vase conformation on the NMR time scale, as revealed by the
broad methine protons of the resorcin[4]arene. When piper-
idinium acetate is introduced, trans-1 folds around the
catalyst forming a vase conformation with sharp NMR
signals. An association constant Ka of 4300mÀ1 was deter-
mined. Separate signals for free and bound piperidinium
indicate slow exchange on the NMR time scale and 2D EXSY
experiments reveal the barrier to be 17.8 kcalmolÀ1 [17]
.
Irradiation with UV light (365 nm) isomerizes the azo wall
of the cavitand to the cis configuration and this has a
remarkable effect—the cavitand assumes an introverted
conformation projecting the iPr substituent into the cavity
(Figure 1) and ejecting the piperidinium acetate into solution.
Surprisingly, cavitand 1 promotes the piperidinium ace-
tate-catalyzed Knoevenagel condensation between malono-
nitrile and aromatic aldehydes (Figure 2, inset). The uncata-
Figure 1. Stick and CPK representations of the introverted cis-1 crystal
structure viewed from the side (left) and the top (right). The
introverted azo wall is colored green.
uncommon for cis-azo compounds.[9] Single, red crystals of 1
were grown by diffusing pentane into an acetone solution
after UV irradiation. Cis-1 crystallizes in the C2/c space group
with one cavitand in the asymmetric unit and 8 molecules per
unit cell.[10] Both enantiomers were observed and modeled
accordingly. The cavitand adopts an introverted conformation
with the iPr group penetrating the cavity stabilized by CH–p
contacts ranging from 3.0 to 3.9 ꢁ (Figure 1 and Figure S4 in
the Supporting Information). The azo geometry is distorted to
maximize contacts with the interior of the cavitand with
average ]CCNN = 588 and ]NNC = 1238 (53.38 and 121.98
respectively for cis-azobenzene).[11]
Knoevenagel reported that formaldehyde and diethyl
malonate could be condensed using diethylamine as the
catalyst.[12,13] The Knoevenagel condensation was extended to
include other active methylene compounds reacting with
aldehydes or ketones and became a reliable method for
preparing carbon–carbon bonds. This reaction is still
employed in the synthesis of natural products, drugs, dyes
and other compounds.[13] and an asymmetric variant has
recently been achieved.[14] Other secondary amines and their
salts catalyze this reaction and, depending on the conditions
and substrates, the reaction proceeds through a Hann-Lap-
worth[15] (b-hydroxy intermediate, I) mechanism and/or a
Knoevenagel (iminium intermediate, II) mechanism
(Scheme 2).[13,16] Piperidine or piperidinium salts are popular
catalysts for the reaction.
Figure 2. Graph depicting % conversions of cavitand 1/piperidinium-
catalyzed Knoevenagel condensations of aromatic aldehydes at room
temperature.
lyzed reaction is quite slow in [D4]acetic acid. After 240 h
little reaction occurs and only 7% or less of the olefin product
is observed (Figure 2). The reaction is significantly acceler-
ated by the host–guest complex: piperidinium acetate (5
mol%) and trans-1 (5–13 mol%).[18] The
The cavitand 1 binds piperidinium acetate in a variety of
organic solvents. In [D4]acetic acid trans-1 exhibits a dynamic
host binds the piperidinium catalyst and
not the substrate. As a result, the
catalyzed reaction tolerates a range of
aromatic aldehydes that do not fit into
the cavity.
The
supramolecular
assembly
appears necessary for the rate enhance-
ment. Comparison of the reaction rates
in the presence and absence of trans-1
highlights the importance of the cavi-
tand/catalyst complex (Table 1). Cavi-
tand 1 produces up to 3.5-fold increase
in the initial reaction rate (kHG/kCAT) as
Scheme 2. Two possible mechanisms for secondary amine-catalyzed Knoevenagel condensa-
tions. Counter ions are omitted for simplicity.
Angew. Chem. Int. Ed. 2011, 50, 9400 –9403
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim