A cavitand stabilizes the Meisenheimer complex of SNAr reactions

Article abstract of DOI:10.1039/b700319f

A deep cavitand binds amine nucleophiles and accelerates their subsequent S_NAr reactions by solvating the intermediate Meisenheimer complex. The Royal Society of Chemistry.

Full text of DOI:10.1039/b700319f

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A cavitand stabilizes the Meisenheimer complex of SNAr reactions{
Sara M. Butterfield and Julius Rebek, Jr.*
Received (in Cambridge, UK) 9th January 2007, Accepted 1st March 2007
First published as an Advance Article on the web 19th March 2007
DOI: 10.1039/b700319f
observed. We propose this effect largely results from the ability of
the secondary amide groups of the cavitand interior to solvate the
charges developing in the transition state.
A deep cavitand binds amine nucleophiles and accelerates their
subsequent SNAr reactions by solvating the intermediate
Meisenheimer complex.
The binding of amines 3–5 (Fig. 1) in 1 was demonstrated by
proton NMR resonances in the far upfield region of the spectra.
The 8 aromatic host walls bestow magnetic shielding effects on the
amine guest. Guest 3 has low affinity, Ka 5 14 M21 for the host
and the larger amines 4 and 5 show Ka’s of 40 M21. Though the
affinities are low, the barriers to exchange are high and separate
signals are seen for free and bound guests in the spectra. The
patterns of the bound guest resonances require that the amine
nitrogens are near the open end of 1, in the circle of amides of the
host (Fig. 2).
Deep cavitands offer hosts with an organized gradient of solvent
polarity for guests. The bottom of the cavity is composed of rigid
aromatic walls and is nonpolar, while the upper rim features
secondary amides and is polar.1 The amides are capable of
donating or accepting hydrogen bonds through simple rotations
about single bonds. Accordingly, the microenvironment of the
cavitand is poised to perturb reaction rates relative to those
occurring in bulk solvent outside and we report here its effects on
nucleophilic aromatic substitution (SNAr) reactions.
The SNAr reactions were followed by 1H NMR, in the absence
or presence of stoichiometric amounts of 1 in d10-p-xylene. For
reactions in the presence of 1, separate signals were also observed
for the bound and free SNAr products (Fig. 3, example of reaction
between 4 and 6). Initial formation of SNAr adducts at sub-
millimolar concentrations led to the immediate displacement of
encapsulated amines due to the stronger binding of the products to
1 (Fig. 3). Accordingly, product inhibition precludes efficient
turnover (true catalysis). Furthermore, the generation of acid
during the course of the SNAr reactions led to protonated amine
reactants which also compete strongly for cavitand binding (Fig. 3).
To remove this complication, all experiments were carried out in
the presence of ‘‘proton sponge’’ 9.
These reactions have long been known to exhibit strong solvent
effects as a result of the dipolar nature of the Meisenheimer
complex intermediate and the transition states that flank it.2 For
the reaction of neutral nucleophiles with electron poor aromatics,
the rates of SNAr adduct formation increase with increasing
solvent polarity:2,3 reactions in DMSO, for example, are 50 times
faster than those in cyclohexane.3 Here we compare the influence
of the supramolecular host 1 (Fig. 1) relative to reactions occurring
in the nonpolar, bulk solvent p-xylene. A clear enhancement in
rates of reaction of amine nucleophiles surrounded by 1 was
The initial rate (velocity) of product formation, Vctrl, was
0.21 mM h21 for the background reaction of piperidine 3 with 6,
and an accelerated rate, Vacc, of 2.7 mM h21 was observed in the
Fig. 1 Cavitand host, wall mimic, amine guests, and aromatic substrates.
The Skaggs Institute for Chemical Biology and The Department of
Chemistry, The Scripps Research Institute, MB-26, 10550 North Torrey
Pines Road, La Jolla, California, 92037, USA.
E-mail: jrebek@scripps.edu; Fax: +1 858-784-2876;
Tel: +1 858-784-2250
{ Electronic supplementary information (ESI) available: Experimental
details and kinetic data. See DOI: 10.1039/b700319f
Fig. 2 Molecular model of encapsulated 4 with front cavitand wall
removed for viewing ease (Spartan, molecular mechanics force field).
