i) the higher apparent acidity, by ca.
2
pK
a
units, of the 2-(hydroxymethyl)pyridine than that
O; (ii) earlier investigations with the action of
2
5c
25d
of H
2
metal chelates of 2-(hydroxymethyl)pyridine derivatives
on p-nitrophenyl picolinate have clearly indicated that
the second slow step indeed involves the hydrolysis of
the transacylation product. We believe that a similar
mechanism is also operative in the present cases. There-
-
2
fore, based on geometric features of 3-5, the CH O
obs
produced upon the ionization of the CH OH group
In Table 3, we collect the values of k
ψ
for the
2
coordinated to Cu(II) must be responsible for esterolytic
activities of the alkanoates in the metallomicelles.
The presence of the CH OH group ortho to the pyridine
2
nitrogen appears to be crucial for the cleavage of the
alkanoate esters, but for the phosphotriester substrate,
cleavages of both PNPH and PNPDPP by each of the
Cu(II) complexes of lipophilic ligands 3-5 at optimized
ligand and CTABr concentrations. Entries 2-4 in Table
include the kinetic parameters under the conditions
where the overall ratio of each catalyst to CTABr is fixed
3
(
1:20) for all four DAAP catalysts in the presence of same
2
PNPDPP, the presence of an CH OH group is not so
-4
[Cu(II)] (2.5 × 10 M). Clearly these complexes afforded
important. We believe that the major difference between
the two types of esters lays in their ability to be involved
in the Cu2 coordination. Such a possibility is open only
for the PNPDPP but not for the carboxylate esters. This
much better kinetic advantage when used in the presence
of Cu(II) ions. This may be caused by the greater Lewis
acidic character of Cu(II), which may also explain why
the Cu(II) complexes form more stable complexes in
micellar solutions than the other transition metal ions.
The most reactive catalyst among the metallomicellar
systems in this study is the Cu(II) complex of 3. It has
a rate acceleration of ∼89-fold for the hydrolysis of PNPH
and ∼22-fold rate acceleration for PNPDPP when com-
pared to background (entry 1, Table 3, CTABr and Cu(II)
+
2
+
is because the affinity of the PdO group for Cu is much
2
5b
greater than that of an alkanoate CdO group.
One
may also speculate that the packing of ligand am-
phiphiles in micelles does not allow the PNPDPP sub-
strate to take advantage of the activation of the CH OH
2
group with the metal ion and the hydrophobic environ-
ment at the same time.
Ta ble 3. Kin etic P a r a m eter s for Cu (II)-Ca ta lyzed Ester olysis of p-Nitr op h en yl Hexa n oa te a n d p-Nitr op h en yl Dip h en yl
P h osp h a tea
PNPH
PNPDPP
catalytic
ligand
pKab
[% ionization]
3
10 kψobs, s-1
kcat , M s-1
c
-1
3
10 kψobs, s-1
kcat, M s-1
c
-1
entry
1
2
3
4
noned
3
4
5
0.04
3.6
0.81
0.98
0.06
1.3
0.14
0.6
7.8 [38.7]
8.0 [28.5]
8.0 [28.5]
37.5
11.4
13.8
13.6
2.0
8.4
a
-4
Conditions: 0.05 M buffer, pH 7.6, µ ) 0.1 M KCl, 25 ( 0.1 °C, 0.3 vol % CH3CN. For entries 2-5 [ligand] ) 5 × 10 M, [Cu(II)] )
obs
-
4
-2
b
c
2
)
.5 × 10 M, [CTABr] ) 1 × 10 M. See text for discussion of pKa values. Values in brackets are percent ionizations at pH 7.6. kcat
kψ /[LnCu], corrected for 100% ionization of a given catalytic system at pH 7.6, where n represent the stoichiometry of the kinetically
d
-2
-4
most efficient formulation. [cat.] ) 0 i.e. without lipophilic ligands, [CTABr] ) 1 × 10 M, [CuCl2] ) 2.5 × 10 M.

Cu(II)-Chelating (Dialkylamino)pyridine Amphiphiles
J . Org. Chem., Vol. 63, No. 1, 1998 33
Ta ble 4. Rela tive Kin etic Ad va n ta ges for th e Cu (II)
Com p lexes of Ca ta lysts 1 a n d 3 for th e Clea va ge of
p-Nitr op h en yl Hexa n oa tea
4
-1
entry
catalyst
10 kψ, s
kψ/kCTABr
1
2
3
noneb
1Cu(II)
3Cu(II)
0.037
5.12
8.59
1
138
232
a
Conditions: 0.05 M MES buffer, µ ) 0.1 M KCl, pH ) 6.25,
-
4
-3
3
5 °C, [ligand] ) [Cu(II)]) 4 × 10 M, [CTABr] ) 4 × 10 M.
b
-3 -4
[
CTABr] ) 4 × 10 M, [Cu(II)] ) 4 × 10 M, [ligand] ) 0.
