C O M M U N I C A T I O N S
Table 1. Alkylation of Quinuclidine in the Presence and
Absence of 1
kacc
/
kctrl
/
1
1
entry
electrophile
M-1min-
M-1min-
kacc/kctrl
1
2
3
4
5
6
7
8
butyl chloride
butyl bromide
butyl mesylate
butyl tosylate
(bromomethyl)cyclopropane
neopentyl bromide
isopropyl bromide
threo-2-bromo-3-methoxybutane
erythro-2-bromo-3-methoxybutane
tert-butyl bromide
allyl chloride
0.44
120
0.68
2.1
47
b
1.0
c
3.3 × 10-4 1300
4.5 × 10-3 150
0.075
1600
0.020
0.065
f
100
720
n.d.
reaction transition state. The nucleophile and electrophile are not
confined together by 1 as would be the case in a capsular host.
Instead, this supramolecular effect increases the intrinsic reactiVity
of the reactants in a rate-determining step that is second order. These
results contribute to a growing body of evidence that the structures
providing the physical barriers of container molecules are not merely
spectators in the reactions of molecules within molecules.
9.5 × 10-4 1000
f
f
f
n.d.
n.d.
n.d.
760
n.d.
n.d.
9
c
10
11
12
13
14
0.014d
84
0.11
e
e
allyl bromide
benzyl bromide
dichloromethane-d2
e
e
0.29
4.3 × 10-4 670
a
Acknowledgment. We thank the National Institutes of Health
(GM27932) and the Skaggs Institute for Chemical Biology for
financial support. B.W.P. is a Skaggs Predoctoral Fellow.
a Used as solvent. b No reaction, even at 50 °C. c No reaction. d The
products are isobutylene and quinuclidine hydrobromide. e Too fast to
measure using this method. f Not measured. n.d. not determined.
Supporting Information Available: Detailed descriptions of
experimental methods, synthetic procedures, characterization of new
compounds, and tabulated kinetic data. This material is available free
develops on the nitrogen, the weak CH/π interactions between guest
and host are “promoted” to stronger cation/π interactions, further
stabilizing the transition state. The congested nature of the
environment around the nucleophilic site is particularly suited to
smaller leaving groups. The much larger mesylate and tosylate
groups are less compatible with the mechanism of rate enhancement.
When dichloromethane-d2 was used as a solvent for quinuclidine
and 1, quaternization to yield (chlorodideuteriomethyl)quinu-
clidinium chloride was observed with a rate constant 670 times
greater than that of the background reaction.18
A limited tolerance for steric crowding around the electrophilic
site was also observed. Isopropyl bromide reacted with a 1000-
fold rate constant enhancement, but the erythro and threo isomers
of 2-bromo-3-methoxybutane were too congested to react (in
addition to being electronically unfavorable). Bromomethyl cyclo-
propane reacted with a 720-fold rate constant enhancement, but
neopentyl bromide was unreactive, even when heated at 50 °C.
tert-Butyl bromide did not alkylate quinuclidine, but the cavitand
did facilitate the elimination reaction, giving rise to isobutylene
and protonated quinuclidinium. Benzyl and allyl bromides were
highly reactive toward quinuclidine (the background rates were too
fast to measure under these conditions), but allyl chloride showed
a 760-fold acceleration.
References
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A molecule 2 was prepared as an analogue of a single wall of
cavitand 1, with octyl chains appended for enhanced solubility. Four
equivalents of 2 had no effect on the rate of the Menschutkin
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Despite the increased steric congestion at the reaction center the
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