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Fig. 4 Acceleration of SNAr reaction between
4 and 6 with 1.
Conditions: [1] 5 10 mM; [4] 5 21 mM; [6] 5 10 mM; [9] 5 21 mM
(#: background reaction (ctrl) in the absence of 1; $: accelerated reaction
(acc)).
Fig. 3 Progress of SNAr reaction between 4 and 6 in the presence of 1 as
1
followed by H NMR (600 MHz, d10-p-xylene, 300 K). a) t 5 0, before
addition of 6; b) t 5 17 min; c) t 5 98 min ($: methine protons of 1 vase;
¤: encapsulated 4; m: starting material 6; &: aromatic proton of bound
SNAr product; %: aromatic proton of free product; e: bound 4 in fast
exchange with protonated bound 4; .: encapsulated product).
background rate constants, kctrl. We attribute this to the ability
of the polar amide upper rim to stabilize the dipolar TS (Fig. 5).5
Cation–p interactions between the aromatic walls of 1 and the
developing positive charge on the amine may also play a role.6
A mechanistic interest in the solvent dependency of SNAr
reactions is apparent in the literature.7 In the present work, we
presence of 1, corresponding to a 12-fold rate enhancement
(Table 1). Additionally, a Vctrl of 3.5 mM h21 for the reaction of 3
with 7 was obtained, while Vacc was too fast to determine
accurately by NMR, indicating a significant rate enhancement
(Table 1). In order to trace the acceleration to the inner
microenvironment of 1, rather than the increased concentration
of polar amides in solution, the reaction of 3 with 6 was followed
in the presence of four equiv. of cavitand wall mimic 2 (Fig. 1). The
rate in the presence of 2 was identical to the background rate,
confirming the specific effect of the host cavity on the rate (see
supporting information).
have shown for the first time the influence of
a polar
supramolecular environment on these classic reactions, and report
an accelerating effect, and combined molecular recognition with
enhancement of chemical reactivity.8 The stabilization of polar
transition states with polar groups in enzyme acitve sites is well-
documented,9
even
for
Meisenheimer
intermediates.10
Accordingly, this work is of relevance to enzyme mimetics.
Molecular modeling suggests hydrogen bonding interactions are
possible between the amides of 1 and the ortho NO2 substituent of
the anionic portion of the intermediate formed from 6. To probe
this possibility, we investigated the influence of 1 on the reaction of
3 with 8. In 8, the para NO2 substituent is too far away from the
amides of 1 to hydrogen bond. In this case, an SNAr reaction was
observed only in the presence of 1 (Table 1), indicating that rate
acceleration does not result solely from interactions with the ortho
NO2 groups.
The reaction of amines 3–5 with substrate 6 in the absence of 1
had identical reaction rates (Table 1). However, with the stronger
binding nucleophiles 4 and 5, initial rate enhancements were
accelerated by y40 to y70-fold in the presence of 1, with the
greatest enhancement observed for the reaction of 4 with 6
(Table 1, Fig. 4). The accelerated rate constants, kacc, were
determined for SNAr reactions with substrate 6 by regression
analysis using KinTekSim software.4 The accelerated rate
constants were 100–400 times greater than those of the
Fig. 5 SNAr reaction between 4 and 6 in 1.
Table 1 Initial rates (V) and rate constants (k) for accelerated (acc) and control (ctrl) SNAr reactionsa
Rxn
Vacc/mM h21
Vctrl/mM h21
Vacc/Vctrl
kacc/M21 s21 d
kctrl/M21 s21
kacc/kctrl
3 + 6
3 + 7
3 + 8
4 + 6
5 + 6
a
2.6
0.21
4.4
12
0.03
n.d.
n.d.
0.12
0.06
b
0.0003
0.006
n.r.
0.0003
0.0003
100
n.d.
n.d.
400
200
c
n.d.b
0.27
14
n.d.
n.d.
67
n.r.c
0.21
0.21
7.3
35
In d10-p-xylene at 300 K; accelerated reactions were carried out with stoichiometric 1. Too fast to monitor by NMR, even at 288 K. No
d
reaction over 4 days. Error limit ¡30%, as determined by fitting error.
1606 | Chem. Commun., 2007, 1605–1607
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L. R. Vottero and A. J. Terenzani, J. Phys. Org. Chem., 2002, 15, 258;
(d) N. S. Nudelman, M. Savini, C. E. S. Alvaro, V. Nicotra and
J. Yankelevich, J. Chem. Soc., Perkin Trans. 2, 1999, 1627; (e)
O. Acevedo and W. L. Jorgensen, Org. Lett., 2004, 6, 2881; (f)
C. Arnone, G. Consiglio, V. Frenna and D. Spinelli, J. Org. Chem.,
1997, 62, 3093; (g) O. Banjoko and I. A. Babatunde, Tetrahedron, 2005,
61, 8035; (h) J. Rebek, Jr., Tetrahedron, 1979, 35, 723.
We are grateful to the Skaggs Institute and the NIH (GM
27953) for support. S. M. B. is an NIH NRSA (GM 73437)
postdoctoral fellow.
Notes and references
8 (a) S. Richeter and J. Rebek, Jr., J. Am. Chem. Soc., 2004, 126,
16280; (b) A. Gissot and J. Rebek, Jr., J. Am. Chem. Soc., 2004,
126, 7424; (c) B. W. Purse, A. Gissot and J. Rebek, Jr., J. Am.
Chem. Soc., 2005, 127, 11222; (d) Y. Zhu and D. G. Drueckhammer,
J. Org. Chem., 2005, 70, 7755; (e) J. Wolfe, A. Muehldorf and
J. Rebek, Jr., J. Am. Chem. Soc., 1991, 113, 1453; (f) T. S. Snowden,
A. P. Bisson and E. V. Anslyn, J. Am. Chem. Soc., 1999, 121,
6324; (g) R. Grotzfeld, N. Branda and J. Rebek, Jr., Science, 1996, 271,
487.
9 For examples, see: (a) A. Kienho¨fer, P. Kast and D. Hilvert, J. Am.
Chem. Soc., 2003, 125, 3206; (b) D. C. Carlow, S. A. Short and
R. Wolfenden, Biochemistry, 1998, 37, 1199; (c) H. Park and S. Lee,
J. Chem. Theory Comput., 2006, 2, 858; (d) D. T. Major, K. Nam and
J. Gao, J. Am. Chem. Soc., 2006, 128, 8114.
1 D. M. Rudkevich, G. Hilmersson and J. Rebek, Jr., J. Am. Chem. Soc.,
1998, 120, 12216.
2 (a) P. M. E. Mancini, R. D. Martinez and L. R. Vottero, J. Chem. Soc.,
Perkin Trans. 2, 1984, 1133; (b) N. S. Nudelman, J. Chem. Soc., Perkin
Trans. 2, 1987, 951; (c) J. F. Bunnett and R. J. Morath, J. Am. Chem.
Soc., 1955, 77, 5051.
3 C. Reichardt, in Solvents and Solvent Effects in Organic Chemistry,
Wiley-VCH, Weinheim, Germany, 2003, pp. 173–174.
4 K. S. Anderson, J. A. Sikorski and K. A. Johnson, Biochemistry, 1988,
27, 7395.
5 L. Forlani, J. Phys. Org. Chem., 1999, 12, 417.
6 (a) F. Hof, L. Trembleau, E. C. Ullrich and J. Rebek, Jr., Angew.
Chem., Int. Ed., 2003, 42, 3150; (b) P. Ballester, A. Shivanyuk, A. R. Far
and J. Rebek, Jr., J. Am. Chem. Soc., 2002, 124, 14014.
7 (a) O. Banjoko and I. A. Babatunde, Tetrahedron, 2004, 60, 4645; (b)
P. M. E. Mancini, A. Terenzani, C. Adam and L. R. Vottero, J. Phys.
Org. Chem., 1999, 12, 430; (c) P. M. Mancini, G. Fortunato, C. Adam,
10 M. M. Benning, K. L. Taylor, R.-Q. Liu, G. Yang, H. Xiang,
G. Wesenberg, D. Dunaway-Mariano and H. M. Holden, Biochemistry,
1996, 35, 8103.
This journal is ß The Royal Society of Chemistry 2007
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