Kinetics and thermodynamics of amine and diamine signaling by a trifluoroacetyl azobenzene reporter group

Article abstract of DOI:10.1021/ol0351605

(Matrix presented) (Trifluoroacetyl)azobenzene dyes were previously employed as amine reporter groups (chemosensors) in a dendrimer-based monomolecular imprinting system. Kinetic and binding studies with a range of amines and diamines show that the highly selective signaling observed for alkane diamines by these imprinted dendrimers arises from a kinetic effect due to intramolecular general base-catalyzed carbinolamine formation with the dye itself. The relationship between diamine structure and carbinolamine stability and rate of formation is described.

Full text of DOI:10.1021/ol0351605

ORGANIC
LETTERS
2
003
Vol. 5, No. 17
127-3130
Kinetics and Thermodynamics of Amine
and Diamine Signaling by a
Trifluoroacetyl Azobenzene Reporter
Group
3
Eric Mertz, James B. Beil, and Steven C. Zimmerman*
Department of Chemistry, 600 S. Matthews AVe, UniVersity of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
sczimmer@uiuc.edu
Received June 23, 2003
ABSTRACT
(Trifluoroacetyl)azobenzene dyes were previously employed as amine reporter groups (chemosensors) in a dendrimer-based monomolecular
imprinting system. Kinetic and binding studies with a range of amines and diamines show that the highly selective signaling observed for
alkane diamines by these imprinted dendrimers arises from a kinetic effect due to intramolecular general base-catalyzed carbinolamine formation
with the dye itself. The relationship between diamine structure and carbinolamine stability and rate of formation is described.
Azo-dye (1a) was developed by Mohr and co-workers as a
amines. In particular, 1,3-diaminopropane (5) and 1,4-
diaminobutane (6) gave strong color changes.
6
polymer-bound reporter group for the detection of amine
1
analytes. As a result of its distinct color change upon
Key control experiments suggested that the selective
signaling of 5 and 6 actually resulted from faster and tighter
binding. Herein we report the first combined spectroscopic,
kinetic, and thermodynamic study on carbinolamine forma-
tion from simple alkyl diamines that quantifies the contribu-
tion played by the second amino group as a function of the
diamine length. The results rule out aminal formation
between diamines and 1b and further indicate a general base-
catalyzed pathway to carbinolamine 2b, which is stabilized
by intramolecular hydrogen bonding. Prior to kinetic studies
exposure to amines (50 nm blue-shift) and the extensive
studies of trifluoroacetophenone-amine interactions by
2
Richie and others, it was proposed that 1a signals amine
binding by forming carbinolamine 2a. Recently, we inte-
3
,4
grated 1b into our monomolecular imprinting method.
Thus, dendrimer 3 was synthesized, cross-linked via the ring-
closing metathesis (RCM) reaction, and cored to give host
4
,5
4.
Despite the small size of the two dendrons linking the
butane diamine template in 3 and the correspondingly small
number of cross-links formed in the imprinting step, 4 proved
to be a remarkably selective chemosensor for alkane di-
7
1
with 1b, evidence for formation of 2b was sought. H NMR
studies were carried out by adding neat butylamine (7) to
3
solutions of 1 in CDCl , whereupon new peaks between 7.70
and 7.90 ppm appeared alongside peaks for 1b (Figure 1).
(
1) (a) Mohr, G. J.; Demuth, C.; Spichiger-Keller, U. E. Anal. Chem.
1
998, 70, 3868-3873. (b) Mohr, G. J.; Tirelli, N.; Lohse, C.; Spichiger-
Keller, U. E. AdV. Mater. 1998, 10, 1353-1357. (c) Mohr, G. J.; Citterio,
D.; Demuth, C.; Fehlmann, M.; Luzi, J.; Lohse, C.; Moradian, A.; Nezel,
T.; Rothmaier, M.; Spichiger, U. E. J. Mater. Chem. 1999, 9, 2259-2264.
(5) Wendland, M. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1999, 121,
1, 1389-1390. Zimmerman, S. C.; Schultz, L. G.; Zhao, Y. Angew. Chem.,
Int. Ed. 2001, 40, 1962-1966.
(2) Ritchie, C. D. J. Am. Chem. Soc. 1984, 106, 7187-7194 and
references therein.
3) Mertz, E.; Zimmerman, S. C. J. Am. Chem. Soc. 2003, 125, 3424-
425.
4) Zimmerman, S. C.; Wendland, M. S.; Rakow, N. A.; Zharov, I.;
Suslick, K. S. Nature 2002, 418, 399-403.
(6) Recent reports of hosts with azobenzene reporter groups: Hayashita,
T.; Teramae, N.; Kuboyama, T.; Nakamura, S.; Yamamoto, H.; Nakamura,
H. J. Inclusion Phenom. 1998, 32, 251-265. Lee, D. H.; Lee, K. H.; Hong,
J.-I. Org. Lett. 2001, 3, 5-8. Ward, C. J.; Patel, P.; Ashton, P. R.; James,
T. D. Chem. Commun. 2000, 229-230.
(
3
(
1
0.1021/ol0351605 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/31/2003