F igu r e 6. Kinetics under excess substrate conditions. Reac-
tion conditions: 0.05 M HEPES buffer (pH 7.6), 25 ( 0.1 °C,
-
5
-5
[
1
5] ) 2.5 × 10 M, [CuCl
2
] ) 1.25 × 10 M, [PNPH] ) 1 ×
-
4
-3
0
M, and [CTABr] ) 1 × 10 M.
2
-fold excess of substrate PNPH, no evidence of burst
kinetics was observed (Figure 6), although p-nitrophe-
noxide is released quantitatively. Monoexponential,
quantitative hydrolysis of PNPH with 5
2
Cu(II) indicates
a fast turnover mechanism. The catalytic effectiveness
of all three ligands remained unaltered even after the
consumption of 10-fold excess of substrate. A similar
observation was also reported by Scrimin and co-work-
ers.13
F igu r e 5. Kinetics under excess substrate conditions. Reac-
tion conditions: 0.05 M HEPES buffer (pH 7.6), 25 ( 0.1 °C,
-
5
-5
[
3] ) 2.5 × 10 M, [CuCl
2
] ) 1.25 × 10 M, [PNPH] ) 5 ×
-
5
-3
1
0
M, and [CTABr] ) 1 × 10 M.
The reactivity of the catalyst 3 toward PNPH cleavage
Con clu sion s
was also compared to that of the pyridine-based catalyst
1
6
1
, which was studied in detail by Scrimin et al.13 At pH
The reactions of the lipophilic ligands 3-5 in CTABr
comicellar conditions with PNPH and PNPDPP in pH )
7.6 show small rate accelerations when compared to
PNPH or PNPDPP cleavage reactions conducted in
CTABr only (background). The observed modest but
definitive rate acceleration is probably caused by the
nucleophilic (dialkylamino)pyridine moiety in 3-5. Comi-
celles of 2/CTABr comicelles represent the best catalytic
formulation for the cleavage of PNPH in the absence of
Cu(II) ions. This result indicates that in the absence of
metal ions, the presence of ortho substituents on the
DAAP moiety mitigates the esterolytic potential of these
catalysts presumably due to steric effects.
.3, 35 °C, under comicellar conditions of CTABr (4 ×
-
3
-4
-4
0
M), 4 × 10 M catalyst, and 4 × 10 M CuCl
2 ψ
, k
s ,
-
4
-4 -1
values for 1 and 3 are 5.1 × 10 and 8.6 × 10
respectively. When compared to the background rate
(
CTABr + Cu(II)), catalyst 1 is 138 times faster and
compound 3 is 232 times faster, Table 4.
The reactivities of ligands 3-5 were also compared
2
with 2, which does not have any CH OH group at the
ortho positions of the DAAP unit. Catalyst 2 alone
cleaves PNPH efficiently under comicellar conditions.1
However, Cu(II) solutions of 2 are unstable and turn
5a
2
turbid immediately after the addition of CuCl . Reac-
tions of Cu(II) complexes of 2 with either PNPH or
PNPDPP deviated from strict pseudo-first-order kinetic
behavior, perhaps because of light scattering during the
reaction.
Tu r n over Exp er im en ts. To examine the true cata-
lytic activities of different Cu(II) complexes of ligands
Cu(II) micellar complexes of lipophilic ligands 3-5 are
effective catalysts for the hydrolysis of PNPH at pH 7.6.
Comparison of the cleavage efficiency and catalytic
behavior of the micellar 3 and 5 shows that differences
in their structures do not significantly influence their
reactivities in the presence or in the absence of Cu(II)
ions. Ligand 3 has a lipophilic n-hexadecyl chain pendent
on the 2-aminomethyl substituent of the DAAP moiety,
but 5 has a lipophilic n-octadecyl chain attached at the
4-(dialkylamino)pyridine residue of DAAP. In ligand 3,
3
-5 under comicellar (CTABr) conditions, experiments
in the presence of excess substrates were performed with
PNPH and PNPDPP. At pH 7.6 and 25 °C, using a
-5
comicellar formulation of [ligand] ) 2.5 × 10 M, [Cu(II)]
-
5
-3
)
1.25 × 10 M, and [CTABr] ) 1 × 10 M), we
the complex-forming part is composed of CH
CH NHR substituents in addition to the pyridine nitro-
gen. In 5, the Cu(II)-coordinating substituents are 2- and
6-CH OH groups in addition to the basic nitrogen on the
2
OH and
observed a quantitative release of p-nitrophenoxide ion
2
in the presence of up to a 4-fold excess of PNPH and a
2
-fold excess of PNPDPP over the catalyst, with 3
2
Cu(II)
2
as catalyst. Clear evidence of slow turnover in this
reaction was seen from the “burst” kinetic profile (Figure
pyridine nucleus. While comicellar 3/CTABr is ca. 2.07-
fold more reactive toward PNPDPP relative to 5/CTABr
in the absence of any Cu(II) ion, 5/CTABr is ca. 2.09-fold
more reactive toward PNPH relative to 3/CTABr. In the
presence of Cu(II) ions, however, comicellar 3/CTABr is
ca. 2.72 and 1.62 times more reactive toward the hy-
drolysis of PNPH and PNPDPP, respectively, relative to
5
). The catalyst with an amide linkage, 4
2
Cu(II), also
showed “burst” kinetics under similar conditions (not
-
4
shown). Turnover rate constants of 1.0 × 10 and 6.5
-
5
-1
×
10 for catalysts 3 and 4, respectively, were
s
obtained from the linear sections of the kinetic profiles.
In contrast, with the Cu(II) complex of 5 under compa-
rable comicellar (CTABr) conditions in the presence of
-
-
5/CTABr. It might be possible that both Br and Cl may
interact with Cu(II) ion in the reaction conditions. In

3
4
J . Org. Chem., Vol. 63, No. 1, 1998
Bhattacharya et al.
that instance it is probable that the differences in k with
and without ligand could be also due to differing reactant
distributions between water and micelles and not entirely
due to the differences in their intrinsic reactivities.
Whatever may be the exact reason of the metal ion
potentiation of the hydrolytic rates, all of the Cu(II)
complexes of the amphiphilic ligand systems discussed
here show true catalytic (either slow or fast turnover)
behavior for the esterolysis of PNPH and PNPDPP in the
presence of excess substrates. We are currently examin-
ing the effectiveness of these catalysts with phosphodi-
ester and phosphothioate substrates.
for 24 h at 160 °C. The reaction mixture was cooled and
treated with concentrated H
SO until it became acidic. The
2 4
product was dried under vacuum to give crude 4-(dimethyl-
amino)pyridine-2,6-dicarboxylic acid as a white solid (0.74 g,
4
3%). Without purification, the solid was refluxed with 3.3 g
of SOCl in 16 mL methanol for 4 h. The solvent was removed
2
under vacuum to give a very hygroscopic material that was
treated with ice-cold, aqueous saturated NaHCO solution, and
3
the aqueous layer was extracted with EtOAc (2 × 25 mL). The
4
organic layer was dried (anhyd MgSO ), and the solvent was
removed by evaporation to give diester, 8, as a white solid (0.83
2
8b
g, 70%): mp 164 °C (lit. mp 167-168 °C); IR (Nujol) 1700
-1 1
cm ; H NMR (δ, CDCl
s, 2H).
Meth yl 6-(Hydr oxym eth yl)-4-(dim eth ylam in o)pyr idin e-
2-ca r boxyla te (9). Solid NaBH (0.08 g, 2.1 mmol) was added
3
, 90 MHz) 3.1 (s, 6H), 4.0 (s, 6H), 7.55
(
Exp er im en ta l Section
4
cautiously to an ice-cold, stirred solution of dimethyl 4-(dimeth-
Gen er a l Meth od s. Descriptions of analytical instruments
ylamino)pyridine-2,6-dicarboxylate, 8 (0.25 g, 1.05 mmol), in
1
and H NMR, IR and UV-Vis spectrometers have been
a mixture of MeOH (11 mL) and CH
2 2
Cl (1 mL). After addition
1
4a,15a
previously published.
Mass spectra (MS) were recorded
of NaBH , the reaction mixture stirred for 5 h, and the
4
on a J EOL Model J MS-DX 303 spectrometer equipped with
J EOL J MA-DA mass data station. Mass spectra of all the
samples were recorded by a direct inlet system (70 eV). The
pH values of all solutions were measured using Schott pH
meter CG 825. EPR spectra were measured for frozen and
other solutions or for the solid samples using Varian E-series
spectrometer operating at X-band frequency of 9.05 GHz. The
EPR spectra were recorded as the first derivative of absorption
with DPPH (R,R′-diphenyl-â-picrylhydroxyl) as internal stan-
dard. Modeling studies were done using Insight II program
version 2.2.0 (Biosym Technology) on a Silicon Graphics Indigo
Workstation.
resulting reaction mixture was neutralized with 1 N HCl and
concentrated. The product residue was partitioned between
CH
repeatedly extracted with dichloromethane (2 × 25 mL), and
the CH Cl layers were combined, washed with water followed
by brine, and finally dried over anhyd MgSO . Evaporation
2 2 3
Cl and aqueous NaHCO (20 mL), the aqueous layer was
2
2
4
1
of CH
(δ, CDCl
1H), 7.3 (d, 1H).
2
Cl
2
gave 11 as a solid (0.20 g, 91%): mp 120 °C; H NMR
, 90 MHz) 3.0 (s, 6H), 3.8 (s, 3H), 4.6 (s, 2H), 6.7 (d,
3
Met h yl 6-F or m yl-4-(d im et h yla m in o)p yr id in e-2-ca r -
boxyla te (10). A mixture of the above alcohol, 9 (0.16 g, 0.76
mmol), and MnO (0.75 g, 8.6 mmol) in dry CH Cl (15 mL)
2 2 2
Ma ter ia ls. All the buffers were made from Millipore water.
The buffering agents MES, HEPES, and EPPS were used as
supplied by Fluka. All reagents and solvents were of highest
grade commercially available and used purified, dried, or
freshly distilled as required by literature procedures.26 The
substrates used in the present study, viz. p-nitrophenyl
alkanoates and p-nitrophenyl diphenyl phosphate were syn-
thesized and purified by methods described.27
was stirred under nitrogen for 24 h, during which almost all
of the alcohol was converted to aldehyde. The reaction mixture
was filtered through Celite, the CH Cl layer evaporated, and
2 2
the residue chromatographed over a silica gel column using
ethyl acetate as an eluent to give 0.14 g (88%) of the aldehyde,
2
8b
10, as a white powder: mp 118 °C (lit. mp 117-117.5 °C);
-
1 1
3
IR (Nujol) 1710, 1735 cm ; H NMR (δ, CDCl , 80 MHz), 3.0
(s, 6H), 4.0 (s, 3H), 7.2 (d, 1H), 7.75 (d, 1H), 9.93 (s, 1H).
2-(Hydr oxym eth yl)-6-(octadecyl)car bam oyl)-4-(dim eth -
yla m in o)p yr id in e (4). A mixture of 0.104 g (0.5 mmol) of
methyl 6-(hydroxymethyl)-4-(dimethylamino)pyridine-2-car-
boxylate, 9, and 0.135 g (0.5 mmol) of n-octadecylamine was
heated to a clear melt and kept for 12 h at ∼90 °C. Upon
cooling a solid was obtained which was purified by column
chromatography (silica gel) using a mixture of (1:1) EtOAc and
petroleum ether (bp 60-80 °C). Evaporation of the organic
solvents from appropriate fractions gave 4 as a solid (0.157 g,
Syn th esis. The synthesis of compound 2 is described in
ref 15a. Compounds 8-12 were synthesized by appropriate
2
8
modification of the literature procedures.
Dim eth yl 4-Ch lor op yr id in e-2,6-d ica r boxyla te (6).
mixture of 4-hydroxypyridine-2,6-dicarboxylic acid (chelidamic
acid) (5.54 g, 30 mmol) and PCl (15.43 g, 74 mmol) in CCl
23 mL) was heated at 120 °C for 10 h and then cooled to room
A
5
4
(
temperature. Dry methanol (23 mL) was added to this mixture
dropwise over a period of 30 min, and the resulting mixture
was refluxed for 3 h. The solvents were evaporated from this
reaction mixture to afford a tan yellow solid which was
dissolved in EtOAc and treated with activated charcoal under
boiling conditions. Repeated crystallizations from EtOAc gave
-
1
7
1%): mp 62 °C (74 °C clear melt); IR (Nujol) 3300, 1650 cm
;