(1) the carbinolamine-dye interconversion rate being faster
than but still comparable to the NMR time scale, (2) higher
order 2b‚7 complexes, or (3) a buffer effect where excess 7
Scheme 1. Amine Signaling Reaction
removes traces of acid present in the CDCl
3
.
Additional characterization of the adduct formed from 1
1
3
19
and amines was provided by C and F NMR. In THF-d
8
,
the trifluoromethyl group of unbound 1 (1.9 mM) appeared
1
9
at -71.8 ppm in the F NMR (Figure 2). Addition of 2
Scheme 2. Monomolecular Imprinting of Butanediamine
Figure 2. 19F NMR spectra of dye 1b with butylamine (7) in
THF-d . Partial spectra of 1 upon addition of (a) [7] ) 0 mM and
b) [7] ) 3.78 mM.
8
(
equiv of butylamine caused appearance of a new peak at
82.3 ppm, consistent with a -CF group attached to a
carbinolamine carbon atom. The change in shift of the
-
3
8
1
3
carbonyl carbon in the C NMR spectra upon adduct
formation was most informative and effectively ruled out
aminal formation from both mono- and diamines. Thus, a
ca. 0.1 M solution of 2b in THF showed a quartet ( JF19C13
2
)
at 179 ppm, which upon addition of 2 equiv of 7, ethylene-
diamine (8), or N,N-dimethyl ethylenediamine (9) disap-
peared and was replaced by a quartet for the carbinolamine
carbon at 86 ppm. Each spectrum showed a 1:1 ratio of free
amine to adduct and other peaks fully consistent with
1
19
formation of 2b. The H and F NMR spectra of 2b‚6 were
similar to those obtained for 2b‚7 and consistent with a
carbinolamine not an aminal.
Equilibrium constants (Keq) for the 1b to 2b interconver-
sion with amine guests in THF were determined by spec-
trophotometric titrations. As the amine concentration in-
creased, the main band blue-shifted from λmax ) 475 nm
(
1b) to λmax ≈ 420-425 nm (2b). Plotting the decrease in
absorbance at 475 nm (∆A475) vs [amine] gave a binding
isotherm that fit a 1:1 complexation model, giving the Keq
values in Table 1. The reversible nature of the binding was
demonstrated by diluting solutions of 2b, whereupon the peak
shifted back to 475 nm.
Figure 1. 1H NMR of carbinolamine formed between 1b and
butylamine (7) in CDCl
3
. Partial spectra of 1 equilibrated with (a)
[7] ) 0 M, (b) [7] ) 0.14 M, and (c) [7] ) 0.26 M.
From the data in Table 1, it appears that a second amino
group contributes up to 1.5 kcal/mol to the stability of 2b.
The stabilization is greatest for 8 and slightly reduced for 9.
Little or no effect is seen for 6, whose Keq is identical to
that for 7 once the statistical correction is applied. These
The doublet at 7.88 ppm was assigned to proton H-c′ and
the multiplet at 7.80 to H-a′ and H-b′. The presence of peaks
from both 1b and 2b indicates that carbinolamine-dye
exchange is slow on the NMR time scale. The upfield shift
in protons H-a, H-b, and H-c on 1 is consistent with adduct
formation. A slight change in chemical shift and appearance
of the H-a′/H-b′ peak was observed with an increase in the
concentration of 7. This observation can be explained by
(
7) Compound 2b was prepared using the procedure reported by Mohr
(ref 1b) with N,N-dimethylaniline in the diazonium coupling reaction.
8) Tamborski, C.; Prabhu, U. D. G.; Eapen, K. C. J. Fluorine Chem.
985, 28, 139-150. Saloutin, V. I.; Burgart, Y. V.; Kuzueva, O. G.; Kappe,
C. O.; Chupakhin, O. N. J. Fluorine Chem. 2000, 103, 17-23.
(
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Org. Lett., Vol. 5, No. 17, 2003

Table 1. Equilibrium Constants (Keq) with Standard Deviations
for Carbinolamine Formation between 1b and Amines
Table 2. Pseudo-first Order Rate Constants (kobs) for
Formation of 2b from 1b and Amines
data suggest that the stabilization arises from an intramo-
lecular hydrogen bond as in 11. The shorter diamines are
expected to provide more stabilization due to a preference
for the 6.5-membered hydrogen bonded ring in 11 vs the
.5-membered ring in 12.9
a
8
Thus, for alkane diamines, Aue reported the highest proton
affinity for 6 and suggested that its 6.5-membered ring
allowed for a linear hydrogen bond. However, the relative
stability of such rings in both ground and transition states is
9b,c
a balance of numerous effects.
The rate of conversion of 1b to 2b upon addition of 17
different amines and diamines in THF was measured by
observing the disappearance of 1b at λmax ) 475 nm over
time. As seen in Figure 3, the rates were qualitatively quite
different for some of the compounds examined. In general,
a
See text and Figure 3 legend for details on conditions and methods
used to determine kobs values. b Determined by stopped-flow method with
addition of 10 mM amine solution to 12.5 µM solution of 1b in THF. Data
were collected, but reaction was too fast for accurate kobs determination.
c
with diamines 5, 6, and 10, formation of 2b proceeded very
rapidly with the reaction being nearly complete within
1
5-30 s. Reaction of 1b with other diamines (e.g., 8, 18)
was slower, requiring 10-20 min to reach completion.
Monoamines 13-15 reacted the slowest, taking over 30 min
to achieve equilibrium.
Under conditions described in the legend to Figure 3,
pseudo-first-order rate constants (kobs) could be calculated
for 13 of the 17 amines studied. The rate of reaction of 5, 6,
and 10 were too fast, so these rates, as well as that of 1,5-
pentanediamine (17), were determined using a stopped-flow
spectrophotometric method (Table 2). For the other 13
amines examined using a standard spectrophotometer, plots
of log(-(A475∞ - A475t)) versus time (t) were linear over
several half-lives, and the slopes afforded the kobs values
1
0
given in Table 2. The measured equilibrium constants for
carbinolamine formation were sufficiently large that cor-
recting for the back reaction (k ) was not necessary.
r
In looking at the data in Table 2, it is clear that the rate of
carbinolamine formation for the monoamines is nearly
independent of the structure. Thus, R- and â-branching and
Figure 3. Plots showing decreased absorbance at λmax ) 475 nm
(
1b) upon addition of 33 equiv of ([) benzylamine (13), (O)
butylamine (7), (4) cis/trans 1,4-bis(aminomethyl)cyclohexane (23),
2) 1,8-diaminooctane (19), (+) 1,6-diaminohexane (18), and (-)
,4-diaminobutane (6) to a 3 µM THF solution of 1b at 22.5 °C.
(
1
Org. Lett., Vol. 5, No. 17, 2003
3129

phenyl substituents have little effect on the amine reactivity.
There is considerably more variation in the kobs values for
the diamines. Linear, unbranched diamines react with 1 at a
faster rate than monoamines and other diamines. Linear
diamines with three or four intervening methylene groups
achieve the most significant rate enhancement.
high-energy intermediate 25 is either trapped or avoided
altogether by intramolecular proton transfer to the second
1
2
amino group.
To distinguish the alkane diamine rates from one another
and quantify their advantage over butylamine (7), a stopped-
flow spectrophotometric method was used to determine the
k
obs values for 5-7, 10, and 17 (Table 2). Because these
measurements required much higher concentrations of both
and diamine, the kobs values are not directly comparable
to those conventionally determined for 7, 8, 13-16, and
8-24. Relative to the kobs value for butylamine (7), there
In summary, we obtained spectroscopic evidence for the
formation of carbinolamine 2b in the reaction of dye 1b and
several mono- and diamines. The rate of formation of 2b is
generally insensitive to the amine structure, but simple alkane
diamines with between three and five methylene groups react
more rapidly most likely as a result of an intramolecular
proton transfer. In our previous work, this kinetic advantage
initially disguised itself as an example of highly selective
monomolecular imprinting.
1
1
is a ca. 6- to 17-fold rate enhancement seen in the alkane
diamines. The order of reactivity observed in Table 2 closely
matches that reported by Page and Jencks in the aminolysis
of acetylimidazole by alkane diamines. Although those rate
enhancements were somewhat larger (15- to 75-fold), it is
likely that the kinetic advantage observed here also originates
in a general base-catalyzed amine addition reaction. Thus,
3
11
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (GM61067) for support and
Christopher McGinley and Wilfred A. Van der Donk for
assistance with stopped-flow kinetics experiments.
(9) (a) We use the ring size nomenclature introduced by R. P. Bell (see
ref 9c for an overview). (b) Aue, D. H.; Webb, H. M.; Bowers, M. T. J.
Am. Chem. Soc. 1973, 95, 2699-2701. (c) Kirby, A. J. AdV. Phys. Org.
Chem. 1980, 17, 183-279.
OL0351605
(10) Moore, J. W.; Pearson, R. G. Kinetics and Mechanism; Wiley-
Interscience: New York, 1981.
11) (a) Page, M. I.; Jencks, W. P. J. Am. Chem. Soc. 1972, 94, 8818-
827.
(
(12) Jencks, W. P. Chem. ReV. 1972, 72, 705-718. Jencks, W. P. Acc.
Chem. Res. 1980, 13, 161-169.
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