1
H NMR (δ, CDCl
br t, 32H), 3.0 (s, 6H), 3.4 (m, 2H), 4.7 (s, 2H), 6.5 (d, 1H), 7.4
s, 1H). Anal. Calcd for C27 : C, 72.48; H, 10.96; N,
3
, 200 MHz), 0.9 (t, 3H), 1.3-1.6 (br s and
(
49 3 2
H N O
2
8a
9.34. Found: C, 72.53; H, 11.02; N, 9.06.
3
1
4
.78 g (54%) of 6 as white crystals: mp 138-140 °C (lit. mp
-1 1
6-[(Hexa d ecyla m in o)m eth yl]-4-(d im eth yla m in o)-2-(h y-
d r oxym et h yl)p yr id in e (3). Methyl 6-(formyl)-4-N,N(di-
methylamino)pyridine-2-carboxylate, 10, (0.2 g, 0.96 mmol),
was taken up in dry THF (10 mL). A solution of n-hexadec-
ylamine (0.23 g, 0.96 mmol) in THF (3 mL) containing a few
3
42 °C); IR (Nujol) 1710 cm ; H NMR (δ, CDCl , 90 MHz)
.0 (s, 6H), 8.3 (s, 2H).
4
-Ch lor op yr id in e-2,6-d ica r boxylic Acid Hyd r och lo-
r id e (7). A suspension of dimethyl 4-chloropyridine-2,6-
dicarboxylate, 6 (1 g, 4.36 mmol), in 1 N NaOH (11 mL) was
stirred at 80 °C for 3 h. The mixture was cooled in a ice bath
and acidified to pH ∼4 with ice-cold 1 N HCl. The white, solid
mass precipitate was filtered and dried to give crude 4-chlo-
ropyridine-2,6-dicarboxylic acid (1.2 g) which was used without
4
Å molecular sieves was added and the reaction mixture was
stirred under N atmosphere for 4 h. The solution was filtered,
2
and the solvent was stripped from the filtrate to give a white
solid. The unpurified solid (imine) was dissolved in dry MeOH,
-
1
0.18 g (0.48 mmol) of NaBH
mixture was stirred at ambient temperature for 15 h. Excess
NaBH was quenched by the addition of small aliquots of 1 N
HCl until pH ∼7. The solvent was evaporated, and the residue
was extracted thoroughly with CHCl . The CHCl layer was
washed with saturated, aqueous NaHCO solution and dried.
CHCl was removed from the organic layer to give a crude solid
which was purified by column chromatography over neutral
alumina with 5% MeOH in CHCl to give 3 as a solid (0.264
g, 68%): mp 55-56 °C; H NMR (δ, CDCl , 200 MHz) 0.9 (t,
H), 1.3-1.5 (br s and br t, 28H), 2.7 (t, 2H), 3.0 (s, 6H), 3.9
(s, 2H), 4.7 (s, 2H), 6.3 (s, 1H), 6.5 (s, 1H). Anal. Calcd for
4
was added, and the reaction
further purification for the next step: IR (Nujol) 1725 cm
.
Dim eth yl 4-(Dim eth yla m in o)p yr id in e-2,6-d ica r boxyl-
a te (8). A suspension of 4-chloropyridine-2,6-dicarboxylic acid,
4
9
(1.0 g, 4.2 mmol), in 15 mL of 45% aqueous dimethylamine
3
3
(10.2 g, 230 mmol) in a screw-top pressure tube was stirred
3
3
(
(
26) Gulik, W. M.; Geske, D. H. J . Am. Chem. Soc. 1966, 88, 2928.
27) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
3
Chemicals, 3rd ed.; Pergamon Press: New York, 1988.
28) (a) Kittaka, A.; Sugano, Y.; Otsuka, M.; Ohno, M. Tetrahedron
988, 44, 2811. (b) Suga, A.; Sugiyama, T.; Otsuka, M.; Ohno, M.;
Sugiura, Y.; Meada, K. Tetrahedron 1991, 47, 1191.
1
3
(
3
1

Cu(II)-Chelating (Dialkylamino)pyridine Amphiphiles
O: C, 74.02; H, 11.68; N, 10.36. Found: C, 73.57;
J . Org. Chem., Vol. 63, No. 1, 1998 35
C
25
H
47
N
3
ester, 11, was dissolved in dry MeOH and cooled to 0 °C.
H, 11.68; N, 9.98.
4
NaBH (0.043 g, 1.13 mmol) was added, and the resulting
Meth yl 4-(N-Meth yl-N-octa d ecyla m in o)p yr id in e-2,6-
d ica r boxyla te (11). A mixture of 0.41 g (1.72 mmol) of
mixture was stirred at ambient temperature for 12 h. The
reaction mixture was neutralized with dilute HCl and the
solvent evaporated in vacuo. The residue was extracted with
4
-chloropyridine-2,6-dicarboxylic acid, 7, and 0.53 g (1.9 mmol)
of N-methyl-N-octadecylamine was taken up in 10 mL of dry
MeOH in a screw-top sealed tube and heated to 120 °C for 48
h. Then the solvent was removed, and the residue was dis-
5
% MeOH in CHCl
3
. Upon evaporation of the solvent, a solid
product, 5, was obtained (0.068 g, 72%): mp 68 °C (soften),
-1
1
1
(
3
20 °C (complete melt); IR (Nujol) 3300 cm (broad); H NMR
δ, CDCl , 200 MHz) 0.9 (t, 3H), 1.4-1.6 (br s and br t, 32H),
.0 (s, 3H), 4.6 (s, 2H), 4.8 (s, 4H), 6.7 (s, 1H), 7.3 (s, 1H); MS
solved in CHCl
water and passed through anhydrous Na
3
. The CHCl
3
layer was washed thrice with
SO from which the
3
2
4
solvent was evaporated to give a crude 4-(N-methyl-N-octa-
decylamino)pyridine-2,6-dicarboxylic acid. Because of the
difficulty in its purification possibly due to aggregation, this
material was converted into the corresponding dimethyl ester
as follows.
+
m/z 420 (M , 20), 181 (100); HRMS mass calcd for C26
20.3716, found 420.3697.
Kin etic Mea su r em en ts. Solutions of ligands and addi-
tives (CTABr) were prepared in 0.05 M HEPES buffer (µ )
.1 KCl). Reaction temperatures were maintained at 25 ( 0.1
48 2 2
H N O
4
0
To 13 mL of ice-cold dry MeOH was added dropwise 4 mL
of SOCl
2
, and the mixture was stirred for 10 min. Then 0.84
°C unless otherwise mentioned. The metallomicelles were
generated in situ by the addition of an appropriate amount of
stock solution of a given metal salt to the cuvette. The solution
was carefully stirred, and the reaction was initiated by
addition of 15 µL of stock solution of a given substrate in
g of crude 4-(N-methyl-N-octadecylamino)pyridine-2,6-dicar-
boxylic acid was added and the mixture refluxed for 8 h. The
solvent was evaporated in vacuo, the residue dissolved in
CHCl
2 × 10 mL) solution. The CHCl
anhydrous Na SO . The evaporation of organic solvent gave
a white solid which was further purified by column chroma-
tography (silica gel) using CHCl as an eluent. Fractions
3
(25 mL), and the solution washed with a 1% NaHCO
3
(
3
layer was passed through
CH CN. Substrate hydrolysis was followed spectrophoto-
3
2
4
metrically by measuring the absorbance at 400 nm for the
release of p-nitrophenoxide ion as a function of time. Ester-
olysis followed pseudo-first-order kinetics when a large excess
3
corresponding to the pure compound as indicated by TLC were
evaporated to give 11 a white, hygroscopic solid (0.4 g, 49%):
mp 67-69 °C; IR (Nujol) 1710 cm ; H NMR (δ, CDCl
MHz) 0.9 (t, 3H), 1.3 (s, 32H), 3.0 (s, 3H), 3.4 (t, 2H), 4.0 (s,
-4
of catalyst (5 × 10 M) was employed over substrate (2.5 ×
-5
1
0
M) and the rate constants were obtained by nonlinear fit
-
1 1
3
, 200
kt
of equation (A
absorbances at infinite time and time t, respectively.
∞
- A
0
)/(A
∞
- A
t
∞ t
) ) e , where A and A are
-
1
6
H), 7.8 (s, 1H), 8.3 (s, 1H); IR (Nujol) 1710 cm ; MS m/z 476
+
(
M , 12), 237 (100). We also obtained a hygroscopic solid upon
the conversion of 11 to its hydrochloride salt which was used
for elemental analysis. Anal. Calcd for C28 ‚HCl‚1.5-
O: C, 66.2; H, 9.46; N, 5.52. Found: C, 66.48; H, 9.27; N,
.52.
,6-Bis(h yd r oxym eth yl)-4-(N-m eth yl-N-octa d ecyla m i-
n o)p yr id in e (5). A 0.1 g (0.23 mmol) sample of dimethyl
Ack n ow led gm en t. This research was sponsored by
the Grants-in-Aid Scheme of DRDO, Government of
India. K.S. thanks the UGC for a senior research
fellowship.
48 2 2
H N O
H
5
2
2
J O9707996